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    Present and Future of Bronchopulmonary Dysplasia. Bonadies Luca,Zaramella Patrizia,Porzionato Andrea,Perilongo Giorgio,Muraca Maurizio,Baraldi Eugenio Journal of clinical medicine Bronchopulmonary dysplasia (BPD) is the most common respiratory disorder among infants born extremely preterm. The pathogenesis of BPD involves multiple prenatal and postnatal mechanisms affecting the development of a very immature lung. Their combined effects alter the lung's morphogenesis, disrupt capillary gas exchange in the alveoli, and lead to the pathological and clinical features of BPD. The disorder is ultimately the result of an aberrant repair response to antenatal and postnatal injuries to the developing lungs. Neonatology has made huge advances in dealing with conditions related to prematurity, but efforts to prevent and treat BPD have so far been only partially effective. Seeing that BPD appears to have a role in the early origin of chronic obstructive pulmonary disease, its prevention is pivotal also in long-term respiratory outcome of these patients. There is currently some evidence to support the use of antenatal glucocorticoids, surfactant therapy, protective noninvasive ventilation, targeted saturations, early caffeine treatment, vitamin A, and fluid restriction, but none of the existing strategies have had any significant impact in reducing the burden of BPD. New areas of research are raising novel therapeutic prospects, however. For instance, early topical (intratracheal or nebulized) steroids seem promising: they might help to limit BPD development without the side effects of systemic steroids. Evidence in favor of stem cell therapy has emerged from several preclinical trials, and from a couple of studies in humans. Mesenchymal stromal/stem cells (MSCs) have revealed a reparatory capability, preventing the progression of BPD in animal models. Administering MSC-conditioned media containing extracellular vesicles (EVs) have also demonstrated a preventive action, without the potential risks associated with unwanted engraftment or the adverse effects of administering cells. In this paper, we explore these emerging treatments and take a look at the revolutionary changes in BPD and neonatology on the horizon. 10.3390/jcm9051539
    Novel biomarkers of bronchopulmonary dysplasia and bronchopulmonary dysplasia-associated pulmonary hypertension. Sahni Mitali,Yeboah Bettie,Das Pragnya,Shah Dilip,Ponnalagu Devasena,Singh Harpreet,Nelin Leif D,Bhandari Vineet Journal of perinatology : official journal of the California Perinatal Association OBJECTIVE:To quantify and compare levels of potential biomarkers in neonates with (i) Bronchopulmonary dysplasia (BPD); (ii) BPD-associated pulmonary hypertension (BPD-PH); (iii) PH without BPD; and (iv) neonates without lung disease at ~36 weeks postmenstrual age. STUDY DESIGN:Multiple potential biomarkers were measured in plasma samples of 90 patients using a multi-spot enzyme-linked immunosorbent assay. Statistical tests done included one-way ANOVA to compare levels of biomarkers between different groups. RESULTS:Higher levels of ICAM-1 were present in infants with BPD and correlated with its severity. Infants with BPD have significantly higher levels of ANG-2 and lower levels of ANG-1. Infants with PH have higher levels of: IL-6, IL-8, IL-10, and TNF-α. Infants with BPD-PH have significantly lower levels of MCP-1 and higher levels of IL-1β than infants with PH without BPD. CONCLUSION:ICAM-1 may be used as a specific biomarker for diagnosis of BPD and its severity. 10.1038/s41372-020-00788-8
    BMP7 regulates lung fibroblast proliferation in newborn rats with bronchopulmonary dysplasia. Sun Yanli,Fu Jianhua,Xue Xindong,Yang Haiping,Wu Linlin Molecular medicine reports The present study investigated the expression of bone morphogenetic protein (BMP) 7 in a newborn rat model of bronchopulmonary dysplasia (BPD) and the biological effects of BMP7 on newborn rat lung fibroblast (LF) cells. For this purpose, a total of 196 newborn rats were randomly and equally assigned to a model group and a control group. Lung tissue was collected at days 3, 7, 14 and 21 for histological analysis. The location and expression of BMP7 was examined by immunohistochemical staining and reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis. A total of 38 full‑term newborn rats on the day of birth were sacrificed and LF cells were isolated and treated with BMP7. The biological effects of BMP7 on LF cells were assessed by cell proliferation and cell cycle analysis. The findings demonstrated that abnormal alveolar development due to BPD was gradually intensified in the model group over time. Immunohistochemical staining revealed that the location of BMP7 in lung tissue was altered. Immunohistochemistry and RT‑qPCR assays demonstrated a gradual decrease in BMP7 expression in the model group induced by hyperoxia. MTT assays demonstrated that BMP7 inhibited LF cells and the inhibitory effect was dose‑dependent and time‑dependent. Flow cytometry revealed that the inhibitory effect of BMP7 in LF cells was causing cell cycle arrest at the G1 phase. The present study demonstrated that BMP7 may serve an important role in alveolar development in a BPD model. BMP7 may be involved in abnormal alveolar development through the regulation of LF proliferation. 10.3892/mmr.2018.8692
    [Effects of antenatal inflammation on the developing lung]. Kunzmann S,Collins J J P,Kuypers E,Gavilanes A W,Kramer B W Zeitschrift fur Geburtshilfe und Neonatologie The developing lung and immune systems are very plastic and their developmental pathway can be influenced by various endogenous and/or exogenous factors. In the last years translational research with various animal models has been helpful to answer some basic questions about the effect of chorioamnionitis on maturation and development of the foetal lung and immune system. Chorioamnionitis can induce a cascade of lung injury, pulmonary inflammation and remodelling in the foetal lung. Chorioamnionitis-induced IL-1 production is consistently associated with lung maturation, induced by enhancing surfactant protein and lipid synthesis. IL-1 therefore seems to be the main link between lung inflammation and lung maturation, which largely prevents RDS in preterm infants. On the other hand, chorioamnionitis can also cause structural lung changes and affect the expression of growth factors, like TGF-β, CTGF, FGF-10 or BMP-4, which are crucial for branching morphogenesis. These changes result in alveolar and microvascular simplification similar to BPD. Neonatal outcome may also be affected by chorioamnionitis by modulating the efficacy of the immune system. Chorioamnionitis can induce LPS-tolerance (endotoxin hyporesponsiveness/immunoparalysis), which may prevent further foetal lung damage but increases susceptibility to postnatal infections. The inflammatory and developmental signalling pathways affected by chorioamnionitis form delicately regulated networks, which interact with each other to control lung development. In addition to chorioamnionitis, these pathways can be affected by other prenatal (steroid) or postnatal factors (mechanical ventilation, oxygen exposure, infection, steroids). Because the postnatal response to injury appears to be highly dependent on prenatal exposures, the "secondary hit" hypothesis is very plausible, in which exposure to chorioamnionitis is a predisposition for the development of adverse neonatal outcomes. 10.1055/s-0032-1321836
    The apelin-APJ axis: A novel potential therapeutic target for organ fibrosis. Huang Shifang,Chen Linxi,Lu Liqun,Li Lanfang Clinica chimica acta; international journal of clinical chemistry Apelin, an endogenous ligand of the G-protein-coupled receptor APJ, is expressed in a diverse number of organs. The apelin-APJ axis helps to control the processes of pathological and physiological fibrosis, including renal fibrosis, cardiac fibrosis, liver fibrosis and pulmonary fibrosis. However, the role of apelin-APJ in organ fibrosis remains controversial due to conflicting study results. The apelin-APJ axis is a detrimental mechanism which promotes liver fibrosis mainly via up-regulation the expression of collagen-II and platelet-derived growth factor receptor β (PDGFRβ). On the contrary, the apelin-APJ axis is beneficial for renal fibrosis, cardiac fibrosis and pulmonary fibrosis. The apelin-APJ axis alleviates renal fibrosis by restraining the expression of transforming growth factor-β1 (TGF-β1). In addition, the apelin-APJ axis attenuates cardiac fibrosis through multiple pathways. Furthermore, the apelin-APJ axis has beneficial effects on experimental bronchopulmonary dysplasia (BPD) and acute respiratory distress syndrome (ARDS) which suggest the apelin-APJ axis potentially alleviates pulmonary fibrosis. In this article, we review the controversies associated with apelin-APJ in organ fibrosis and introduce the drugs that target apelin-APJ. We conclude that future studies should place more emphasis on the relationship among apelin isoforms, APJ receptor subtypes and organ fibrosis. The apelin-APJ axis will be a potential therapeutic target and those drugs targeted for apelin-APJ may constitute a novel therapeutic strategy for renal fibrosis, cardiac fibrosis, liver fibrosis and pulmonary fibrosis. 10.1016/j.cca.2016.02.025
    Association of increased pulmonary interleukin-6 with the priming effect of intra-amniotic lipopolysaccharide on hyperoxic lung injury in a rat model of bronchopulmonary dysplasia. Kim Do-Hyun,Choi Chang Won,Kim Ee-Kyung,Kim Han-Suk,Kim Beyong Il,Choi Jung-Hwan,Lee Myong Jin,Yang Eun Gyeong Neonatology BACKGROUND:The authors previously demonstrated the priming effect of intra-amniotic lipopolysaccharide (LPS) on hyperoxic lung injury in a rat model of bronchopulmonary dysplasia (BPD). OBJECTIVES:To investigate the mechanism underlying this priming effect by determining biochemical profiles in a rat model of BPD. METHODS:The rat model involved intra-amniotic LPS administration and postnatal hyperoxia (85%). The mRNA expressions of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), basic fibroblast growth factor (bFGF), and transforming growth factor beta(1) (TGF-beta(1)), as well as the protein levels of IL-6, VEGF, and protein carbonyl in lung tissue were compared between the LPS plus hyperoxia, the LPS only, the hyperoxia only, and the control groups. RESULTS:Morphometric analysis of lung tissues demonstrated that alveolarization was significantly inhibited only in the LPS plus hyperoxia group. IL-6 protein levels and its mRNA expression in the lungs were significantly increased only in the LPS plus hyperoxia group. Neither LPS nor hyperoxia increased IL-6 in the lungs independently. bFGF mRNA expression was significantly decreased in the LPS-treated groups. VEGF protein levels were significantly reduced by hyperoxia, whereas protein carbonyl levels were increased by intra-amniotic LPS or hyperoxia. No additional significant change to VEGF or protein carbonyl levels was produced by intra-amniotic LPS or hyperoxia. There were no significant differences in the mRNA expressions of VEGF, VEGFR-2, and TGF-beta(1). CONCLUSIONS:The priming effect of intra-amniotic LPS on hyperoxic lung injury may be associated with IL-6 elevation in the lungs. 10.1159/000263056
    Receptor for advanced glycation end products contributes to postnatal pulmonary development and adult lung maintenance program in mice. Fineschi Silvia,De Cunto Giovanna,Facchinetti Fabrizio,Civelli Maurizio,Imbimbo Bruno P,Carnini Chiara,Villetti Gino,Lunghi Benedetta,Stochino Stefania,Gibbons Deena L,Hayday Adrian,Lungarella Giuseppe,Cavarra Eleonora American journal of respiratory cell and molecular biology The role of the receptor for advanced glycation end products (RAGE) in promoting the inflammatory response through activation of NF-κB pathway is well established. Recent findings indicate that RAGE may also have a regulative function in apoptosis, as well as in cellular proliferation, differentiation, and adhesion. Unlike other organs, lung tissue in adulthood and during organ development shows relatively high levels of RAGE expression. Thus a role for the receptor in lung organogenesis and homeostasis may be proposed. To evaluate the role of RAGE in lung development and adult lung homeostasis, we generated hemizygous and homozygous transgenic mice overexpressing human RAGE, and analyzed their lungs from the fourth postnatal day to adulthood. Moderate RAGE hyperexpression during lung development influenced secondary septation, resulting in an impairment of alveolar morphogenesis and leading to significant changes in morphometric parameters such as airspace number and the size of alveolar ducts. An increase in alveolar cell apoptosis and a decrease in cell proliferation were demonstrated by the terminal deoxy-nucleotidyltransferase-mediated dUTP nick end labeling reaction, active caspase-3, and Ki-67 immunohistochemistry. Alterations in elastin organization and deposition and in TGF-β expression were observed. In homozygous mice, the hyperexpression of RAGE resulted in histological changes resembling those changes characterizing human bronchopulmonary dysplasia (BPD). RAGE hyperexpression in the adult lung is associated with an increase of the alveolar destructive index and persistent inflammatory status leading to "destructive" emphysema. These results suggest an important role for RAGE in both alveolar development and lung homeostasis, and open new doors to working hypotheses on the pathogenesis of BPD and chronic obstructive pulmonary disease. 10.1165/rcmb.2012-0111OC
    LPS-mediated endothelial activation in pulmonary endothelial cells: role of Nox2-dependent IKK-β phosphorylation. Menden Heather,Tate Everett,Hogg Neil,Sampath Venkatesh American journal of physiology. Lung cellular and molecular physiology Lipopolysaccharide (LPS)-mediated endothelial activation contributes to lung inflammation and alveolar remodeling seen in premature infants with bronchopulmonary dysplasia (BPD). The mechanisms underlying LPS-mediated oxidative stress and proinflammatory signaling in human pulmonary microvascular endothelial cells (HPMEC) remain unclear. We hypothesized that NADPH oxidase (Nox) mediates LPS-induced endothelial activation in HPMEC by regulating phosphorylation of Toll-like receptor (TLR) pathway proteins. LPS-induced expression of intercellular adhesion molecule 1 (ICAM-1) was associated with increased 2-OH-E(+) (marker for superoxide formation) levels and was attenuated by apocynin and the Nox inhibitor, VAS2870. LPS triggered membrane translocation of p67phox, suggesting activation of Nox2. Silencing Nox2, but not Nox4, suppressed LPS-induced ICAM-1 expression in HPMEC. Immunoprecipitation studies showed that inhibitor of κ-B kinase-β (IKK-β) serine phosphorylation induced by LPS was inhibited by Nox2 silencing. We examined whether Nox2-dependent, LPS-mediated IKK-β phosphorylation was regulated by protein phosphatase 2A (PP2A) or TGF-β associated kinase-1 (TAK1) in HPMEC. LPS increased PP2A activity in HPMEC, and inhibition of PP2A did not alter LPS-mediated ICAM-1 expression but attenuated IKK-β phosphorylation. TAK1 inhibition decreased LPS-induced ICAM-1 expression in HPMEC, and Nox2 silencing attenuated LPS-mediated TAK1 phosphorylation (Thr184/187). We demonstrate that Nox2 regulates LPS-mediated endothelial activation in pulmonary endothelial cells by modulating phosphorylation of key kinases in the TLR signaling cascade. Our data support a novel mechanism by which Nox-dependent signaling regulates proinflammatory signaling in pulmonary endothelial cells. Inhibition of vascular Nox may potentially limit lung injury and alveolar remodeling caused by infections in BPD. 10.1152/ajplung.00261.2012
