HMGB1/PI3K/Akt/mTOR Signaling Participates in the Pathological Process of Acute Lung Injury by Regulating the Maturation and Function of Dendritic Cells.
Li Ruiting,Zou Xiaojing,Huang Haiyan,Yu Yuan,Zhang Hongmei,Liu Pei,Pan Shangwen,Ouyang Yaqi,Shang You
Frontiers in immunology
High-mobility group box 1 protein (HMGB1) was identified as a highly conserved DNA binding nuclear protein, which participates in the processes of acute lung injury (ALI). HMGB1 binds to its specific receptors not only to activate the nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) pathways but also to regulate the activation of the phosphatidylinositol 3'-kinase/protein kinase B/mammalian target of the rapamycin (PI3K/AKT/mTOR) pathway. Mature dendritic cells (DCs) regulate acute lung inflammation and pathological injury in ALI. In addition, studies have shown that the activation of the PI3K/AKT/mTOR signaling pathway may regulate the function and maturation of DCs. Therefore, we speculate that HMGB1/PI3K/Akt/mTOR signaling participates in regulating the pathological process of ALI by regulating the maturation and function of DCs. Anti-HMGB1 antibody, rHMGB1, or LY294002 (PI3K inhibitor) was administered in a murine model of lipopolysaccharide (LPS)-induced ALI. For studies, generated bone marrow-derived dendritic cells (BMDCs) primed by LPS were stimulated with the same reagents. The effects of these different treatments were observed on the expression of PI3K, AKT, and mTOR and on the function of DCs. HMGB1 upregulated the expression of PI3K, Akt, and mTOR mRNA and phosphorylated proteins in BMDCs. The HMGB1/PI3K/Akt/mTOR signaling pathway induced the maturation and antigen-presenting ability of lung DCs, mediated the percentage of myeloid DCs (mDCs), and enhanced the adhesion and chemotactic ability of lung DCs. HMGB1/PI3K/Akt/mTOR signaling participates in the pathological process of ALI by regulating the maturation and functions of DCs.
The role of P2Y₁₂ receptor and activated platelets during inflammation.
Liverani Elisabetta,Kilpatrick Laurie E,Tsygankov Alexander Y,Kunapuli Satya P
Current drug targets
Platelets play an important role not only during thrombosis, but also in modulating immune responses through their interaction with immune cells and by releasing inflammatory mediators upon activation. The P2Y12 receptor is a Gi-coupled receptor that not only regulates ADP-induced aggregation but can also dramatically potentiate secretion, when platelets are activated by other stimuli. Considering the importance of P2Y12 receptor in platelet function, a class of antiplatelet drugs, thienopyridines, have been designed and successfully used to prevent thrombosis. This review will focus on the role of activated platelets in inflammation and the effects that P2Y12 antagonism exerts on the inflammatory process. A change in platelet functions was noted in patients treated with thienopyridines during inflammatory conditions, suggesting that platelets may modulate the inflammatory response. Further experiments in a variety of animal models of diseases, such as sepsis, rheumatoid arthritis, myocardial infarction, pancreatitis and pulmonary inflammation have also demonstrated that activated platelets influence the inflammatory state. Platelets can secrete inflammatory modulators in a P2Y12-dependent manner, and, as a result, directly alter the inflammatory response. P2Y12 receptor may also be expressed in other cells of the immune system, indicating that thienopyridines could directly influence the immune system rather than only through platelets. Overall the results obtained to date strongly support the notion that activated platelets significantly contribute to the inflammatory process and that antagonizing P2Y12 receptor can influence the immune response.
Annexin A1 Mimetic Peptide AC2-26 Inhibits Sepsis-induced Cardiomyocyte Apoptosis through LXA4/PI3K/AKT Signaling Pathway.