    Lipopolysaccharide disrupts the directional persistence of alveolar myofibroblast migration through EGF receptor. Li Huiping,Yuan Xiaobing,Tang Jun,Zhang Yongjun American journal of physiology. Lung cellular and molecular physiology Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification with decreased alveolar number and increased airspace size. Formation of alveoli involves a process known as secondary septation triggered by myofibroblasts. This study investigated the underlying mechanisms of altered lung morphogenesis in a rat model of BPD induced by intra-amniotic injection of lipopolysaccharide (LPS). Results showed that LPS disrupted alveolar morphology and led to abnormal localization of myofibroblasts in the lung of newborn rats, mostly in primary septa with few in secondary septa. To identify potential mechanisms, in vitro experiments were carried out to observe the migration behavior of myofibroblasts. The migration speed of lung myofibroblasts increased with LPS treatment, whereas the directional persistence decreased. We found that LPS induced activation of EGFR and overexpression of its ligand, TGF-α in myofibroblasts. AG1478, an EGFR inhibitor, abrogated the enhanced locomotivity of myofibroblasts by LPS and also increased the directional persistence of myofibroblast migration. Myofibroblasts showed a high asymmetry of phospho-EGFR localization, which was absent after LPS treatment. Application of rhTGF-α to myofibroblasts decreased the directional persistence. Our findings indicated that asymmetry of phospho-EGFR localization in myofibroblasts was important for cell migration and its directional persistence. We speculate that LPS exposure disrupts the asymmetric localization of phospho-EGFR, leading to decreased stability of cell polarity and final abnormal location of myofibroblasts in vivo, which is critical to secondary septation and may contribute to the arrested alveolar development in BPD. 10.1152/ajplung.00217.2011
    High-Mobility Group Box-1 Protein Disrupts Alveolar Elastogenesis of Hyperoxia-Injured Newborn Lungs. Yu Benli,Li Xiaoyu,Wan Qiufeng,Han Wenli,Deng Chun,Guo Chunbao Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research Although high-mobility group box-1 (HMGB1) levels in tracheal aspirates are associated with the pathological features of bronchopulmonary dysplasia (BPD), the role of HMGB1 in the terminal stage of abnormal alveologenesis has not yet been understood. In this study, we addressed the role of HMGB1 in the elastogenesis disruption in the lungs of newborn mice with BPD. We found that elevations of whole lung HMGB1 level were associated with impaired alveolar development and aberrant elastin production in 85% O2-exposed lungs. HMGB1 neutralizing antibody attenuated the structural disintegration developed in hyperoxia-damaged lungs. Furthermore, HMGB1 inhibition rescued the neutrophil influx in hyperoxia-injured lung and partially abolished the mRNA level of the proinflammatory mediators, interleukin (IL)-1β and transforming growth factor (TGF)-β1. These data suggested that pulmonary HMGB1 plays an important role in the disruption of elastogenesis in the terminal stage of lung development through reduced pulmonary inflammatory response. 10.1089/jir.2015.0080
    Recombinant human elafin promotes alveologenesis in newborn mice exposed to chronic hyperoxia. Han Wenli,Li Xiaomei,Zhang Han,Yu Benli,Guo Chunbao,Deng Chun The international journal of biochemistry & cell biology BACKGROUND/AIMS:Elastase inhibitors reverse elastin degradation and abnormal alveologenesis and attenuate the lung structural abnormalities induced by mechanical ventilation with O-rich gas. The potential of these molecules to improve endothelial function and to ameliorate severe bronchopulmonary dysplasia (BPD) during lung development is not yet understood. We sought to determine whether the intratracheal treatment of newborn mice with the elastase inhibitor elafin would prevent hyperoxia-induced lung elastin degradation and the cascade of events that cause abnormal alveologenesis. METHODS:Newborn mice were exposed to 85% O for 3, 7, 14 or 21days. Recombinant human elafin was administered by intratracheal instillation from the first day every two days for 20days. We next used morphometric analyses, quantitative RT-PCR, immunostaining, Western blotting, and ELISA methods to assess the key variables involved in elastogenesis disruption and the potential signaling pathways noted below in recombinant human elafin-treated mouse pups that had been exposed to 85% O. RESULTS:We found that impaired alveolar development and aberrant elastin production were associated with elevations in whole lung elastase levels in 85% O-exposed lungs. Elafin attenuated the structural disintegration that developed in the hyperoxia-damaged lungs. Furthermore, elafin prevented the elastin degradation, neutrophil influx, activation of TGF-β1 and apoptosis caused by 85% O exposure. CONCLUSIONS:Pulmonary elastase plays an important role in disrupting elastogenesis during O-induced damage, which is the result of a pulmonary inflammatory response. Elafin prevents these changes by inhibiting elastase and the TGF-β1 signalling cascade and may be a new therapeutic target for preventing O-induced lung injury in neonates. 10.1016/j.biocel.2017.08.004
    Nitric oxide attenuates epithelial-mesenchymal transition in alveolar epithelial cells. Vyas-Read Shilpa,Shaul Philip W,Yuhanna Ivan S,Willis Brigham C American journal of physiology. Lung cellular and molecular physiology Patients with interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF) and bronchopulmonary dysplasia (BPD), suffer from lung fibrosis secondary to myofibroblast-mediated excessive ECM deposition and destruction of lung architecture. Transforming growth factor (TGF)-beta1 induces epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AEC) to myofibroblasts both in vitro and in vivo. Inhaled nitric oxide (NO) attenuates ECM accumulation, enhances lung growth, and decreases alveolar myofibroblast number in experimental models. We therefore hypothesized that NO attenuates TGF-beta1-induced EMT in cultured AEC. Studies of the capacity for endogenous NO production in AEC revealed that endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) are expressed and active in AEC. Total NOS activity was 1.3 pmol x mg protein(-1) x min(-1) with 67% derived from eNOS. TGF-beta1 (50 pM) suppressed eNOS expression by more than 60% and activity by 83% but did not affect iNOS expression or activity. Inhibition of endogenous NOS with l-NAME led to spontaneous EMT, manifested by increased alpha-smooth muscle actin (alpha-SMA) expression and a fibroblast-like morphology. Provision of exogenous NO to TGF-beta1-treated AEC decreased stress fiber-associated alpha-SMA expression and decreased collagen I expression by 80%. NO-treated AEC also retained an epithelial morphology and expressed increased lamellar protein, E-cadherin, and pro-surfactant protein B compared with those treated with TGF-beta alone. These findings indicate that NO serves a critical role in preserving an epithelial phenotype and in attenuating EMT in AEC. NO-mediated regulation of AEC fate may have important implications in the pathophysiology and treatment of diseases such as IPF and BPD. 10.1152/ajplung.00475.2006
    Pilot feasibility study to detect mesenchymal stem cell biomarkers of bronchopulmonary dysplasia in the tracheal aspirate fluid of preterm infants. LaGrandeur R G,Singhal M,Bany-Mohammed F,Uy C,Koeppel R,Zaldivar F,Haddad F,Nalbandian A,Donovan P,Cooper D M,Aslam M Journal of neonatal-perinatal medicine OBJECTIVE:This study aimed to detect novel mesenchymal stem cell peptides/biomarkers of bronchopulmonary dysplasia (BPD) in the tracheal aspirate fluid (TAF) of preterm infants. STUDY DESIGN:Participants included infants less than 32 weeks' gestational age or birth weight under 1500 grams who required endotracheal intubation and mechanical ventilation within first 24 hours of life. TAF sample collection was performed at the time of the first clinically indicated routine suctioning. Standardization curves for human levels of osteopontin (Opn), macrophage colony stimulating factor 1 (Csf1), transforming growth factor beta 1 (TGF-β1), and secretory immunoglobulin A (sIgA) were generated for 15 enrolled participants. RESULTS:We demonstrated that stem cell biomarkers are secreted into the TAF of preterm infants and their concentrations can be easily measured during the first week of life. CONCLUSIONS:Further studies are warranted to determine a causal relationship between these biomarkers and BPD development and severity. 10.3233/NPM-181722
    Decreased expression of transforming growth factor-beta1 in bronchoalveolar lavage cells of preterm infants with maternal chorioamnionitis. Choi Chang Won,Kim Beyong Il,Joung Kyoung Eun,Lee Jin-A,Lee Yun Kyoung,Kim Ee-Kyung,Kim Han-Suk,Park June Dong,Choi Jung-Hwan Journal of Korean medical science Maternal chorioamnionitis has been associated with abnormal lung development. We examined the effect of maternal chorioamnionitis on the expression of transforming growth factor-beta1 (TGF-beta1) in the lungs of preterm infants. A total of 63 preterm (<or=34 weeks) infants who were intubated in the delivery room were prospectively enrolled. Their placentas were examined for the presence of chorioamnionitis. Bronchoalveolar lavage (BAL) fluid and cells were obtained shortly after birth. TGF-beta1 was measured in BAL fluid and TGF-beta1 mRNA expression was determined by reverse transcription polymerase chain reaction (RT-PCR) in BAL cells. TGF-beta1 mRNA expression in BAL cells showed a positive correlation with gestational age (r=0.414, p=0.002). TGF-beta1 mRNA expression was significantly decreased in the presence of maternal chorioamnionitis (0.70+/-0.12 vs. 0.81+/-0.15, p=0.007). Adjustment for gestational age, birth weight, and delivery mode did not nullify the significance. TGF-beta1 mRNA expression was marginally significantly decreased in preterm infants who developed bronchopulmonary dysplasia (BPD) later (0.75+/-0.11 vs. 0.82+/-0.15, p=0.055). However, adjustment for gestational age, patent ductus arteriosus (PDA), and maternal chorioamnionitis nullified the significance. These results might be an indirect evidence that maternal chorioamnionitis may inhibit normal lung development of fetus. 10.3346/jkms.2008.23.4.609
    Beneficial Effect of Etanercept on Hyperoxic Lung Injury Model in Neonatal Rats. Oncel Mehmet Yekta,Yurttutan Sadik,Alyamac Dizdar Evrim,Gokce Ismail Kursat,Gonul Ipek Isik,Topal Turgut,Canpolat Fuat Emre,Dilmen Ugur Journal of investigative surgery : the official journal of the Academy of Surgical Research PURPOSE:To determine whether prophylaxis with etanercept, an anti-inflammatory drug, would decrease the severity of lung injury in a neonatal rat model of bronchopulmonary dysplasia (BPD); MATERIALS AND METHODS:Rat pups were divided into three groups: pups exposed to room air (group 1; n = 10), to hyperoxia + placebo (group 2; n = 9), and to hyperoxia + etanercept (group 3; n = 8). Lung morphology was assessed by alveolar surface area percentage, which is a measure of alveolar size. The severities of lung inflammation and antioxidant capacity were assessed by quantifying tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), malondialdehyde (MDA), and superoxide dismutase (SOD) from lung homogenate; RESULTS:The percentage of alveolar surface areas were significantly higher in group 3 compared to group 2 (p = .004) and similar in both group 1 and group 3 (p = .21). The mean level of lung MDA was significantly higher in group 2 compared to group 1 and group 3 (p < .05 for both). Lung homogenate SOD activities in group 3 was significantly higher than group 2 (p < .001). Furthermore, group 3 pups had lower levels of TNF-α and TGF-β in lung homogenate than that in group 2 (p < .05 for both) but similar in both group 1 and group 3; CONCLUSION:Etanercept has favorable effects on alveolarization as well as inflammation and oxidative stress markers in a neonatal rat model of BPD. 10.3109/08941939.2015.1034898
    14-3-3β Is necessary in the regulation of polarization and directional migration of alveolar myofibroblasts by lipopolysaccharide. Li Jianhui,Gong Xiaohui Experimental lung research Bronchopulmonary dysplasia (BPD) is characterized by alveolarization arrest. During alveolarization, alveolar myofibroblasts are thought to migrate into the septal tips and elongate secondary septa. Lipopolysaccharide (LPS) exposure has been reported to disrupt directional migration and final location of alveolar myofibroblasts in a rat model of BPD induced by intra-amniotic injection of LPS. However, molecular mechanisms that control directional migration of alveolar myofibroblasts have not so far been investigated clearly. We assessed the polarization of myofibroblast using scrape wounding assays combined with Golgi tracking. Transwell migration assay was used to detect the directional migration of myofibroblasts. Pull-down assays were performed to isolate the active GTP-bound form using the RhoA activation assay kits. Western blotting analysis was performed to evaluate the changes in protein expression. Functional analysis was performed via siRNA interference. Here, we showed that LPS might affect the directional migration of myofibroblasts by disturbing the polarization of myofibroblasts. In addition, as a main member of RhoGTPases family which plays a vital role in establishing and maintaining cell polarity, RhoA activity was significantly upregulated in myofibroblasts treated with LPS, while activity of epidermal growth factor receptor (EGFR) was upregulated and overexpression of its ligand, TGF-α, in myofibroblasts by LPS treatment. AG1478, an EGFR inhibitor, could abrogate the upregulated RhoA activity of myofibroblasts by LPS and rhTGF-α. Moreover, if we knock down 14-3-3β, LPS and rhTGF-α could not activate RhoA and disturb myofibroblasts polarization. Taken together, our findings suggest that LPS exposure may increase RhoA activity of myofibroblasts by TGF-α/EGFR/14-3-3β signaling pathway, and then disturb myofibroblasts polarization and directional migration. 10.1080/01902148.2019.1711464
    Conditional overexpression of bioactive transforming growth factor-beta1 in neonatal mouse lung: a new model for bronchopulmonary dysplasia? Vicencio Alfin G,Lee Chun Geun,Cho Soo Jung,Eickelberg Oliver,Chuu Ying,Haddad Gabriel G,Elias Jack A American journal of respiratory cell and molecular biology Research interest in bronchopulmonary dysplasia (BPD) has steadily increased, and numerous potential mediators have been implicated in the development of the disease. Among such mediators is transforming growth factor (TGF)-beta. Unfortunately, commonly utilized murine transgenic models are not optimal to investigate the effects of TGF-beta specifically during the 2-3 wk period of alveolar formation, the developmental stage that corresponds histologically to early alveolar development in humans, and the time frame during which BPD develops. In the current study, we utilized a triple-transgenic construct to overexpress bioactive TGF-beta1 in the neonatal mouse lung during the period of alveolar formation. Lungs were then examined by histologic, Western blot, and immunofluorescent methods. We found that overexpression of bioactive TGF-beta1 in neonatal mouse lungs resulted in structural changes that have been described in BPD. Included in those characteristics are abnormal alveolar structure, cellular composition, and vascular development. Our study indicates that TGF-beta1 overexpression in the neonatal mouse lung results in histologic alterations that have striking similarities to pathologic descriptions of BPD. We encourage the use of conditional transgenic models for the study of BPD, and hypothesize that the TGF-beta system is a central mediator for the histologic alterations described in association with the disease. 10.1165/rcmb.2004-0092OC
    Expression of transforming growth factor-β1 in neonatal rats with hyperoxia-induced bronchopulmonary dysplasia and its relationship with lung development. Yan B,Zhong W,He Q M,Zhang S Y,Yu J K,Pan Y L Genetics and molecular research : GMR The aim of this study was to detect the expression of transforming growth factor-ß1 (TGF-ß1) in neonatal rats with hyperoxia-induced bronchopulmonary dysplasia (BPD) and to explore its relationship with lung development. Forty-eight rats (2-3 days old) were randomly divided into a hyperoxia group and a control group (N = 24) which were then fed in ≥95% oxygen atmosphere and air, respectively. On the 1st, 3rd and 7th days of hyperoxia exposure, morphological changes of lung tissues were observed under an optical microscope. TGF-ß1 mRNA and protein levels in lung tissues were detected by real-time quantitative polymerase chain reaction and western blot, respectively. With increasing time of hyperoxia exposure, the hyperoxia group gradually suffered from pathological changes such as poor development of lung tissues, alveolar simplification, decrease in the number of alveoli, and hindered pulmonary microvascular development. On the 7th day of hyperoxia exposure, TGF-ß1 mRNA and protein levels (relative to b-actin) of the hyperoxia group (0.34 ± 0.19 and 0.21 ± 0.09, respectively) were significantly lower than those of the control group (0.83 ± 0.45 and 0.57 ± 0.45, respectively; P < 0.05). TGF-ß1 participates in the pathogenesis of BPD as an important regulatory factor during pulmonary vascular development. 10.4238/gmr.15028064
    Caffeine modulates glucocorticoid-induced expression of CTGF in lung epithelial cells and fibroblasts. Fehrholz Markus,Glaser Kirsten,Speer Christian P,Seidenspinner Silvia,Ottensmeier Barbara,Kunzmann Steffen Respiratory research BACKGROUND:Although caffeine and glucocorticoids are frequently used to treat chronic lung disease in preterm neonates, potential interactions are largely unknown. While anti-inflammatory effects of glucocorticoids are well defined, their impact on airway remodeling is less characterized. Caffeine has been ascribed to positive effects on airway inflammation as well as remodeling. Connective tissue growth factor (CTGF, CCN2) plays a key role in airway remodeling and has been implicated in the pathogenesis of chronic lung diseases such as bronchopulmonary dysplasia (BPD) in preterm infants. The current study addressed the impact of glucocorticoids on the regulation of CTGF in the presence of caffeine using human lung epithelial and fibroblast cells. METHODS:The human airway epithelial cell line H441 and the fetal lung fibroblast strain IMR-90 were exposed to different glucocorticoids (dexamethasone, budesonide, betamethasone, prednisolone, hydrocortisone) and caffeine. mRNA and protein expression of CTGF, TGF-β1-3, and TNF-α were determined by means of quantitative real-time PCR and immunoblotting. H441 cells were additionally treated with cAMP, the adenylyl cyclase activator forskolin, and the selective phosphodiesterase (PDE)-4 inhibitor cilomilast to mimic caffeine-mediated PDE inhibition. RESULTS:Treatment with different glucocorticoids (1 μM) significantly increased CTGF mRNA levels in H441 (p < 0.0001) and IMR-90 cells (p < 0.01). Upon simultaneous exposure to caffeine (10 mM), both glucocorticoid-induced mRNA and protein expression were significantly reduced in IMR-90 cells (p < 0.0001). Of note, 24 h exposure to caffeine alone significantly suppressed basal expression of CTGF mRNA and protein in IMR-90 cells. Caffeine-induced reduction of CTGF mRNA expression seemed to be independent of cAMP levels, adenylyl cyclase activation, or PDE-4 inhibition. While dexamethasone or caffeine treatment did not affect TGF-β1 mRNA in H441 cells, increased expression of TGF-β2 and TGF-β3 mRNA was detected upon exposure to dexamethasone or dexamethasone and caffeine, respectively. Moreover, caffeine increased TNF-α mRNA in H441 cells (6.5 ± 2.2-fold, p < 0.05) which has been described as potent inhibitor of CTGF expression. CONCLUSIONS:In addition to well-known anti-inflammatory features, glucocorticoids may have adverse effects on long-term remodeling by TGF-β1-independent induction of CTGF in lung cells. Simultaneous treatment with caffeine may attenuate glucocorticoid-induced expression of CTGF, thereby promoting restoration of lung homeostasis. 10.1186/s12931-017-0535-8
    Neonatal periostin knockout mice are protected from hyperoxia-induced alveolar simplication. Bozyk Paul D,Bentley J Kelley,Popova Antonia P,Anyanwu Anuli C,Linn Marisa D,Goldsmith Adam M,Pryhuber Gloria S,Moore Bethany B,Hershenson Marc B PloS one In bronchopulmonary dysplasia (BPD), alveolar septae are thickened with collagen and α-smooth muscle actin, transforming growth factor (TGF)-β-positive myofibroblasts. Periostin, a secreted extracellular matrix protein, is involved in TGF-β-mediated fibrosis and myofibroblast differentiation. We hypothesized that periostin expression is required for hypoalveolarization and interstitial fibrosis in hyperoxia-exposed neonatal mice, an animal model for this disease. We also examined periostin expression in neonatal lung mesenchymal stromal cells and lung tissue of hyperoxia-exposed neonatal mice and human infants with BPD. Two-to-three day-old wild-type and periostin null mice were exposed to air or 75% oxygen for 14 days. Mesenchymal stromal cells were isolated from tracheal aspirates of premature infants. Hyperoxic exposure of neonatal mice increased alveolar wall periostin expression, particularly in areas of interstitial thickening. Periostin co-localized with α-smooth muscle actin, suggesting synthesis by myofibroblasts. A similar pattern was found in lung sections of infants dying of BPD. Unlike wild-type mice, hyperoxia-exposed periostin null mice did not show larger air spaces or α-smooth muscle-positive myofibroblasts. Compared to hyperoxia-exposed wild-type mice, hyperoxia-exposed periostin null mice also showed reduced lung mRNA expression of α-smooth muscle actin, elastin, CXCL1, CXCL2 and CCL4. TGF-β treatment increased mesenchymal stromal cell periostin expression, and periostin treatment increased TGF-β-mediated DNA synthesis and myofibroblast differentiation. We conclude that periostin expression is increased in the lungs of hyperoxia-exposed neonatal mice and infants with BPD, and is required for hyperoxia-induced hypoalveolarization and interstitial fibrosis. 10.1371/journal.pone.0031336
    Aberrant elastin remodeling in the lungs of O₂-exposed newborn mice; primarily results from perturbed interaction between integrins and elastin. Han Wenli,Guo Chunbao,Liu Qiutong,Yu Benli,Liu Zhaoyun,Yang Junqing,Deng Chun Cell and tissue research Excessive localization of elastin from septal tips to alveolar walls is a key feature of bronchopulmonary dysplasia (BPD). The abnormal accumulation of lung elastin, involving the structural and functional interaction of a series of proteins, remains poorly understood. To further investigate the mechanisms accounting for the abnormal accumulation of elastin in the lungs of newborn mice with BPD, we evaluate elastin distribution and its interaction with proteins involved in its aberrant localization, such as integrin αv, fibulin-5 and transforming growth factor β1 (TGF-β1), in lungs of newborn mice exposed to 60% O2 for 21 days. Lung histology revealed aberrant elastin production and impaired lung septation in O2-exposed lungs, while tropoelastin, integrin αv, fibulin-1, fibulin-2 and fibulin-4 gene expression were elevated. Dual staining image analysis of lung sections revealed that co-localization of integrin αv and elastin increased following O2 exposure with elastin distributed throughout the walls of air spaces rather than at septal tips. Furthermore, integrin αv appeared to be induced initially. Concurrently, increased fibulin-5 and TGF-β1 (which may regulate elastic fiber assembly) expression was detected, which may explain the altered lung elastin deposition and defective septation that are observed during BPD. These data support the hypothesis that excessive and aberrant αv integrin expression was initially induced by hyperoxia; αv integrin then interacted with and recruited elastin. These alterations were accompanied by fibulin-5 deposition and TGF-β1 activation, which may impede normal matrix remodeling, thereby contributing to the pathological pulmonary features of BPD. 10.1007/s00441-014-2035-1
    Hyperoxia induces epigenetic changes in newborn mice lungs. Bik-Multanowski Miroslaw,Revhaug Cecilie,Grabowska Agnieszka,Dobosz Artur,Madetko-Talowska Anna,Zasada Magdalena,Saugstad Ola Didrik Free radical biology & medicine Supplemental oxygen exposure is a risk factor for the development of bronchopulmonary dysplasia (BPD). Reactive oxygen species may damage lung tissue, but hyperoxia also has the potential to alter genome activity via changes in DNA methylation. Understanding the epigenetic potential of hyperoxia would enable further improvement of the therapeutic strategies for BPD. Here we aimed to identify hyperoxia-related alterations in DNA methylation, which could affect the activity of crucial genetic pathways involved in the development of hyperoxic lung injury. Newborn mice (n = 24) were randomized to hyperoxia (85% O) or normoxia groups for 14 days, followed by normoxia for the subsequent 14 days. The mice were sacrificed on day 28, and lung tissue was analyzed using microarrays developed for the assessment of genome methylation and expression profiles. The mean DNA methylation level was higher in the hyperoxia group than the normoxia group. The analysis of specific DNA fragments revealed hypermethylation of > 1000 gene promoters in the hyperoxia group, confirming the presence of the DNA-hypermethylation effect of hyperoxia. Further analysis showed significant enrichment of the TGF-β signaling pathway (p = 0.0013). The hypermethylated genes included Tgfbr1, Crebbp, and Creb1, which play central roles in the TGF-β signaling pathway and cell cycle regulation. Genome expression analysis revealed in the hyperoxia group complementary downregulation of genes that are crucial for cell cycle regulation (Crebbp, Smad2, and Smad3). These results suggest the involvement of the methylation of TGF-β pathway genes in lung tissue reaction to hyperoxia. The data also suggest that hyperoxia may be a programming factor in newborn mice. 10.1016/j.freeradbiomed.2018.04.566
    Glycogen synthase kinase-3β/β-catenin signaling regulates neonatal lung mesenchymal stromal cell myofibroblastic differentiation. Popova Antonia P,Bentley J Kelley,Anyanwu Anuli C,Richardson Michelle N,Linn Marisa J,Lei Jing,Wong Elizabeth J,Goldsmith Adam M,Pryhuber Gloria S,Hershenson Marc B American journal of physiology. Lung cellular and molecular physiology In bronchopulmonary dysplasia (BPD), alveolar septa are thickened with collagen and α-smooth muscle actin-, transforming growth factor (TGF)-β-positive myofibroblasts. We examined the biochemical mechanisms underlying myofibroblastic differentiation, focusing on the role of glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling pathway. In the cytoplasm, β-catenin is phosphorylated on the NH(2) terminus by constitutively active GSK-3β, favoring its degradation. Upon TGF-β stimulation, GSK-3β is phosphorylated and inactivated, allowing β-catenin to translocate to the nucleus, where it activates transcription of genes involved in myofibroblastic differentiation. We examined the role of β-catenin in TGF-β1-induced myofibroblastic differentiation of neonatal lung mesenchymal stromal cells (MSCs) isolated from tracheal aspirates of premature infants with respiratory distress. TGF-β1 increased β-catenin expression and nuclear translocation. Transduction of cells with GSK-3β S9A, a nonphosphorylatable, constitutively active mutant that favors β-catenin degradation, blocked TGF-β1-induced myofibroblastic differentiation. Furthermore, transduction of MSCs with ΔN-catenin, a truncation mutant that cannot be phosphorylated on the NH(2) terminus by GSK-3β and is not degraded, was sufficient for myofibroblastic differentiation. In vivo, hyperoxic exposure of neonatal mice increases expression of β-catenin in α-smooth muscle actin-positive myofibroblasts. Similar changes were found in lungs of infants with BPD. Finally, low-passage unstimulated MSCs from infants developing BPD showed higher phospho-GSK-3β, β-catenin, and α-actin content compared with MSCs from infants not developing this disease, and phospho-GSK-3β and β-catenin each correlated with α-actin content. We conclude that phospho-GSK-3β/β-catenin signaling regulates α-smooth muscle actin expression, a marker of myofibroblast differentiation, in vitro and in vivo. This pathway appears to be activated in lung mesenchymal cells from patients with BPD. 10.1152/ajplung.00408.2011
    Lack of association between FXIII-Val34Leu, FVII-323 del/ins, and transforming growth factor beta1 (915G/T) gene polymorphisms and bronchopulmonary dysplasia: a single-center study. Ataç Fatma Belgin,Ince Deniz Anuk,Verdi Hasibe,Gökmen Zeynel,Yazici Ayse Canan,Gülcan Hande,Tarcan Aylin,Taneri Ayse,Sezgin Ezgi,Ozbek Namik DNA and cell biology Bronchopulmonary dysplasia (BPD) is a multifactorial disease of preterm infants that is characterized by airway injury, inflammation, and parenchymal remodeling. Extravascular fibrin deposits in septae and alveoli due to the altered fibrin turnover are the pathological hallmarks of BPD that strongly indicates the importance of the imbalance in the competing activities of coagulation and fibrinolysis. Activation of the coagulation cascade leads to intraalveolar fibrin deposition in many inflammatory pulmonary disorders. Increased fibrin formation or decreased fibrinolysis may cause extravascular fibrin deposition. We evaluated the association between FXIII-Val34Leu, FVII-323 del/ins, and transforming growth factor beta1 (TGF-beta(1)) (915G/T) gene polymorphisms in patients with BPD. The study group consisted of 98 preterm infants with BPD. Ninety-four of the 192 preterm neonates were without BPD and sampled for the control group. Restriction fragment size analyses were performed by examining digested PCR products for FXIII-Val34Leu, FVII-323 del/ins, and TGF-beta(1) (915G/C) genotypes. No significant associations were found between FXIII-Val34Leu, FVII-323 del/ins, TGF-beta(1) (915G/C) gene polymorphisms and BPD phenotype in our population. Further studies with other genes are required for the identification of molecular predisposing factors for BPD that may help in the development of new treatments and hence might allow for targeting of this treatment to a "high-risk" subgroup, reducing unnecessary exposure to potentially harmful therapies. 10.1089/dna.2009.0928
    Inflammatory Mediators in Tracheal Aspirates of Preterm Infants Participating in a Randomized Trial of Inhaled Nitric Oxide. Laube Mandy,Amann Elena,Uhlig Ulrike,Yang Yang,Fuchs Hans W,Zemlin Michael,Mercier Jean-Christophe,Maier Rolf F,Hummler Helmut D,Uhlig Stefan,Thome Ulrich H PloS one BACKGROUND:Ventilated preterm infants frequently develop bronchopulmonary dysplasia (BPD) which is associated with elevated inflammatory mediators in their tracheal aspirates (TA). In animal models of BPD, inhaled nitric oxide (iNO) has been shown to reduce lung inflammation, but data for human preterm infants is missing. METHODS:Within a European multicenter trial of NO inhalation for preterm infants to prevent BPD (EUNO), TA was collected to determine the effects of iNO on pulmonary inflammation. TA was collected from 43 premature infants randomly assigned to receive either iNO or placebo gas (birth weight 530-1230 g, median 800 g, gestational age 24 to 28 2/7 weeks, median 26 weeks). Interleukin (IL)-1β, IL-6, IL-8, transforming growth factor (TGF)-β1, interferon γ-induced protein 10 (IP-10), macrophage inflammatory protein (MIP)-1α, acid sphingomyelinase (ASM), neuropeptide Y and leukotriene B4 were measured in serial TA samples from postnatal day 2 to 14. Furthermore, TA levels of nitrotyrosine and nitrite were determined under iNO therapy. RESULTS:The TA levels of IP-10, IL-6, IL-8, MIP-1α, IL-1β, ASM and albumin increased with advancing postnatal age in critically ill preterm infants, whereas nitrotyrosine TA levels declined in both, iNO-treated and placebo-treated infants. The iNO treatment generally increased nitrite TA levels, whereas nitrotyrosine TA levels were not affected by iNO treatment. Furthermore, iNO treatment transiently reduced early inflammatory and fibrotic markers associated with BPD development including TGF-β1, IP-10 and IL-8, but induced a delayed increase of ASM TA levels. CONCLUSION:Treatment with iNO may have played a role in reducing several inflammatory and fibrotic mediators in TA of preterm infants compared to placebo-treated infants. However, survival without BPD was not affected in the main EUNO trial. TRIAL REGISTRATION:NCT00551642. 10.1371/journal.pone.0169352