Zhang Li,Zheng Yan-Lei,Hu Rong-Hua,Zhu Li,Hu Chen-Chen,Cheng Fei,Li Shi,Li Jian-Guo
Current medical science
The aim of the present study was to explore the effects of annexin A1 (ANXA1) mimetic peptide AC2-26 on sepsis-induced cardiomyocyte apoptosis in vivo and in vitro and the underlying mechanisms. In the in vivo study, a rat septic model was established by the cecal ligation and puncture (CLP). The rats were divided into control group, sepsis group and AC2-26 group. The rats in the AC2-26 group were intraperitoneally injected with AC2-26 (1 mg/kg) 2 h before CLP, and those in the control group and sepsis group were injected with the same volume of normal saline. The myocardial tissue was examined by hematoxylin and eosin (HE) staining and transmission electron microscopy (TEM). Furthermore, myocardial apoptosis was measured by terminal dUTP nick end-labeling (TUNEL) assay. In the in vitro study, H9C2 cells were cultured and divided into three groups: control group, in which cells were only given the basic culture medium; LPS group, in which cells were treated with 10 μg/mL LPS; AC2-26 group, in which cells were treated with 0.5 μmol/L AC2-26 2 h before 10 μg/mL LPS was given. The apoptosis of H9C2 cells was detected by flow cytometry. The levels of lipoxin A4 receptor (LXA4), phosphoinositide-3-kinase (PI3K) and protein kinase B (PKB or AKT) protein were measured by Western blotting, the activity of NF-κB and the level of TNF-α by ELISA and the activities of caspase-3/8 by using the caspase activity kits. The in vivo study showed that the myocardial pathological damage and myocardial ultrastructural damage were significantly alleviated and the myocardial apoptosis significantly decreased in the AC2-26 group as compared with the sepsis group (P<0.05 for all). The in vivo study revealed that the apoptosis of H9C2 cells was profoundly ameliorated in the AC2-26 group relative to the sepsis group (P<0.05). The protein expression levels of LXA4 were significantly up-regulated, and those of PI3K and AKT prominently down-regulated in the AC2-26 group when compared with those in the LPS group (P<0.05 for all). The activity of NF-κB was greatly inhibited and the level of TNF-α markedly decreased in the AC2-26 group as compared with those in the LPS group (P<0.05 for all). AC2-26 treatment also significantly suppressed the activities of caspase-3/8 in H9C2 cells. In conclusion, these findings suggest that AC2-26 may alleviate the sepsis-induced cardiomyocyte apoptosis in vivo and in vivo through the LXA4/PI3K/AKT signaling pathway.
Sepsis causes heart injury through endoplasmic reticulum stress-mediated apoptosis signaling pathway.
Li Lei,Peng Xin,Guo Lichun,Zhao Yuhan,Cheng Qinghong
International journal of clinical and experimental pathology
Endoplasmic reticulum stress (ERS), arising from the loss of dynamic balance in endoplasmic reticulum function under stress and inflammation, has been implicated in the progression of sepsis. Multiple organ failure caused by sepsis still has a high mortality rate, of which the heart is one of the more damaged organs. In this research, a rat model of sepsis was set up by cecal ligation and puncture (CLP); serum myocardial enzyme levels were measured using an automated biochemical analyzer, inflammatory cytokine levels were measured by ELISA kit, and cardiac histology and cardiomyocyte apoptosis were measured by hematoxylin and eosin (H&E) staining and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay to assess the extent of myocardial damage. Western blot was used to detect expression of related proteins. The results showed that serum myocardial enzymes and pro-inflammatory factors were elevated in septic rats, and the increase was most significant in the CLP 24 h group. At the same time, the myocardium of septic rats had a histopathologic abnormality. After CLP, levels of endoplasmic reticulum stress related protein were upregulated. After 12 and 24 hours, the density of apoptotic cells in the myocardium of CLP-treated rats increased significantly, and the expression of apoptosis-related proteins changed significantly. This suggests that the unfolded protein response occurs during sepsis and causes damage to the heart muscle. Endoplasmic reticulum stress-mediated apoptotic signaling pathway is one of the causes of cardiac injury caused by sepsis, and may be a key to clinical prevention of cardiac dysfunction caused by sepsis.
Valproic acid attenuates sepsis-induced myocardial dysfunction in rats by accelerating autophagy through the PTEN/AKT/mTOR pathway.