    Early alterations of growth factor patterns in bronchoalveolar lavage fluid from preterm infants developing bronchopulmonary dysplasia. Been Jasper V,Debeer Anne,van Iwaarden J Freek,Kloosterboer Nico,Passos Valéria Lima,Naulaers Gunnar,Zimmermann Luc J Pediatric research UNLABELLED:Chronic lung disease of prematurity (bronchopulmonary dysplasia; BPD) is characterized by an arrest in lung development. We hypothesized that early alterations in pulmonary expression of growth factors important for normal lung development would precede development of BPD. Bronchoalveolar lavage fluid (BALF) was obtained from ventilated preterm infants (n = 62) on postnatal d 0, 1, 3, and 7 and analyzed for total phospholipids (PL), VEGF, PDGF-BB, TGF-alpha and -beta1, granulocyte macrophage colony stimulating factor (GM-CSF), and keratinocyte growth factor (KGF). Levels (Ln transformed) were compared between infants developing BPD and BPD-free survivors, adjusted for potential confounders. BPD was associated with higher overall GM-CSF (beta (95% CI) = 0.69 (0.13;1.25); p < 0.05), lower overall latent TGF-beta1 (beta (95% CI) = -1.19 (-1.87, -0.39); p < 0.01) and total PL (beta (95% CI) = -0.64 (-1.23, -0.05); p < 0.05), and lower d 0 and 3 levels of VEGF (mean difference (95% CI) = -1.75 (-2.72, -0.77), p < 0.001; and -1.18 (-2.30, -0.06), p < 0.05, respectively) and TGF-alpha (mean difference (95% CI) = -0.73 (-1.42, -0.04), p < 0.05; and -1.01 (-1.64, -0.38), p < 0.01, respectively). Day 0 VEGF levels had the highest predictive value for BPD (area under receiver operating characteristic curve = 0.87; p < 0.01). In conclusion, substantial alterations in BALF growth factor levels are present in infants developing BPD. An early imbalance in pulmonary growth factors may contribute to the developmental arrest of the lung seen in BPD. ABBREVIATIONS:: 10.1203/PDR.0b013e3181c13276
    Amniotic fluid transforming growth factor-beta1 and the risk for the development of neonatal bronchopulmonary dysplasia. Ichiba Hiroyuki,Saito Mika,Yamano Tsunekazu Neonatology Chorioamnionitis (CAM) can initiate fetal lung injury resulting in neonatal bronchopulmonary dysplasia (BPD). While neonates with BPD have higher amniotic fluid concentrations of proinflammatory cytokines, overexpression of transforming growth factor (TGF)-beta(1) also appears important in the pathogenesis of BPD. The aim of this study was to investigate the relationship between TGF-beta(1) and CAM-induced fetal lung injury. Forty-four amniotic fluid samples were obtained at delivery of preterm infants (median gestation, 28 weeks; birth weight, 908 g). TGF-beta(1) and interleukin (IL)-6 concentrations in the amniotic fluid were measured with ELISA. Both TGF-beta(1) and IL-6 concentrations in the amniotic fluid increased with increasing histological severity of CAM (each p < 0.0001). The presence of both BPD and histological CAM was associated with significantly higher amniotic fluid TGF-beta(1) and IL-6 concentrations than the presence of BPD without histological CAM, or the absence of both (each p < 0.0001). Both concentrations also correlated with the duration of oxygen administration in the neonates (each p < 0.0001). Amniotic fluid TGF-beta(1) seems to be important in CAM-induced fetal lung injury progressing to neonatal BPD. 10.1159/000210088
    Endothelial to mesenchymal transition during neonatal hyperoxia-induced pulmonary hypertension. Gong Jiannan,Feng Zihang,Peterson Abigail L,Carr Jennifer F,Vang Alexander,Braza Julie,Choudhary Gaurav,Dennery Phyllis A,Yao Hongwei The Journal of pathology Bronchopulmonary dysplasia (BPD), a chronic lung disease in premature infants, results from mechanical ventilation and hyperoxia, amongst other factors. Although most BPD survivors can be weaned from supplemental oxygen, many show evidence of cardiovascular sequelae in adulthood, including pulmonary hypertension and pulmonary vascular remodeling. Endothelial-mesenchymal transition (EndoMT) plays an important role in mediating vascular remodeling in idiopathic pulmonary arterial hypertension. Whether hyperoxic exposure, a known mediator of BPD in rodent models, causes EndoMT resulting in vascular remodeling and pulmonary hypertension remains unclear. We hypothesized that neonatal hyperoxic exposure causes EndoMT, leading to the development of pulmonary hypertension in adulthood. To test this hypothesis, newborn mice were exposed to hyperoxia and then allowed to recover in room air until adulthood. Neonatal hyperoxic exposure gradually caused pulmonary vascular and right ventricle remodeling as well as pulmonary hypertension. Male mice were more susceptible to developing pulmonary hypertension compared to female mice, when exposed to hyperoxia as newborns. Hyperoxic exposure induced EndoMT in mouse lungs as well as in cultured lung microvascular endothelial cells (LMVECs) isolated from neonatal mice and human fetal donors. This was augmented in cultured LMVECs from male donors compared to those from female donors. Using primary mouse LMVECs, hyperoxic exposure increased phosphorylation of both Smad2 and Smad3, but reduced Smad7 protein levels. Treatment with a selective TGF-β inhibitor SB431542 blocked hyperoxia-induced EndoMT in vitro. Altogether, we show that neonatal hyperoxic exposure caused vascular remodeling and pulmonary hypertension in adulthood. This was associated with increased EndoMT. These novel observations provide mechanisms underlying hyperoxia-induced vascular remodeling and potential approaches to prevent BPD-associated pulmonary hypertension by targeting EndoMT. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 10.1002/path.5534
    Theophylline improves lipopolysaccharide-induced alveolarization arrest through inflammatory regulation. He Hua,Chen Fei,Ni Wensi,Li Jianhui,Zhang Yongjun Molecular medicine reports Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification with decreased numbers of alveoli and increased airspace. BPD, frequently suffered by very low birth weight infants, has been closely associated with intrauterine infection. However, the underlying mechanisms of BPD remain unclear. In the present study, it was identified that administration of intra-amniotic lipopolysaccharide (LPS) to pregnant rats on embryonal day 16.5 (E16.5) induced significant alveolarization arrest similar to that of BPD in neonatal pups, and theophylline injected subcutaneously into the newborns improved the pathological changes. To further investigate the underlying mechanism of the morphogenesis amelioration of theophylline, cytokine antibody arrays were performed with the lung lysates of neonatal rats. The results indicated that LPS upregulated a series of pro-inflammatory cytokines and theophylline significantly attenuated the expression levels of pro-inflammatory cytokines tumor necrosis factor‑α, macrophage inflammatory protein (MIP)-1α and MIP-2, and markedly elevated the production of tumor growth factor (TGF)-β family members TGF-β1, TGF-β2 and TGF-β3, which are anti‑inflammatory cytokines. Accordingly, it was hypothesized that theophylline may protect against BPD and improve chorioamnionitis‑induced alveolar arrest by regulating the balance between pro‑and anti-inflammatory cytokine expression. 10.3892/mmr.2014.2188
    Human umbilical cord-derived mesenchymal stem cells protect from hyperoxic lung injury by ameliorating aberrant elastin remodeling in the lung of O-exposed newborn rat. Hou Chen,Peng Danyi,Gao Li,Tian Daiyin,Dai Jihong,Luo Zhengxiu,Liu Enmei,Chen Hong,Zou Lin,Fu Zhou Biochemical and biophysical research communications The incidence and mortality rates of bronchopulmonary dysplasia (BPD) remain very high. Therefore, novel therapies are imminently needed to improve the outcome of this disease. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) show promising therapeutic effects on oxygen-induced model of BPD. In our experiment, UC-MSCs were intratracheally delivered into the newborn rats exposed to hyperoxia, a well-established BPD model. This study demonstrated that UC-MSCs reduce elastin expression stimulated by 90% O in human lung fibroblasts-a (HLF-a), and inhibit HLF-a transdifferentiation into myofibroblasts. In addition, the therapeutic effects of UC-MSCs in neonatal rats with BPD, UC-MSCs could inhibit lung elastase activity and reduce aberrant elastin expression and deposition in the lung of BPD rats. Overall, this study suggested that UC-MSCs could ameliorate aberrant elastin expression in the lung of hyperoxia-induced BPD model which may be associated with suppressing increased TGFβ1 activation. 10.1016/j.bbrc.2017.12.055
    Lysyl oxidase activity is dysregulated during impaired alveolarization of mouse and human lungs. Kumarasamy Arun,Schmitt Isabelle,Nave Alexander H,Reiss Irwin,van der Horst Irene,Dony Eva,Roberts Jesse D,de Krijger Ronald R,Tibboel Dick,Seeger Werner,Schermuly Ralph T,Eickelberg Oliver,Morty Rory E American journal of respiratory and critical care medicine RATIONALE:Disordered extracellular matrix production is a feature of bronchopulmonary dysplasia (BPD). The basis of this phenomenon is not understood. OBJECTIVES:To assess lysyl oxidase expression and activity in the injured developing lungs of newborn mice and of prematurely born infants with BPD or at risk for BPD. METHODS:Pulmonary lysyl oxidase and elastin gene and protein expression were assessed in newborn mice breathing 21 or 85% oxygen, in patients who died with BPD or were at risk for BPD, and in control patients. Signaling by transforming growth factor (TGF-beta) was preemptively blocked in mice exposed to hyperoxia using TGF-beta-neutralizing antibodies. Lysyl oxidase promoter activity was assessed using plasmids containing the lox or loxl1 promoters fused upstream of the firefly luciferase gene. MEASUREMENTS AND MAIN RESULTS:mRNA and protein levels and activity of lysyl oxidases (Lox, LoxL1, LoxL2) were elevated in the oxygen-injured lungs of newborn mice and infants with BPD or at risk for BPD. In oxygen-injured mouse lungs, increased TGF-beta signaling drove aberrant lox, but not loxl1 or loxl2, expression. Lox expression was also increased in oxygen-injured fibroblasts and pulmonary artery smooth muscle cells. CONCLUSIONS:Lysyl oxidase expression and activity are dysregulated in BPD in injured developing mouse lungs and in prematurely born infants. In developing mouse lungs, aberrant TGF-beta signaling dysregulated lysyl oxidase expression. These data support the postulate that excessive stabilization of the extracellular matrix by excessive lysyl oxidase activity might impede the normal matrix remodeling that is required for pulmonary alveolarization and thereby contribute to the pathological pulmonary features of BPD. 10.1164/rccm.200902-0215OC
    Deregulation of the lysyl hydroxylase matrix cross-linking system in experimental and clinical bronchopulmonary dysplasia. Witsch Thilo J,Turowski Pawel,Sakkas Elpidoforos,Niess Gero,Becker Simone,Herold Susanne,Mayer Konstantin,Vadász István,Roberts Jesse D,Seeger Werner,Morty Rory E American journal of physiology. Lung cellular and molecular physiology Bronchopulmonary dysplasia (BPD) is a common and serious complication of premature birth, characterized by a pronounced arrest of alveolar development. The underlying pathophysiological mechanisms are poorly understood although perturbations to the maturation and remodeling of the extracellular matrix (ECM) are emerging as candidate disease pathomechanisms. In this study, the expression and regulation of three members of the lysyl hydroxylase family of ECM remodeling enzymes (Plod1, Plod2, and Plod3) in clinical BPD, as well as in an experimental animal model of BPD, were addressed. All three enzymes were localized to the septal walls in developing mouse lungs, with Plod1 also expressed in the vessel walls of the developing lung and Plod3 expressed uniquely at the base of developing septa. The expression of plod1, plod2, and plod3 was upregulated in the lungs of mouse pups exposed to 85% O2, an experimental animal model of BPD. Transforming growth factor (TGF)-β increased plod2 mRNA levels and activated the plod2 promoter in vitro in lung epithelial cells and in lung fibroblasts. Using in vivo neutralization of TGF-β signaling in the experimental animal model of BPD, TGF-β was identified as the regulator of aberrant plod2 expression. PLOD2 mRNA expression was also elevated in human neonates who died with BPD or at risk for BPD, compared with neonates matched for gestational age at birth or chronological age at death. These data point to potential roles for lysyl hydroxylases in normal lung development, as well as in perturbed late lung development associated with BPD. 10.1152/ajplung.00109.2013
    Transglutaminase 2: a new player in bronchopulmonary dysplasia? Witsch Thilo J,Niess Gero,Sakkas Elpidoforos,Likhoshvay Tatyana,Becker Simone,Herold Susanne,Mayer Konstantin,Vadász István,Roberts Jesse D,Seeger Werner,Morty Rory E The European respiratory journal Aberrant remodelling of the extracellular matrix in the developing lung may underlie arrested alveolarisation associated with bronchopulmonary dysplasia (BPD). Transglutaminases are regulators of extracellular matrix remodelling. Therefore, the expression and activity of transglutaminases were assessed in lungs from human neonates with BPD and in a rodent model of BPD. Transglutaminase expression and localisation were assessed by RT-PCR, immunoblotting, activity assay and immunohistochemical analyses of human and mouse lung tissues. Transglutaminase regulation by transforming growth factor (TGF)-β was investigated in lung cells by luciferase-based reporter assay and RT-PCR. TGF-β signalling was neutralised in vivo in an animal model of BPD, to determine whether TGF-β mediated the hyperoxia-induced changes in transglutaminase expression. Transglutaminase 2 expression was upregulated in the lungs of preterm infants with BPD and in the lungs of hyperoxia-exposed mouse pups, where lung development was arrested. Transglutaminase 2 localised to the developing alveolar septa. TGF-β was identified as a regulator of transglutaminase 2 expression in human and mouse lung epithelial cells. In vivo neutralisation of TGF-β signalling partially restored normal lung structure and normalised lung transglutaminase 2 mRNA expression. Our data point to a role for perturbed transglutaminase 2 activity in the arrested alveolarisation associated with BPD. 10.1183/09031936.00075713
    Expression of transforming growth factor beta (TGF-b1) by human preterm lung inflammatory cells. Kwong K Y,Niang S,Literat A,Zhu N L,Ramanathan R,Jones C A,Minoo P Life sciences Using a previously published model of human BPD this study examines whether preterm lung inflammatory cells produce transforming growth factor beta 1 (TGF-beta1), a cytokine pivotal in pathogenesis of bronchopulmonary dysplasia (BPD), and whether TGF-beta1 expression is regulated by inflammation. Lung inflammatory cells (neutrophils and macrophages) recovered in the broncho-alveolar (BAL) fluid of premature infants intubated for respiratory distress after birth expressed TGF-b1 mRNA and protein. Total and bioactive TGF-beta1 were abundantly found in the BAL fluid of the same infants. In cell culture stimulation by lipopolysaccharide (LPS) did not result in any further expression of total or bioactive TGF-beta1 by neonatal lung inflammatory cells over constitutive concentrations. In conclusion, lung inflammatory cells from premature infants are a source of TGF-beta1 but LPS does not regulate TGF-b1 production in these cells. 10.1016/j.lfs.2006.07.040
    Circulating Fibrocytes Are Increased in Neonates with Bronchopulmonary Dysplasia. Li Chun,Li Xiaoyu,Deng Chun,Guo Chunbao PloS one BACKGROUND:Bronchopulmonary dysplasia (BPD) is characterized by the aberrant remodeling of the lung parenchyma, resulting from accumulation of fibroblasts or myofibroblasts. Circulating fibrocytes are implied in pulmonary fibrosis, but whether these cells are associated with the development of BPD or the progressive fibrosis is unknown. The aim of the present study was to investigate the occurrence of fibrocytes in peripheral venous blood and explore whether these cells might be associated with severity of BPD. METHODS:We investigated circulating fibrocytes in 66 patients with BPD, 23 patients with acute respiratory distress syndrome(ARDS) and 11 normal subjects. Circulating fibrocytes were defined and quantified as cells positive for CD45 andcollagen-1 by flow cytometry. Furthermore, serum SDF-1/CXCL12 and TGF-β1 were evaluated using ELISA methods. We also investigated the clinical value of fibrocyte counts by comparison with standard clinical parameters. RESULTS:The patients with BPD had significantly increased numbers of fibrocytes compared to the controls (p < 0.01). Patients with ARDS were not different from healthy control subjects. There was a correlation between the number of fibrocytes and pulmonary hypertension or oxygen saturation (p < 0.05). Fibrocyte numbers were not correlated with other clinical or functional variables or radiologic severity scores. The fibrocyte attractant chemokine CXCL12 increased in plasma (p < 0.05) and was detectable in the bronchoalveolar lavage fluid of 40% of the patients but not in controls. CONCLUSION:These findings indicate that circulating fibrocytes are increased in patients with BPD and may contribute to pulmonary fibrosis in BPD. Circulating fibrocytes, likely recruited through the CXCR4/CXCL12 axis, might contribute to the production of TGF-β1 for the expansion of fibroblast/myofibroblast population in BPD. 10.1371/journal.pone.0157181
    Hyperoxia-induced neonatal rat lung injury involves activation of TGF-{beta} and Wnt signaling and is protected by rosiglitazone. Dasgupta Chiranjib,Sakurai Reiko,Wang Ying,Guo Pinzheng,Ambalavanan Namasivayam,Torday John S,Rehan Virender K American journal of physiology. Lung cellular and molecular physiology Despite tremendous technological and therapeutic advances, bronchopulmonary dysplasia (BPD) remains a leading cause of respiratory morbidity in very low birth weight infants, and there are no effective preventive and/or therapeutic options. We have previously reported that hyperoxia-induced neonatal rat lung injury might be prevented by rosiglitazone (RGZ). Here, we characterize 1) perturbations in wingless/Int (Wnt) and transforming growth factor (TGF)-beta signaling, and 2) structural aberrations in lung morphology following 7-day continuous in vivo hyperoxia exposure to neonatal rats. We also tested whether treatment of neonatal pups with RGZ, concomitant to hyperoxia, could prevent such aberrations. Our study revealed that hyperoxia caused significant upregulation of Wnt signaling protein markers lymphoid enhancer factor 1 (Lef-1) and beta-catenin and TGF-beta pathway transducers phosphorylated Smad3 and Smad7 proteins in whole rat lung extracts. These changes were also accompanied by upregulation of myogenic marker proteins alpha-smooth muscle actin (alpha-SMA) and calponin but significant downregulation of the lipogenic marker peroxisome proliferator-activated receptor-gamma (PPARgamma) expression. These molecular perturbations were associated with reduction in alveolar septal thickness, radial alveolar count, and larger alveoli in the hyperoxia-exposed lung. These hyperoxia-induced molecular and morphological changes were prevented by systemic administration of RGZ, with lung sections appearing near normal. This is the first evidence that in vivo hyperoxia induces activation of both Wnt and TGF-beta signal transduction pathways in lung and of its near complete prevention by RGZ. Hyperoxia-induced arrest in alveolar development, a hallmark of BPD, along with these molecular changes strongly implicates these proteins in hyperoxia-induced lung injury. Administration of PPARgamma agonists may thus be a potential strategy to attenuate hyperoxia-induced lung injury and subsequent BPD. 10.1152/ajplung.90392.2008
    Montelukast improves bronchopulmonary dysplasia by inhibiting epithelial‑mesenchymal transition via inactivating the TGF‑β1/Smads signaling pathway. Chen Xin,Peng Wansheng,Zhou Rui,Zhang Zhen,Xu Jiali Molecular medicine reports The present study investigated the role of montelukast (MK) during the progression of bronchopulmonary dysplasia (BPD) and the underlying mechanism of action. A rat model of BPD was induced by hyperoxia and subsequently, the rats were treated with 10 mg/kg MK. On day 14 post‑hyperoxia induction, lung function was assessed by detecting the mean linear intercept (MLI; the average alveolar diameter), the radial alveolar count (RAC; alveolar septation and alveologenesis) and the lung weight/body weight (LW/BW) ratio. Type II alveolar epithelial (AEC II) cells were isolated from normal rats to investigate the mechanism underlying the effect of MK on BPD in vitro. Western blotting and reverse transcription‑quantitative PCR were performed to measure the expression levels of surfactant protein C (SP‑C), E‑cadherin, N‑cadherin, Vimentin, collagen I (Col I), matrix metallopeptidase (MMP)1/3, transforming growth factor (TGF)‑β1 and Smad3. MK significantly reduced the MLI and the LW/BW ratio, and increased the RAC of the BPD group compared with the control group. MK upregulated the expression of SP‑C and E‑cadherin, and downregulated the expression levels of N‑cadherin and Vimentin in the lung tissues of the rat model of BPD, as well as in TGF‑β1‑ and hyperoxia‑induced AEC II cells. In addition, MK reduced the expression of Col I, MMP1, MMP3, TGF‑β1 and Smad3 in the lung tissues of the rat model of BPD, as well as in TGF‑β1‑ and hyperoxia‑induced AEC II cells. The present study demonstrated that MK improved BPD by inhibiting epithelial‑mesenchymal transition via inactivating the TGF‑β1/Smads signaling pathway. 10.3892/mmr.2020.11306
    Histologic Chorioamnionitis, Amniotic Fluid Interleukin 6, Krebs von den Lungen 6, and Transforming Growth Factor β for the Development of Neonatal Bronchopulmonary Dysplasia. Matsumura Hisako,Ichiba Hiroyuki,Ohnishi Satoshi,Saito Mika,Shintaku Haruo Japanese clinical medicine BACKGROUND:Chorioamnionitis (CAM) is an important risk factor for the development of bronchopulmonary dysplasia (BPD) in preterm infants. OBJECTIVES:To evaluate the effects of CAM on the development of BPD using interleukin 6 (IL-6), Krebs von den Lungen 6 (KL-6), and transforming growth factor β (TGF-β) in the amniotic fluid as markers for inflammation, lung injury, and fibrosis/remodeling, respectively. METHODS:Amniotic fluid concentrations of IL-6, KL-6, and TGF-β were measured with enzyme-linked immunosorbent assay or electro-chemiluminescence immunoassay. RESULTS:Of the 36 preterm infants, 18 were exposed to histologically confirmed CAM. Of these, 12 were later diagnosed as having BPD. The IL-6, KL-6, and TGF-β levels in the amniotic fluid significantly increased with increasing histologic severity of CAM. Moreover, these markers were higher in the BPD group with histologic CAM than those without. CONCLUSIONS:Our study suggests that CAM is likely to induce inflammatory, injury, and remodeling processes in the fetal lung. 10.1177/1179066017696076
    Hyperoxia modulates TGF-beta/BMP signaling in a mouse model of bronchopulmonary dysplasia. Alejandre-Alcázar Miguel A,Kwapiszewska Grazyna,Reiss Irwin,Amarie Oana V,Marsh Leigh M,Sevilla-Pérez Julia,Wygrecka Malgorzata,Eul Bastian,Köbrich Silke,Hesse Mareike,Schermuly Ralph T,Seeger Werner,Eickelberg Oliver,Morty Rory E American journal of physiology. Lung cellular and molecular physiology Prematurely born infants who require oxygen therapy often develop bronchopulmonary dysplasia (BPD), a debilitating disorder characterized by pronounced alveolar hypoplasia. Hyperoxic injury is believed to disrupt critical signaling pathways that direct lung development, causing BPD. We investigated the effects of normobaric hyperoxia on transforming growth factor (TGF)-beta and bone morphogenetic protein (BMP) signaling in neonatal C57BL/6J mice exposed to 21% or 85% O(2) between postnatal days P1 and P28. Growth and respiratory compliance were significantly impaired in pups exposed to 85% O(2), and these pups also exhibited a pronounced arrest of alveolarization, accompanied by dysregulated expression and localization of both receptor (ALK-1, ALK-3, ALK-6, and the TGF-beta type II receptor) and Smad (Smads 1, 3, and 4) proteins. TGF-beta signaling was potentiated, whereas BMP signaling was impaired both in the lungs of pups exposed to 85% O(2) as well as in MLE-12 mouse lung epithelial cells and NIH/3T3 and primary lung fibroblasts cultured in 85% O(2). After exposure to 85% O(2), primary alveolar type II cells were more susceptible to TGF-beta-induced apoptosis, whereas primary pulmonary artery smooth muscle cells were unaffected. Exposure of primary lung fibroblasts to 85% O(2) significantly enhanced the TGF-beta-stimulated production of the alpha(1) subunit of type I collagen (Ialpha(1)), tissue inhibitor of metalloproteinase-1, tropoelastin, and tenascin-C. These data demonstrated that hyperoxia significantly affects TGF-beta/BMP signaling in the lung, including processes central to septation and, hence, alveolarization. The amenability of these pathways to genetic and pharmacological manipulation may provide alternative avenues for the management of BPD. 10.1152/ajplung.00050.2006
    Antenatal inflammation induced TGF-beta1 but suppressed CTGF in preterm lungs. Kunzmann Steffen,Speer Christian P,Jobe Alan H,Kramer Boris W American journal of physiology. Lung cellular and molecular physiology Chorioamnionitis is frequently associated with preterm birth and increases the risk of adverse outcomes such as bronchopulmonary dysplasia (BPD). Transforming growth factor (TGF)-beta1 is a key regulator of lung development, airway remodeling, lung fibrosis, and regulation of inflammation, and all these processes contribute to the development of BPD. Connective tissue growth factor (CTGF) is a downstream mediator of some of the profibrotic effects of TGF-beta1, vascular remodeling, and angiogenesis. TGF-beta1-induced CTGF expression can be blocked by TNF-alpha. We asked whether chorioamnionitis-associated antenatal inflammation would regulate TGF-beta1, the TGF-beta1 signaling pathway, and CTGF in preterm lamb lungs. Fetal sheep were exposed to 4 mg of intra-amniotic endotoxin or saline for 5 h, 24 h, 72 h, or 7 days before preterm delivery at 125 days gestation (full term = 150 days). Intra-amniotic endotoxin increased lung TGF-beta1 mRNA and protein expression. Elevated TGF-beta1 levels were associated with TGF-beta1-induced phosphorylation of Smad2. CTGF was selectively expressed in lung endothelial cells in control lungs, and intra-amniotic endotoxin caused CTGF expression to decrease to 30% of control values and TNF-alpha protein to increase. The antenatal inflammation-induced TGF-beta1 expression and Smad signaling in the fetal lamb lung may contribute to impaired lung alveolarization and reduced lung inflammation. Decreased CTGF expression may inhibit vascular development or remodeling and limit lung fibrosis during remodeling. These effects may contribute to the impaired alveolar and pulmonary vascular development that is the hallmark of the new form of BPD. 10.1152/ajplung.00159.2006
    TGF-beta-neutralizing antibodies improve pulmonary alveologenesis and vasculogenesis in the injured newborn lung. Nakanishi Hidehiko,Sugiura Takahiro,Streisand James B,Lonning Scott M,Roberts Jesse D American journal of physiology. Lung cellular and molecular physiology Pulmonary injury is associated with the disruption of alveologenesis in the developing lung and causes bronchopulmonary dysplasia (BPD) in prematurely born infants. Transforming growth factor (TGF)-beta is an important regulator of cellular differentiation and early lung development, and its levels are increased in newborn lung injury. Although overexpression of TGF-beta in the lungs of newborn animals causes pathological features that are consistent with BPD, the role of endogenous TGF-beta in the inhibition of the terminal stage of lung development is incompletely understood. In this investigation, the hypothesis that O(2)-induced injury of the maturing lung is associated with TGF-beta-mediated disruption of alveologenesis and microvascular development was tested using a murine model of BPD. Here we report that treatment of developing mouse lungs with TGF-beta-neutralizing antibodies attenuates the increase in pulmonary cell phospho-Smad2 nuclear localization, which is indicative of augmented TGF-beta signaling, associated with pulmonary injury induced by chronic inhalation of 85% oxygen. Importantly, the neutralization of the abnormal TGF-beta activity improves quantitative morphometric indicators of alveologenesis, extracellular matrix assembly, and microvascular development in the injured developing lung. Furthermore, exposure to anti-TGF-beta antibodies is associated with improved somatic growth in hyperoxic mouse pups and not with an increase in pulmonary inflammation. These studies indicate that excessive pulmonary TGF-beta signaling in the injured newborn lung has an important role in the disruption of the terminal stage of lung development. In addition, they suggest that anti-TGF-beta antibodies may be an effective therapy for preventing some important developmental diseases of the newborn lung. 10.1152/ajplung.00389.2006
    Insights into the expression profiles and functions of circRNAs in a newborn hyperoxia-induced rat bronchopulmonary dysplasia model. Cheng Hanrong,Wu Benqing,Wang Lingwei,Hu Tianyong,Deng Zhuhui,Li Dongcai The journal of gene medicine BACKGROUND:Bronchopulmonary dysplasia (BPD) is a severe chronic lung disease in preterm infants. Circular RNAs (circRNAs) are key regulators of various biological processes. The present study aimed to explore the biological roles of circRNAs in BPD pathogenesis. METHODS:A newborn BPD rat model was developed to construct a circRNA library; Illumina deep sequencing (Illumina, San Diego, CA, USA) was used to reveal differential expression of circRNAs in the hyperoxia-induced BPD rat models. Sanger sequencing and a reverse transcription-polymerase chain reaction were performed to confirm circRNAs that may be related to BPD. After miRNA binding-site prediction, we constructed a network diagram of circRNA-competing endogenous RNAs (ceRNAs) related to transforming growth factor (TGF)-β and p53 pathways using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. RESULTS:In total, 256 differentially expressed circRNAs were detected between the hyperoxia group and the normoxia group. Of these circRNAs, 195 were up-regulated and 61 were down-regulated. The differences of circRNA distribution between the two groups were analyzed and six circRNAs were validated in the tissue samples. GO analysis indicated that 6519 target genes were enriched in cell location and biological processes. KEGG pathway enrichment analysis showed that circRNAs involved in 242 KEGG pathways. A network diagram of circRNA-ceRNA related to TGF-β and p53 pathways was constructed. CONCLUSIONS:CircRNAs are differentially expressed between the BPD model and control group. Many target genes of circRNAs are involved in the developmental process, which suggests that BPD may be associated with pathways including extracellular matrix-receptor interaction, vascular endothelial growth factor signaling and vascular smooth muscle contraction. 10.1002/jgm.3163