Shi Xiaohui,Liu Yan,Zhang Daquan,Xiao Dong
AIMS:Sepsis is a leading cause of death and disability worldwide. Autophagy may play a protective role in sepsis-induced myocardial dysfunction (SIMD). The present study investigated whether valproic acid (VPA), a class I histone deacetylase (HDAC) inhibitor, can attenuate SIMD by accelerating autophagy. MAIN METHODS:A sepsis model was established via the cecum ligation and puncture of male Sprague-Dawley rats. Cardiac injuries were measured using serum markers, echocardiographic cardiac parameters, and hematoxylin and eosin staining. Cardiac mitochondria injuries were detected with transmission electron microscopy, adenosine triphosphate (ATP) and cardiac mitochondrial DNA (mtDNA) contents. Cardiac oxidative levels were measured using redox markers in the cardiac homogenate. Real-time polymerase chain reaction (RT-PCR) and Western blot were performed to detect the expression levels of relative genes and proteins. HDAC binding to the phosphatase and tensin homolog deleted on chromosome ten (PTEN) promoters and histone acetylation levels of the PTEN promoters were analyzed via chromatin immunoprecipitation and quantitative RT-PCR. KEY FINDINGS:VPA can ameliorate SIMD by enhancing the autophagy level of the myocardium to reduce mitochondrial damage, oxidative stress, and myocardial inflammation in septic rats. Moreover, this study demonstrated that VPA induces autophagy by inhibiting HDAC1- and HDAC3-mediated PTEN expression in the myocardial tissues of septic rats. SIGNIFICANCE:This study found that VPA attenuates SIMD through myocardial autophagy acceleration by increasing PTEN expression and inhibiting the AKT/mTOR pathway. These findings preliminarily suggest that VPA may be a potential approach for the intervention and treatment of SIMD.
Sodium tanshinone IIA sulfonate attenuates cardiac dysfunction and improves survival of rats with cecal ligation and puncture-induced sepsis.
Meng Zheng-Jie,Wang Chao,Meng Ling-Tong,Bao Bei-Hua,Wu Jin-Hui,Hu Yi-Qiao
Chinese journal of natural medicines
Cardiac dysfunction, a common consequence of sepsis, is the major contribution to morbidity and mortality in patients. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of Tanshinone IIA (TA), a main active component of Salvia miltiorrhiza Bunge, which has been widely used in China for the treatment of cardiovascular and cerebral system diseases. In the present study, the effect of STS on sepsis-induced cardiac dysfunction was investigated and its effect on survival rate of rats with sepsis was also evaluated. STS treatment could significantly decrease the serum levels of C-reactive protein (CRP), procalcitonin (PCT), cardiac troponin I (cTn-I), cardiac troponin T (cTn-T), and brain natriuretic peptide (BNP) in cecal ligation and puncture (CLP)-induced) septic rats and improve left ventricular function, particularly at 48 and 72 h after CLP. As the pathogenesis of septic myocardial dysfunction is attributable to dysregulated systemic inflammatory responses, several key cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10) and high mobility group protein B1 (HMGB1), were detected to reveal the possible mechanism of attenuation of septic myocardial dysfunction after being treated by STS. Our study showed that STS, especially at a high dose (15 mg·kg), could efficiently suppress inflammatory responses in myocardium and reduce myocardial necrosis through markedly reducing production of myocardial TNF-α, IL-6 and HMGB1. STS significantly improved the 18-day survival rate of rats with sepsis from 0% to 30% (P < 0.05). Therefore, STS could suppress inflammatory responses and improve left ventricular function in rats with sepsis, suggesting that it may be developed for the treatment of sepsis.
Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice.