    Association of serum angiogenic factors with bronchopulmonary dysplasia. The ANGIODYS cohort study. Torchin Héloïse,Combarel David,Aubelle Marie-Stéphanie,Lopez Clémence,Dubray Lauréline,El Ayoubi Mayass,Tsatsaris Vassilis,Jarreau Pierre-Henri,Guibourdenche Jean,Zana-Taïeb Elodie Pregnancy hypertension OBJECTIVES:Angiogenic factors may be involved in lung development. To evaluate the relations between maternal and cord blood angiogenic factors (sFlt-1, placental growth factor [PlGF], soluble endogline [sEng], transforming growth factor β [TGF-beta]) and their association with moderate and severe bronchopulmonary dysplasia (BPD) in very preterm growth-restricted infants. STUDY DESIGN:Prospective monocentric cohort study. Twenty-four mother-child dyads featuring antepartum preeclampsia, intra-uterine growth restriction (IUGR) and birth before 30 weeks' gestation were included. This ensured a 80% power to test whether sFlt-1 maternal levels would be twice as high in cases of BPD as in the absence of BPD. MAIN OUTCOME MEASURES:Four pro/anti-angiogenic factors from two pathways (sFlt-1, PlGF and sEng, TGF-beta) were measured in maternal serum before delivery (at the time of hospitalization or the day of birth) and in neonates' cord blood. Neonatal outcome was moderate to severe BPD, defined as oxygen requirement for at least 28 days and persistent need for oxygen or ventilatory support at 36 weeks' postmenstrual age. RESULTS:sFlt-1 levels were positively correlated in maternal serum and cord blood (r = 0.83, p < .001) but levels of PlGF and TGF-beta and its receptor sEng were not. Among all the factors studied in cord and maternal blood, none was associated with BPD. CONCLUSIONS:In IUGR preterm babies born before 30 weeks' gestation from preeclamptic mothers, serum sFlt-1, PlGF and sEng, TGF-β levels were not correlated with BPD. The increased BPD risk in preterm neonates born from preeclamptic mothers cannot be related to high sFlt-1 levels. 10.1016/j.preghy.2019.09.015
    Curcumin augments lung maturation, preventing neonatal lung injury by inhibiting TGF-β signaling. Sakurai Reiko,Li Yishi,Torday John S,Rehan Virender K American journal of physiology. Lung cellular and molecular physiology There is no effective intervention to prevent or treat bronchopulmonary dysplasia (BPD). Curcumin has potent antioxidant and anti-inflammatory properties, and it modulates signaling of peroxisome proliferator-activated receptor-γ (PPARγ), an important molecule in the pathobiology of BPD. However, its role in the prevention of BPD is not known. We determined 1) if curcumin enhances neonatal lung maturation, 2) if curcumin protects against hyperoxia-induced neonatal lung injury, and 3) if this protection is mediated by blocking TGF-β. Embryonic day 19 fetal rat lung fibroblasts were exposed to 21% or 95% O(2) for 24 h following 1 h of treatment with curcumin. Curcumin dose dependently accelerated e19 fibroblast differentiation [increased parathyroid hormone-related protein (PTHrP) receptor, PPARγ, and adipocyte differentiation-related protein (ADRP) levels and triolein uptake] and proliferation (increased thymidine incorporation). Pretreatment with curcumin blocked the hyperoxia-induced decrease (PPARγ and ADRP) and increase (α-smooth muscle actin and fibronectin) in markers of lung injury/repair, as well as the activation of TGF-β signaling. In a separate set of experiments, neonatal Sprague-Dawley rat pups were exposed to 21% or 95% O(2) for 7 days with or without intraperitoneal administration of curcumin. Analysis for markers of lung injury/repair [PTHrP receptor, PPARγ, ADRP, fibronectin, TGF-β receptor (activin receptor-like kinase 5), and Smad3] and lung morphology (radial alveolar count) demonstrated that curcumin effectively blocks TGF-β activation and hyperoxia-induced lung injury. Therefore, curcumin accelerates lung maturation by stimulating key alveolar epithelial-mesenchymal interactions and prevents hyperoxia-induced neonatal lung injury, possibly by blocking TGF-β activation, suggesting that it is a potential intervention against BPD. 10.1152/ajplung.00076.2011
    Interleukin-1β Promotes Epithelial-Derived Alveolar Elastogenesis via αvβ6 Integrin-Dependent TGF-β Activation. Wang Jiarong,Bao Lei,Yu Benli,Liu Zhaoyun,Han Wenli,Deng Chun,Guo Chunbao Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology BACKGROUND/AIMS:IL-1β creates persistent pulmonary inflammation accompanied by elevated transforming growth factor β (TGF-β levels and is associated with abnormal elastogenesis, which is observed in bronchopulmonary dysplasia (BPD). Although progress has been made in this field, the mechanisms underlying this process remain only partially understood. METHODS:We assessed aberrant elastin localization-associated signaling in mouse pups exposed to 85% O2 treated with either IL-1Ra or 1D11, using morphometric analyses, quantitative RT-PCR, immunostaining, and ELISA. We also evaluated the derivation of elastin-producing cells using dual marker tracking. The regulatory mechanisms of IL-1β were investigated in vitro in lung epithelial and mesenchymal cells. RESULTS:Elevated levels of IL-1β, αvβ6 and TGF-β1 were each associated with aberrant elastin production in O2-exposed lungs. IL-1Ra abolished TGF-β1 activation and αvβ6 upregulation, which occurred as a result of exposure to hyperoxia, whereas 1D11 had no discernible effect on the expression of either αvβ6 or IL-1β even following O2-exposure, suggesting that IL-1β was initially induced. Additionally, double staining revealed the presence of epithelium-derived elastin-producing cells, which was confirmed via in vitro IL-1β stress-induced epithelial-mesenchymal transformation (EMT) morphological and molecular marker changes, which may explain the altered lung elastin deposition and defective septation observed in BPD. CONCLUSIONS:These data support the hypothesis that IL-1β was initially induced by hyperoxia; αvβ6 subsequently interacted with and activated TGF-β1, acting as an epithelial/mesenchymal signaling molecule that contributed to excessive alveolar elastogenesis, the primary pathological feature of BPD. 10.1159/000430185
    Antenatal glucocorticoids counteract LPS changes in TGF-β pathway and caveolin-1 in ovine fetal lung. Collins Jennifer J P,Kunzmann Steffen,Kuypers Elke,Kemp Matthew W,Speer Christian P,Newnham John P,Kallapur Suhas G,Jobe Alan H,Kramer Boris W American journal of physiology. Lung cellular and molecular physiology Inflammation and antenatal glucocorticoids, the latter given to mothers at risk for preterm birth, affect lung development and may contribute to the development of bronchopulmonary dysplasia (BPD). The effects of the combined exposures on inflammation and antenatal glucocorticoids on transforming growth factor (TGF)-β signaling are unknown. TGF-β and its downstream mediators are implicated in the etiology of BPD. Therefore, we asked whether glucocorticoids altered intra-amniotic lipopolysaccharide (LPS) effects on TGF-β expression, its signaling molecule phosphorylated sma and mothers against decapentaplegic homolog 2 (pSmad2), and the downstream mediators connective tissue growth factor (CTGF) and caveolin-1 (Cav-1). Ovine singleton fetuses were randomized to receive either an intra-amniotic injection of LPS and/or maternal betamethasone (BTM) intramuscularly 7 and/or 14 days before delivery at 120 days gestational age (GA; term = 150 days GA). Saline was used for controls. Protein levels of TGF-β1 and -β2 were measured by ELISA. Smad2 phosphorylation was assessed by immunohistochemistry and Western blot. CTGF and Cav-1 mRNA and protein levels were determined by RT-PCR and Western blot. Free TGF-β1 and -β2 and total TGF-β1 levels were unchanged after LPS and/or BTM exposure, although total TGF-β2 increased in animals exposed to BTM 7 days before LPS. pSmad2 immunostaining increased 7 days after LPS exposure although pSmad2 protein expression did not increase. Similarly, CTGF mRNA and protein levels increased 7 days after LPS exposure as Cav-1 mRNA and protein levels decreased. BTM exposure before LPS prevented CTGF induction and Cav-1 downregulation. This study demonstrated that the intrauterine inflammation-induced TGF-β signaling can be inhibited by antenatal glucocorticoids in fetal lungs. 10.1152/ajplung.00251.2012
    Failure to Down-Regulate Expression in Early Postnatal Mouse Lung Epithelium Suppresses Alveologenesis, with Changes in Tgf-β Signaling Similar to those Induced by Exposure to Hyperoxia. Chao Cho-Ming,Carraro Gianni,Rako Zvonimir A,Kolck Johannes,Sedighi Jamschid,Zimmermann Volker,Moiseenko Alena,Wilhelm Jochen,Young Brittany M,Chong Lei,Wu Jin,Contreras Adriana,Minoo Parviz,Barreto Guillermo,Warburton David,Bellusci Saverio Cells BACKGROUND:Bronchopulmonary dysplasia (BPD) is a lung disease of preterm born infants, characterized by alveolar simplification. MicroRNA ( are known to be involved in many biological and pathological processes in the lung. Although a changed expression has been described for several in BPD, a causal role remains to be established. RESULTS:Our results showed that the expression level of increases during lung development and decreases postnatally. Further, hyperoxia treatment maintains high levels of in alveolar type 2 cells (AT2). We hypothesized that the decrease in expression in AT2 cells is required for normal alveologenesis. To test this hypothesis, we generated a novel transgenic mouse allowing doxycycline-based overexpression. Maintenance of expression in the postnatal distal lung epithelium under normoxia conditions is sufficient to reproduce the hypoalveologenesis phenotype triggered by hyperoxia. Using a pull-down assay, we identified as a key downstream target of . Caveolin1 protein is downregulated in response to overexpression of . This is associated with increased phosphorylation of Smad3 and Tgf-ß signaling. We found that AT2 cells overexpressing display decreased expression of AT2 markers and increased expression of AT1 markers. CONCLUSION:Our results suggest that down-regulation of in postnatal lung may function as an important physiological switch that permits the induction of the correct alveolar developmental program, while conversely, failure to down-regulate suppresses alveolarization, leading to the common clinically observed phenotype of alveolar simplification. 10.3390/cells9040859
    Mesenchymal stem cells in combination with erythropoietin repair hyperoxia-induced alveoli dysplasia injury in neonatal mice via inhibition of TGF-β1 signaling. Luan Yun,Zhang Luan,Chao Sun,Liu Xiaoli,Li Kaili,Wang Yibiao,Zhang Zhaohua Oncotarget The aim of the present study is to investigate the protection effects of bone marrow mesenchymal stem cells (MSCs) in combination with EPO against hyperoxia-induced bronchopulmonary dysplasia (BPD) injury in neonatal mice. BPD model was prepared by continuous high oxygen exposure, 1×106 bone marrow MSCs and 5000U/kg recombinant human erythropoietin (EPO) were injected respectively. Results showed that administration of MSCs, EPO especially MSCs+EPO significant attenuated hyperoxia-induced lung damage with a decrease of fibrosis, radical alveolar counts and inhibition of the occurrence of epithelial-mesenchymal transition (EMT). Furthermore, MSCs+EPO co-treatment more significantly suppressed the levels of transforming growth factor-β1(TGF-β1) than MSCs or EPO alone. Collectively, these results suggested that MSCs, EPO in particular MSCs+EPO co-treatment could promote lung repair in hyperoxia-induced alveoli dysplasia injury via inhibition of TGF-β1 signaling pathway to further suppress EMT process and may be a promising therapeutic strategy. 10.18632/oncotarget.9314
    Caffeine and rolipram affect Smad signalling and TGF-β1 stimulated CTGF and transgelin expression in lung epithelial cells. Fehrholz Markus,Speer Christian P,Kunzmann Steffen PloS one Caffeine administration is an important part of the therapeutic treatment of bronchopulmonary dysplasia (BPD) in preterm infants. However, caffeine mediated effects on airway remodelling are still undefined. The TGF-β/Smad signalling pathway is one of the key pathways involved in airway remodelling. Connective tissue growth factor (CTGF), a downstream mediator of TGF-β, and transgelin, a binding and stabilising protein of the cytoskeleton, are both regulated by TGF-β1 and play an important role in airway remodelling. Both have also been implicated in the pathogenesis of BPD. The aim of the present study was to clarify whether caffeine, an unspecific phosphodiesterase (PDE) inhibitor, and rolipram, a prototypical PDE-4 selective inhibitor, were both able to affect TGF-β1-induced Smad signalling and CTGF/transgelin expression in lung epithelial cells. Furthermore, the effect of transgelin knock-down on Smad signalling was studied. The pharmacological effect of caffeine and rolipram on Smad signalling was investigated by means of a luciferase assay via transfection of a TGF-β1-inducible reporter plasmid in A549 cells. The regulation of CTGF and transgelin expression by caffeine and rolipram were studied by promoter analysis, real-time PCR and Western blot. Endogenous transgelin expression was down-regulated by lentiviral transduction mediating transgelin-specific shRNA expression. The addition of caffeine and rolipram inhibited TGF-β1 induced reporter gene activity in a concentration-related manner. They also antagonized the TGF-β1 induced up-regulation of CTGF and transgelin on the promoter-, the mRNA-, and the protein-level. Functional analysis showed that transgelin silencing reduced TGF-β1 induced Smad-signalling and CTGF induction in lung epithelial cells. The present study highlights possible new molecular mechanisms of caffeine and rolipram including an inhibition of Smad signalling and of TGF-β1 regulated genes involved in airway remodelling. An understanding of these mechanisms might help to explain the protective effects of caffeine in prevention of BPD and suggests rolipram to be a potent replacement for caffeine. 10.1371/journal.pone.0097357
    Lipopolysaccharide induces up-regulation of TGF-α through HDAC2 in a rat model of bronchopulmonary dysplasia. Ni Wensi,Lin Ning,He Hua,Zhu Jianxing,Zhang Yongjun PloS one Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification with decreased alveolar number and increased airspace. Previous studies suggested that transforming growth factor-α (TGF-α) may contribute to arrested alveolar development in BPD. Histone deacetylases (HDACs) control cellular signaling and gene expression. HDAC2 is crucial for suppression of inflammatory gene expression. Here we investigated whether HDAC2 was involved in the arrest of alveolarization, as well as the ability of HDAC2 to regulate TGF-α expression in a rat model of BPD induced by intra-amniotic injection of lipopolysaccharide (LPS). Results showed that LPS exposure led to a suppression of both HDAC1 and HDAC2 expression and activity, induced TGF-α expression, and disrupted alveolar morphology. Mechanistic studies showed that overexpression of HDAC2, but not HDAC1, suppressed LPS-induced TGF-α expression. Moreover, the HDAC inhibitor TSA or downregulation of HDAC2 by siRNA both significantly increased TGF-α expression in cultured myofibroblasts. Finally, preservation of HDAC activity by theophylline treatment improved alveolar development and attenuated TGF-α release. Together, these findings indicate that attenuation of TGF-α-mediated effects in the lung by enhancing HDAC2 may have a therapeutic effect on treating BPD. 10.1371/journal.pone.0091083
    Potent anti-inflammatory effect of a novel furan-2,5-dione derivative, BPD, mediated by dual suppression of COX-2 activity and LPS-induced inflammatory gene expression via NF-κB inactivation. Shin Ji-Sun,Park Seung-Jae,Ryu Suran,Kang Han Byul,Kim Tae Woo,Choi Jung-Hye,Lee Jae-Yeol,Cho Young-Wuk,Lee Kyung-Tae British journal of pharmacology BACKGROUND AND PURPOSE:We previously reported that 3-(benzo[d]-1,3-dioxol-5-yl)-4-phenylfuran-2,5-dione (BPD) showed strong inhibitory effects on PGE(2) production. However, the exact mechanism for the anti-inflammatory effect of BPD is not completely understood. In this study, we investigated the molecular mechanism involved in the effects of BPD on inflammatory mediators in LPS-stimulated macrophages and animal models of inflammation. EXPERIMENTAL APPROACH:The expressions of COX-2, inducible NOS (iNOS), TNF-α, IL-6 and IL-1β, in LPS-stimulated RAW 264.7 cells and murine peritoneal macrophages, were determined by Western blot and/or qRT-PCR, respectively. NF-κB activation was investigated by EMSA, reporter gene assay and Western blotting. Anti-inflammatory effects of BPD were evaluated in vivo in carrageenan-induced paw oedema in rats and LPS-induced septic shock in mice. KEY RESULTS:BPD not only inhibited COX-2 activity but also reduced the expression of COX-2. In addition, BPD inhibited the expression of iNOS, TNF-α, IL-6 and IL-1β at the transcriptional level. BPD attenuated LPS-induced DNA-binding activity and the transcription activity of NF-κB; this was associated with a decrease in the phosphorylation level of inhibitory κB-α (IκB-α) and reduced nuclear translocation of NF-κB. Furthermore, BPD suppressed the formation of TGF-β-activated kinase-1 (TAK1)/TAK-binding protein1 (TAB1), which was accompanied by a parallel reduction of phosphorylation of TAK1 and IκB kinase (IKK). Pretreatment with BPD inhibited carrageenan-induced paw oedema and LPS-induced septic death. CONCLUSION AND IMPLICATIONS:Taken together, our data indicate that BPD is involved in the dual inhibition of COX-2 activity and TAK1-NF-κB pathway, providing a molecular basis for the anti-inflammatory properties of BPD. 10.1111/j.1476-5381.2011.01670.x
    Bronchopulmonary Dysplasia: Crosstalk Between PPARγ, WNT/β-Catenin and TGF-β Pathways; The Potential Therapeutic Role of PPARγ Agonists. Lecarpentier Yves,Gourrier Elizabeth,Gobert Vincent,Vallée Alexandre Frontiers in pediatrics Bronchopulmonary dysplasia (BPD) is a serious pulmonary disease which occurs in preterm infants. Mortality remains high due to a lack of effective treatment, despite significant progress in neonatal resuscitation. In BPD, a persistently high level of canonical WNT/β-catenin pathway activity at the canalicular stage disturbs the pulmonary maturation at the saccular and alveolar stages. The excessive thickness of the alveolar wall impairs the normal diffusion of oxygen and carbon dioxide, leading to hypoxia. Transforming growth factor (TGF-β) up-regulates canonical WNT signaling and inhibits the peroxysome proliferator activated receptor gamma (PPARγ). This profile is observed in BPD, especially in animal models. Following a premature birth, hypoxia activates the canonical WNT/TGF-β axis at the expense of PPARγ. This gives rise to the differentiation of fibroblasts into myofibroblasts, which can lead to pulmonary fibrosis that impairs the respiratory function after birth, during childhood and even adulthood. Potential therapeutic treatment could target the inhibition of the canonical WNT/TGF-β pathway and the stimulation of PPARγ activity, in particular by the administration of nebulized PPARγ agonists. 10.3389/fped.2019.00176
    Alteration of TGF-β-ALK-Smad signaling in hyperoxia-induced bronchopulmonary dysplasia model of newborn rats. Jin Meihua,Lee Juyoung,Lee Kyung-Yup,Jin Zhengyong,Pak Jhang Ho,Kim Han-Suk Experimental lung research BACKGROUND:Bronchopulmonary dysplasia (BPD) is a main chronic lung disease commonly occurs in preterm infants. BPD is characterized by impaired alveolarization and vascularization of the developing lung. Transforming growth factor-β (TGF-β) signaling pathway is known to play an important role during lung vascular development. In the present study, we examined whether the regulation of TGF-β-ALK-Smad signaling pathway influence on the disruption of pulmonary vascular development in newborn rats as hyperoxia-induced BPD model. MATERIALS AND METHODS:Newborn rats were continuously exposed to 21% or 85% O2 for 7 days, and subsequently kept in normoxic condition for another 14 days. Lung tissues harvested at each time point were evaluated for the expression of TGF-β1, ALK1, ALK5, phosphorylated Smad1/5, phosphorylated Smad2/3, VEGF, and endoglin, as accessed by both biochemical and immunohistological analyses. RESULTS:Double-fluorescence immunohistochemical staining indicated these molecules were mainly expressed in pulmonary endothelial cells. The expression of TGF-β1 and ALK5 mRNA and protein were significantly increased in D5 hyperoxia group, while that of ALK1 mRNA and protein were significantly decreased. The level of phosphorylated Smad1/5 was significantly decreased in D7 hyperoxia group, whereas that of phosphorylated Smad2/3 was oppositely increased. In addition, the expression of vascular endothelial growth factor (VEGF) mRNA was increased at D1 with subsequent decrease in D7 hyperoxia group. There was no significantly difference in endoglin expression in entire experimental period. CONCLUSION:These results indicate that exposure to hyperoxia altered the balance between TGF-β-ALK1-Smad1/5 and TGF-β-ALK5-Smad2/3 pathways in pulmonary endothelial cells, which may ultimately lead to the development of BPD. 10.1080/01902148.2016.1226448
    Caffeine administration modulates TGF-β signaling but does not attenuate blunted alveolarization in a hyperoxia-based mouse model of bronchopulmonary dysplasia. Rath Philipp,Nardiello Claudio,Surate Solaligue David E,Agius Ronald,Mižíková Ivana,Hühn Sebastian,Mayer Konstantin,Vadász István,Herold Susanne,Runkel Frank,Seeger Werner,Morty Rory E Pediatric research BACKGROUND:Caffeine is widely used to manage apnea of prematurity, and reduces the incidence of bronchopulmonary dysplasia (BPD). Deregulated transforming growth factor (TGF)-β signaling underlies arrested postnatal lung maturation in BPD. It is unclear whether caffeine impacts TGF-β signaling or postnatal lung development in affected lungs. METHODS:The impact of caffeine on TGF-β signaling in primary mouse lung fibroblasts and alveolar epithelial type II cells was assessed in vitro. The effects of caffeine administration (25 mg/kg/d for the first 14 d of postnatal life) on aberrant lung development and TGF-β signaling in vivo was assessed in a hyperoxia (85% O)-based model of BPD in C57BL/6 mice. RESULTS:Caffeine downregulated expression of type I and type III TGF-β receptors, and Smad2; and potentiated TGF-β signaling in vitro. In vivo, caffeine administration normalized body mass under hyperoxic conditions, and normalized Smad2 phosphorylation detected in lung homogenates; however, caffeine administration neither improved nor worsened lung structure in hyperoxia-exposed mice, in which postnatal lung maturation was blunted. CONCLUSION:Caffeine modulated TGF-β signaling in vitro and in vivo. Caffeine administration was well-tolerated by newborn mice, but did not influence the course of blunted postnatal lung maturation in a hyperoxia-based experimental mouse model of BPD. 10.1038/pr.2017.21
    [Expression of TGF-β1 and PAI-1 in premature infants with bronchopulmonary dysplasia]. Zhang Jin-Feng,Hunag Run-Zhong,Huang Guan-Fen,Ou Wei-Ming,Li Jian-Feng,Chen Jin-Jin Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics OBJECTIVE:To study the expression of transforming growth factor-β1 (TGF-β1) and plasminogen activator inhibitor-1 (PAI-1) and its significance in premature infants with bronchopulmonary dysplasia (BPD). METHODS:A retrospective analysis was performed on the clinical data of 96 very low birth weight infants (gestational age of ≤ 32 weeks) who survived for more than 28 days and were admitted to the Neonatal Intensive Care Unit between January 2010 and December 2012. These subjects were divided into BPD group (n=21) and non-BPD group (n=75). The expression of TGF-β1 and PAI-1 in blood was measured by ELISA. RESULTS:The levels of TGF-β1 and PAI-1 in the BPD group increased gradually from the 7th day to the 14th day and then to the 21st day after birth, and were significantly higher than in the non-BPD group at all time points (P<0.01). The TGF-β1 and PAI-1 levels in the non-BPD group on the 7th, 14th, and 21st days after birth were not significantly different from each other (P>0.05). CONCLUSIONS:The expression of TGF-β1 and PAI-1 in blood is elevated in premature infants with BPD, which may be associated with the development of BPD.
    Lipoxin A Attenuates Bronchopulmonary Dysplasia via Upregulation of Let-7c and Downregulation of TGF-β Signaling Pathway. Chen Xiao-Qing,Wu Sheng-Hua,Luo Yan-Yan,Li Bing-Jie,Li Shu-Jun,Lu Hong-Yan,Jin Rui,Sun Zhong-Yi Inflammation Transforming growth factor-β (TGF-β) superfamily members are key regulators for lung development and progress of bronchopulmonary dysplasia (BPD). The mechanisms by which lipoxin A (LXA) attenuates development of BPD have not been clarified. Neonatal murine BPD models were inducted by hyperoxia treatment. Neonatal mice were exposed to room air or 85% O hyperoxia with or without treatment with 5S,6R-methyl-LXA or anti-TGF-β antibodies. Mouse lung epithelial cells (MLE-12 cells) and mouse embryonic fibroblasts (NIH/3T3 cells) were cultured in room air or 85% O followed by treatment of LXA, anti-TGF-β antibodies, and let-7c mimic/anti-microRNA transfections. Treatment with 5S,6R-methyl-LXA and anti-TGF-β antibodies both attenuated the mice alveolar simplification induced by hyperoxia. Hyperoxia treatment significantly altered pulmonary basal mRNA and protein expressions of several important extracellular matrix (ECM) and ECM remodeling proteins including fibronectin, α-smooth muscle actin (α-SMA), tissue inhibitor of metalloproteinase-1 (TIMP-1), elastin, tenascin C, collagen I, and matrix metalloproteinase-1 (MMP-1). 5S,6R-methyl-LXA and anti-TGF-β antibodies suppressed the mRNA and protein expressions of TGF-β and TGF-βR1 but not TGF-βR2 in the lungs exposed to hyperoxia. Treatment with LXA and anti-TGF-β antibodies alleviated hyperoxia-induced injury of the NIH/3T3 cells identified by morphologic observation and flow cytometry, and expressions of ECM, ECM remodeling proteins, and TGF-β signaling pathway, but reversed by transfection with let-7c anti-miRNA. LXA upregulated the let-7c expression in MLE-12 cells, transfection with let-7c anti-miRNA, inhibited the LXA-induced let-7c expression in MLE-12 cells exposed to hyperoxia and reduced the relative luciferase activity of let-7c binding with let-7c binding sites of the TGF-βR1 3' UTR. Treatment with 5S,6R-methyl-LXA and anti-TGF-β antibodies significantly improved histology, ECM, and ECM remodeling proteins in the lungs isolated from the murine BPD model induced by hyperoxia. The LXA-imparted protective effects on hyperoxia-induced lung injury are mediated by upregulation of let-7c and inhibition of TGF-β and subsequent downregulation of TGF-β signaling pathway. 10.1007/s10753-017-0649-7
    Effect of progesterone on Smad signaling and TGF-β/Smad-regulated genes in lung epithelial cells. Kunzmann Steffen,Ottensmeier Barbara,Speer Christian P,Fehrholz Markus PloS one The effect of endogenous progesterone and/or exogenous pre- or postnatal progesterone application on lung function of preterm infants is poorly defined. While prenatal progesterone substitution may prevent preterm birth, in vitro and in vivo data suggest a benefit of postnatal progesterone replacement on the incidence and severity of bronchopulmonary dysplasia (BPD). However, the molecular mechanisms responsible for progesterone's effects are undefined. Numerous factors are involved in lung development, airway inflammation, and airway remodeling: the transforming growth factor beta (TGF-β)/mothers against decapentaplegic homolog (Smad) signaling pathway and TGF-β-regulated genes, such as connective tissue growth factor (CTGF), transgelin (TAGLN), and plasminogen activator inhibitor-1 (PAI-1). These processes contribute to the development of BPD. The aim of the present study was to clarify whether progesterone could affect TGF-β1-activated Smad signaling and CTGF/transgelin/PAI-1 expression in lung epithelial cells. The pharmacological effect of progesterone on Smad signaling was investigated using a TGF-β1-inducible luciferase reporter and western blotting analysis of phosphorylated Smad2/3 in A549 lung epithelial cells. The regulation of CTGF, transgelin, and PAI-1 expression by progesterone was studied using a promoter-based luciferase reporter, quantitative real-time PCR, and western blotting in the same cell line. While progesterone alone had no direct effect on Smad signaling in lung epithelial cells, it dose-dependently inhibited TGF-β1-induced Smad3 phosphorylation, as shown by luciferase assays and western blotting analysis. Progesterone also antagonized the TGF-β1/Smad-induced upregulation of CTGF, transgelin, and PAI-1 at the promoter, mRNA, and/or protein levels. The present study highlights possible new molecular mechanisms involving progesterone, including inhibition of TGF-β1-activated Smad signaling and TGF-β1-regulated genes involved in BPD pathogenesis, which are likely to attenuate the development of BPD by inhibiting TGF-β1-mediated airway remodeling. Understanding these mechanisms might help to explain the effects of pre- or postnatal application of progesterone on lung diseases of preterm infants. 10.1371/journal.pone.0200661
    Spatial and temporal expression of SP-B and TGF-β1 in hyperoxia-induced neonatal rat lung injury. Liu Dongyun,Liu Yingzi,Dou Liping,Sun Mengya,Jiang Hong,Yi Mingji International journal of clinical and experimental pathology OBJECTIVE:Bronchopulmonary dysplasia (BPD) is a severe complication of extreme prematurity that can be caused by hyperoxia inhalation. SP-B and TGF-β have been reported to be implicated in the development of lung. This study aimed to reveal the spatial and temporal expression patterns of these two factors in an animal model of BPD. METHODS:Newborn Sprague-Dawley (SD) rats were subjected to hyperoxia conditions to establish an animal model of BPD. The levels of SP-B, TGF-β, MDA and TAOC, as well as the activations of MAPK and PI3K/AKT pathways in lung tissues were monitored during newborn rats prolonged exposure to hyperoxia. RESULTS:We found that hyperoxia exposure significantly induced body weight loss of SD rats. H&E staining for morphometric analyses revealed that hyperoxia arrested alveolar development or loss of alveoli, with fewer and dysmorphic capillaries. mRNA and protein levels of SP-B and TGF-β were high expressed in hyperoxic lung tissues. The concentrations of SP-B and TGF-β in bronchoalveolar lavage fluid were also increased. All these increases begin at the 3th day of hyperoxia exposure. MDA content was increased while TAOC content was decreased in response to hyperoxia. Furthermore, hyperoxia activated p38, and deactivated PI3K and AKT expression. CONCLUSION:Our research demonstrated that SP-B and TGF-β1 were highly expressed in three levels: mRNA and protein levels in lung tissues, and the release of SP-B and TGF-β1 in bronchoalveolar lavage fluid, beginning at the 3th day of hyperoxia exposure.