Zhang Wen-Xuan,He Bai-Mei,Wu Ying,Qiao Jian-Feng,Peng Zhen-Yu
AIMS:The apoptosis and autophagy play an important role in the pathogenesis of sepsis-induced cardiac dysfunction. Previous studies have demonstrated that melatonin protects against cardiac dysfunction during sepsis. In addition, silent information regulator 1 (SIRT1) is a therapeutic target for sepsis-induced myocardial dysfunction. The aims of this study were to investigate whether SIRT1 was involved in melatonin's cardioprotection during sepsis and the mechanisms. MATERIALS AND METHODS:In this study, twenty-four male C57BL/6 mice were randomly assigned to four groups: Control group, LPS group, LPS + Melatonin group and LPS + Melatonin + EX527 group. Mice were treated with lipopolysaccharide for 8 h with or without melatonin or EX527. The cardiac function, myocardial injury biomarkers, cardiac histopathology, cardiomyocyte apoptosis, autophagosome as well as the protein expressions of SIRT1, cleaved caspase-3, LC3-II/LC3-I ratio and p62 in the myocardium were assayed. KEY FINDINGS:The results demonstrated that melatonin significantly improved cardiac function, decreased creatine kinase (CK) and creatine kinase-MB (CK-MB) levels, attenuated myocardial architecture destruction, inhibited cardiomyocyte apoptosis and increased cardiac autophagy as compared with the LPS group. In addition, melatonin significantly increased SIRT1 protein expression in the myocardium of mice with sepsis, while inhibition of SIRT1 by EX527 abolished melatonin's cardioprotection during sepsis. SIGNIFICANCE:In this study, we found that melatonin protected against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice.
PPARα augments heart function and cardiac fatty acid oxidation in early experimental polymicrobial sepsis.
Standage Stephen W,Bennion Brock G,Knowles Taft O,Ledee Dolena R,Portman Michael A,McGuire John K,Liles W Conrad,Olson Aaron K
American journal of physiology. Heart and circulatory physiology
Children with sepsis and multisystem organ failure have downregulated leukocyte gene expression of peroxisome proliferator-activated receptor-α (PPARα), a nuclear hormone receptor transcription factor that regulates inflammation and lipid metabolism. Mouse models of sepsis have likewise demonstrated that the absence of PPARα is associated with decreased survival and organ injury, specifically of the heart. Using a clinically relevant mouse model of early sepsis, we found that heart function increases in wild-type (WT) mice over the first 24 h of sepsis, but that mice lacking PPARα (Ppara) cannot sustain the elevated heart function necessary to compensate for sepsis pathophysiology. Left ventricular shortening fraction, measured 24 h after initiation of sepsis by echocardiography, was higher in WT mice than in Ppara mice. Ex vivo working heart studies demonstrated greater developed pressure, contractility, and aortic outflow in WT compared with Ppara mice. Furthermore, cardiac fatty acid oxidation was increased in WT but not in Ppara mice. Regulatory pathways controlling pyruvate incorporation into the citric acid cycle were inhibited by sepsis in both genotypes, but the regulatory state of enzymes controlling fatty acid oxidation appeared to be permissive in WT mice only. Mitochondrial ultrastructure was not altered in either genotype indicating that severe mitochondrial dysfunction is unlikely at this stage of sepsis. These data suggest that PPARα expression supports the hyperdynamic cardiac response early in the course of sepsis and that increased fatty acid oxidation may prevent morbidity and mortality. NEW & NOTEWORTHY:In contrast to previous studies in septic shock using experimental mouse models, we are the first to demonstrate that heart function increases early in sepsis with an associated augmentation of cardiac fatty acid oxidation. Absence of peroxisome proliferator-activated receptor-α (PPARα) results in reduced cardiac performance and fatty acid oxidation in sepsis.
Diminished responsiveness to dobutamine as an inotrope in mice with cecal ligation and puncture-induced sepsis: attribution to phosphodiesterase 4 upregulation.