    The BPD trio? Interaction of dysregulated PDGF, VEGF, and TGF signaling in neonatal chronic lung disease. Oak Prajakta,Hilgendorff Anne Molecular and cellular pediatrics The development of neonatal chronic lung disease (nCLD), i.e., bronchopulmonary dysplasia (BPD) in preterm infants, significantly determines long-term outcome in this patient population. Risk factors include mechanical ventilation and oxygen toxicity impacting on the immature lung resulting in impaired alveolarization and vascularization. Disease development is characterized by inflammation, extracellular matrix remodeling, and apoptosis, closely intertwined with the dysregulation of growth factor signaling. This review focuses on the causes and consequences of altered signaling in central pathways like transforming growth factor (TGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) driving these above indicated processes, i.e., inflammation, matrix remodeling, and vascular development. We emphasize the shared and distinct role of these pathways as well as their interconnection in disease initiation and progression, generating important knowledge for the development of future treatment strategies. 10.1186/s40348-017-0076-8
    Mesenchymal stromal cells and TGF-β1 in tracheal aspirate of premature infants: early predictors for bronchopulmonary dysplasia? Aly Hany,Mansi Yasmeen,Ez El Din Zahraa,Gabr Metwally Hala,Sabry Amira Journal of perinatal medicine Background The pathogenesis of bronchopulmonary dysplasia (BPD) includes arrest of alveolar septation and enhanced fibrosis. We hypothesized that mesenchymal stromal cells (MSC) and transforming growth factor-β1 (TGF-β1) in tracheal aspirates of mechanically ventilated premature infants differ in BPD and non-BPD infants. Methods Tracheal aspirates were collected during the first week of life. Mononuclear cells were separated, cultured and immunophenotyped by flow cytometry. MSCs colony/cluster ratio was calculated as an index for dysplastic potentials. TGF-β1 was assessed by enzyme-linked immunosorbent assay (ELISA). Setting: Neonatal intensive care unit. Patients Premature infants at risk for BPD. Results A total of 121 preterm infants were enrolled; 27 of them died and among the 94 survivors 23 infants had BPD. MSCs were identified in younger [gestational age (GA): 30.9±1.7 vs. 31.8±1.8, P=0.025] and smaller [birth weight (BW): 1.3±0.28 vs. 1.44±0.37 kg, P=0.04] infants with lower Apgar scores. The recovery rate of MSCs in BPD and non-BPD groups did not differ. BPD group had significantly smaller colony/cluster ratio compared to non-BPD (0.97 vs. 4.25, P=0.002). TGF-β1 was significantly greater in BPD infants (4173.9±864.3 vs. 3705.8±540.5 pg/mL, P=0.021). Conclusion Infants with BPD had different MSCs morphology and greater TGF-β1 expression. The pathogenesis for these morphological changes of resident lung MSCs needs further studying. 10.1515/jpm-2018-0305
    Postnatal serum insulin-like growth factor I deficiency is associated with retinopathy of prematurity and other complications of premature birth. Hellström Ann,Engström Eva,Hård Anna-Lena,Albertsson-Wikland Kerstin,Carlsson Björn,Niklasson Aimon,Löfqvist Chatarina,Svensson Elisabeth,Holm Sture,Ewald Uwe,Holmström Gerd,Smith Lois E H Pediatrics OBJECTIVE:Insulin-like growth factor I (IGF-I) is necessary for normal development of retinal blood vessels in mice and humans. Because retinopathy of prematurity (ROP) is initiated by abnormal postnatal retinal development, we hypothesized that prolonged low IGF-I in premature infants might be a risk factor for ROP. DESIGN:We conducted a prospective, longitudinal study measuring serum IGF-I concentrations weekly in 84 premature infants from birth (postmenstrual ages: 24-32 weeks) until discharge from the hospital. Infants were evaluated for ROP and other morbidity of prematurity: bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC). RESULTS:Low serum IGF-I values correlated with later development of ROP. The mean IGF-I +/- SEM level during postmenstrual ages 30-33 weeks was lowest with severe ROP (25 +/- 2.41 micro g/L), 29 +/- 1.76 micro g/L with moderate ROP, and 33 +/- 1.72 micro g/L with no ROP. The duration of low IGF-I also correlated strongly with the severity of ROP. The interval from birth until serum IGF-I levels reached >33 micro g/L was 23 +/- 2.6 days for no ROP, 44 +/- 4.8 days for moderate ROP, and 52 +/- 7.5 days for severe ROP. Each adjusted stepwise increase of 5 micro g/L in mean IGF-I during postmenstrual ages 30 to 33 weeks decreased the risk of proliferative ROP by 45%. Other complications (NEC, BPD, IVH) were correlated with ROP and with low IGF-I levels. The relative risk for any morbidity (ROP, BPD, IVH, or NEC) was increased 2.2-fold (95% confidence interval: 1.41-3.43) if IGF-I was <or=33 micro g/L at 33 weeks' postmenstrual age. CONCLUSIONS:These results indicate that persistent low serum concentrations of IGF-I after premature birth are associated with later development of ROP and other complications of prematurity. IGF-I is at least as strong a determinant of risk for ROP as postmenstrual age at birth and birth weight. 10.1542/peds.112.5.1016
    [Effects of recombinant human insulin-like growth factor-1 on the expression of Clara cell secretory protein in lung of hyperoxia-exposed newborn rats]. Jin Zhen-ai,Jin Zheng-yong,Chi Yong-xue,Lu Ji-rong Zhonghua er ke za zhi = Chinese journal of pediatrics OBJECTIVE:The development of neonatology and the availability of pulmonary surfactant have been helpful in effective reduction of the mortality of very low birth weight infants at the expense of an increasing number of survivors with bronchopulmonary dysplasia (BPD) caused by lung immaturity. BPD is a common syndrome in newborns, especially in preterm infants, when treated with hyperoxia and mechanical ventilation. Unfortunately, there have been no effective measure for the prevention and treatment of BPD. The purpose of this study was to investigate the influence of recombinant human insulin-like growth factor-1 (rh-IGF-1) on cell apoptosis and Clara cell secretory protein (CCSP) expression during the lung injury induced by hyperoxia, so as to assess its effect on the inflammatory lung injury and its developmental repair. METHODS:Eighty full term neonatal Wistar rats under the same condition were divided randomly into four groups on the second day after birth. Group I was air control, group II was exposed to hyperoxia, group III air + rh-IGF-1, and group IV was treated with hyperoxia + rh-IGF-1. The pups in the control group were kept in room air, while pups in hyperoxia group were kept in a Plexiglas chamber and exposed to over 85% oxygen. Pups in group III were under the same raising condition except for exposure to room air and treated with intraperitoneal injection of rh-IGF-1 (1 microg/Kg) everyday from the third day. Pups in group IV were treated with intraperitoneal injection of rh-IGF-1 (1 microg/Kg) everyday from the third day of exposure to hyperoxia. Lung tissue sections of the neonatal rats were stained with hematoxylin and eosin (HE) after 7 d of hyperoxia exposure, expression of CCSP was examined by immunohistochemical method, and apoptotic cell index of lung tissue was calculated by using TUNEL method. RESULTS:It was observed from immunohistochemical examination that positive staining of CCSP was distributed mainly in distal and respiratory bronchioles. The percentage of Clara cells in distal and respiratory bronchioles epithelium decreased in hyperoxia group (32.17 +/- 3.19)% compared to that in air control group (68.32 +/- 2.04)%, P < 0.01. Statistically significant differences were found in intensity of positiveness of Clara cells between hyperoxia (29.45 +/- 5.56) and air control group (42.37 +/- 3.24), P < 0.01. TUNEL assay showed that most apoptotic cells were alveolar and bronchial epithelial cells. The apoptotic index increased significantly in the hyperoxia group (55.77 +/- 6.09)% compared to the air control group (16.41 +/- 4.01)%, (P < 0.01). The positive rate (52.98 +/- 2.68)% of Clara cells and the expression (41.22 +/- 6.36) of CCSP in hyperoxia + rh-IGF-1 group increased significantly when compared with hyperoxia group, and the differences between these two group were also statistically significant (P < 0.01). The apoptotic index increased significantly in the hyperoxia + rh-IGF-1 group (27.98 +/- 3.09)% compared to the hyperoxia group (P < 0.01). CONCLUSIONS:Hyperoxia exposure can promote the pneumocyte apoptosis and inhibit the expression of CCSP. Rh-IGF-1 can remove the block of the formation of lung alveoli, increase the secretion of CCSP, mitigate inflammatory responses in airway and alleviate lung injury via pneumocyte apoptosis. Therefore, the results of this study provide a theoretic and experimental evidence for clinical application of rh-IGF-1 in prevention and treatment of BPD.
    rhIGF-1/BP3 Preserves Lung Growth and Prevents Pulmonary Hypertension in Experimental Bronchopulmonary Dysplasia. Seedorf Gregory,Kim Christina,Wallace Bradley,Mandell Erica W,Nowlin Taylor,Shepherd Douglas,Abman Steven H American journal of respiratory and critical care medicine Antenatal factors, such as chorioamnionitis, preeclampsia, and postnatal injury, are associated with an increased risk for bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) after preterm birth. IGF-1 (insulin-like growth factor-1) is markedly decreased in normal preterm infants, but whether IGF-1 treatment can prevent BPD or PH is unknown. To evaluate whether postnatal treatment with rhIGF-1 (recombinant human IGF-1)/BP3 (binding peptide 3) improves lung growth and prevents PH in two antenatal models of BPD induced by intraamniotic exposure to endotoxin (ETX) or sFlt-1 (soluble fms-like tyrosine kinase 1), and in a postnatal model due to prolonged hyperoxia. ETX or sFlt-1 were administered into the amniotic sac of pregnant rats at Embryonic Day 20 to simulate antenatal models of chorioamnionitis and preeclampsia, respectively. Pups were delivered by cesarean section at Embryonic Day 22 and treated with rhIGF-1/BP3 (0.02-20 mg/kg/d intraperitoneal) or buffer for 2 weeks. Study endpoints included radial alveolar counts (RACs), vessel density, and right ventricular hypertrophy (RVH). Direct effects of rhIGF-1/BP3 (250 ng/ml) on fetal lung endothelial cell proliferation and tube formation and alveolar type 2 cell proliferation were studied by standard methods . Antenatal ETX and antenatal sFlt-1 reduced RAC and decreased RVH in infant rats. In both models, postnatal rhIGF-1/BP3 treatment restored RAC and RVH to normal values when compared with placebo injections. rhIGF-1/BP3 treatment also preserved lung structure and prevented RVH after postnatal hyperoxia. studies showed that rhIGF-1/BP3 treatment increased lung endothelial cell and alveolar type 2 cell proliferation. Postnatal rhIGF-1/BP3 treatment preserved lung structure and prevented RVH in antenatal and postnatal BPD models. rhIGF-1/BP3 treatment may provide a novel strategy for the prevention of BPD in preterm infants. 10.1164/rccm.201910-1975OC
    Epithelial lining fluid free IGF-I-to-PAPP-A ratio is associated with bronchopulmonary dysplasia in preterm infants. Capoluongo Ettore,Ameglio Franco,Lulli Paola,Minucci Angelo,Santonocito Concetta,Concolino Paola,Di Stasio Enrico,Boccacci Simona,Vendettuoli Valentina,Giuratrabocchetta Giuseppe,De Cunto Angela,Tana Milena,Romagnoli Costantino,Zuppi Cecilia,Vento Giovanni American journal of physiology. Endocrinology and metabolism Preterm newborns developing retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD) show persistently low levels of insulin-like growth factor-I (IGF-I) in sera. They also present higher free IGF-I concentrations in epithelial lining fluids (ELFs) and lung tissues. Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase that dissociates three binding proteins from the active form of IGF-I, namely free IGF-I. The present study analyzes the ELF concentrations of free IGF-I, PAPP-A, and their ratios in preterm newborns developing or not BPD, defined as O(2) dependence at 36 wk postmenstrual age. Bronchoalveolar lavage fluids of 41 infants (34 without and 7 with BPD) were analyzed on the 2nd and 4th day after birth. Infants developing BPD showed increased ELF free IGF-I and decreased PAPP-A concentrations on both days 2 and 4 compared with newborns without BPD. A nonsignificant trend between these 2 days was observed for free IGF-I (increasing) and PAPP-A (decreasing). On the same days, the free IGF-I-to-PAPP-A ratio was always significantly higher in patients developing BPD. These differences were more significant than those of IGF-I or PAPP-A when individually evaluated. A multivariate analysis confirmed the significance for free IGF-I on day 4, whereas the ratio was confirmed on both days 2 and 4. The same ratio was significantly correlated with some indexes of disease severity, such as hours of oxygen administration, days of hospitalization, and ROP severity scores. Finally, the ratio between ELF free IGF-I and PAPP-A appears to be a useful marker for lung injury of premature newborns. 10.1152/ajpendo.00251.2006
    Insulin-like growth factor-1 (IGF-1) and IGF-1 receptor (IGF-1R) expression in human lung in RDS and BPD. Chetty Anne,Andersson Sture,Lassus Patrik,Nielsen Heber C Pediatric pulmonology We hypothesize that IGF-1 and IGF-1R proteins are upregulated in lung epithelia and fibroblasts in RDS compared to normal development, and are further upregulated in BPD. We used immunohistochemistry to evaluate IGF-1 and IGF-R expression in lungs from autopsies of human stillbirths and RDS and BPD patients. IGF-1 and IGF-R immunostaining were present in fetal, RDS, and BPD lungs. In RDS, IGF-1 was present in alveolar epithelium and prominent in columnar and cuboidal airway epithelia. In BPD lungs, immunostaining was intensely increased in both airway and alveolar epithelia and in mesenchyme. The immunostaining index in bronchial epithelial cells and peribronchial myofibroblasts was significantly higher in BPD compared to RDS. IGF-1R expression was minimal in fetal lung and found mainly in mesenchyme. IGF-1R was increased in mesenchyme in RDS. In BPD it was especially increased in peribronchial and perialveolar mesenchyme. Immunostaining index for IGF-1R in epithelial cells and peribronchial myofibroblasts was increased in BPD compared to RDS. IGF-1 and IGF-R expression is low during fetal development, but is acutely upregulated in RDS, and persists with further upregulation in BPD. 10.1002/ppul.10415
    Low serum IGF-1 and increased cytokine levels in tracheal aspirate samples are associated with bronchopulmonary dysplasia. Yılmaz Cansu,Köksal Nilgün,Özkan Hilal,Dorum Bayram Ali,Bağcı Onur The Turkish journal of pediatrics Yılmaz C, Köksal N, Özkan H, Dorum BA, Bağcı O. Low serum IGF-1 and increased cytokine levels in tracheal aspirate samples are associated with bronchopulmonary dysplasia. Turk J Pediatr 2017; 59: 122-129. Despite developments in the perinatal and neonatal care, bronchopulmonary dysplasia (BPD) is still the most frequently seen long-term complication in preterm infants. The aim of this prospective study is to investigate the association between the development of BPD and serial measurements of IGF-1 levels and their relationship with levels of IGF-1 and cytokine in tracheal aspirate fluids. A total of 40 premature infants, born at a gestational age of ≤ 32 weeks, were enrolled in the study. On postnatal day-1, 3, 7, 21 and 28 serum IGF-1 levels and IGF-1 levels, IL-6, IL-8, IL-10 and TNF-alpha levels in tracheal aspirate fluid samples of intubated cases were examined. Mean gestational age of 40 patients included in the study was 29.41 ± 2.23 weeks, and their mean birth weight was 1,256.85 ± 311.48 g. BPD was detected in 35% of cases. Mean gestational week and birth weight of the cases that developed BPD were 30 ± 3 weeks and 1,150 ± 295 g, respectively. Serum IGF-1 levels on postnatal day-1, 3, 7, 21 and 28 in cases who developed BPD were significantly lower when compared with those without BPD (p < 0.01). Levels of IL-6, IL-8, IL-10, and TNF-alpha in tracheal aspirate samples were significantly higher in cases with BPD compared to those without BPD (p < 0.05). IGF-1 levels in tracheal aspirate fluid samples did not differ significantly based on the presence of BPD (p > 0.05). Severity of BPD was associated with decreased serum IGF-1 levels and increased cytokine levels in tracheal aspirate samples. 10.24953/turkjped.2017.02.003
    Low postnatal serum IGF-I levels are associated with bronchopulmonary dysplasia (BPD). Löfqvist Chatarina,Hellgren Gunnel,Niklasson Aimon,Engström Eva,Ley David,Hansen-Pupp Ingrid, Acta paediatrica (Oslo, Norway : 1992) AIM:To characterize postnatal changes in serum insulin-like growth factor-1 (IGF-I) in relation to development of bronchopulmonary dysplasia (BPD) in very preterm infants. METHODS:Longitudinal study of 108 infants with mean (SD) gestational age (GA) 27.2 (2.2) weeks. Weekly serum samples of IGF-I were analysed from birth until postmenstrual age (PMA) 36 weeks. Multivariate models were developed to identify independent predictors of BPD. RESULTS:Postnatal mean IGF-I levels at postnatal day (PND) 3-21 were lower in infants with BPD compared with infants with no BPD (16 vs. 26 μg/L, p < 0.001). Longitudinal postnatal change in IGF-I levels (IGF-I regression coefficient (β)), PNDs 3-21, was lower in infants with BPD compared with infants with no BPD (0.28 vs. 0.97, p = 0.002) and mean IGF-I during PMA 30-33 weeks was lower in infants with BPD as compared with infants without BPD (22 vs. 29 μg/L, p < 0.001). In a binomial multiple regression model, lower GA, male gender and lower mean serum IGF-I levels during PND 3-21 were the most predictive risk factors associated with BPD (r(2) = 0.634, p < 0.001). CONCLUSION:Lower IGF-I concentrations during the first weeks after very preterm birth are associated with later development of BPD. 10.1111/j.1651-2227.2012.02826.x