Sakai Mari,Suzuki Tokiko,Tomita Kengo,Yamashita Shigeyuki,Palikhe Sailesh,Hattori Kohshi,Yoshimura Naoki,Matsuda Naoyuki,Hattori Yuichi
American journal of physiology. Heart and circulatory physiology
Dobutamine has been used in septic shock for many years as an only inotrope, but its benefit has been questioned. We weighed the effects of dobutamine and milrinone as inotropes in mice with cecal ligation and puncture (CLP)-induced polymicrobial sepsis. CLP-induced septic mice exhibited significant cardiac inflammation, as indicated by greatly increased mRNAs of proinflammatory cytokines and robust infiltration of inflammatory cells in the ventricular myocardium. Elevations of plasma cardiac troponin-I showed cardiac injury in CLP mice. Noninvasive echocardiographic assessment of cardiac function revealed that despite preserved left ventricular function in the presence of fluid replacement, the dobutamine inotropic response was significantly impaired in CLP mice compared with sham-operated controls. By contrast, milrinone exerted inotropic effects in sham-operated and CLP mice in an equally effective manner. Surface expression levels of β-adrenoceptors and α-subunits of three main G protein families in the myocardium were unaffected by CLP-induced sepsis. Plasma cAMP levels were significantly elevated in both sham-operated and CLP mice in response to milrinone but only in sham-operated controls in response to dobutamine. Of phosphodiesterase (PDE) isoforms, PDE4D, but not PDE3A, both of which are responsible for cardiac cAMP hydrolysis, was significantly upregulated in CLP mouse myocardium. We define a novel mechanism for the impaired responsiveness to dobutamine as an inotrope in sepsis, and understanding the role of PDE4D in modulating cardiac functional responsiveness in sepsis may open the potential of a PDE4D-targeted therapeutic option in septic patients with low cardiac output who have a need for inotropic support. Advisability of the usefulness of dobutamine in septic shock management is limited. Here, we reveal that the effect of dobutamine as a positive inotrope is impaired in mice with cecal ligation and puncture-induced sepsis without changes in cardiac β-adrenoceptor signaling as a result of cAMP breakdown achieved by upregulated phosphodiesterase 4D.
The down-regulation of cardiac contractile proteins underlies myocardial depression during sepsis and is mitigated by carbon monoxide.
Unuma Kana,Aki Toshihiko,Nagano Suguru,Watanabe Ryo,Uemura Koichi
Biochemical and biophysical research communications
The aim of this study is to investigate the mechanism underling cardiac dysfunction during sepsis, as well as the possible amelioration of this dysfunction by exogenous carbon monoxide (CO) administration. For this purpose, rats (six-week-old, male, Sprague-Dawley) were administered LPS (15 mg/kg body weight, i.p. 6 h) and/or CORM (30 mg/kg, i.p.). The decreased left ventricular ejection fraction (EF) observed in LPS group rats was recovered in the LSP + CORM group, confirming the protective role of CO against sepsis-induced myocardial depression. Proteomic as well as immunoblot analysis showed that the levels of myosin heavy and light chains (MHC and MLC) as well as α-cardiac actin (ACTC) were decreased in the LPS group, and these decreases were mitigated in the LSP + CORM group, suggesting that the amounts of major contractile proteins are decreased in depressed myocardium. Not only LPS-induced inflammatory cytokine (TNFα and IL-1β) production but also the decrease in myofilament proteins was mitigated by CORM. These results confirm the protective action of exogenously administered CO against myocardial depression during sepsis, and reveal a novel mechanism underling cardiac dysfunction during sepsis.
rhTNFR:Fc increases Nrf2 expression via miR-27a mediation to protect myocardium against sepsis injury.
Xue Wei-Liang,Bai Xiaoyan,Zhang Ling
Biochemical and biophysical research communications
OBJECTIVE:Sepsis is a whole-body inflammation disease and can result in septic shock and multiple organ failure. The previous study demonstrated that miR-27a plays a critical role in inflammation regulation. Here, we investigated that effect and its possible mechanism of rhTNFR:Fc on sepsis treatment. METHODS:LPS induced sepsis mice model was established. 10 mg/kg rhTNFR:Fc was used to treat sepsis mice by intravenous injection. RESULTS:RhTNFR:Fc improved cardiac function of sepsis mice, and markedly decreased miR-27a but increased Nrf2 expression level of myocardium in LPS treated mice. In H9C2 cells, rhTNFR:Fc also increased Nrf2 expression, elevated cell viability and decreased cell apoptosis. However, the effects were reversed by miR-27a mimic. In addition, miR-27a mimic reduced the activity of Nrf2 3'UTR while miR-27a inhibitor elevated enhanced its level. CONCLUSION:rhTNFR:Fc activated Nrf2 pathway to protect myocardium against LPS-induced sepsis injury via miR-27a regulation.
Resveratrol Protects the Myocardium in Sepsis by Activating the Phosphatidylinositol 3-Kinases (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) Pathway and Inhibiting the Nuclear Factor-κB (NF-κB) Signaling Pathway.
Shang Xiuling,Lin Kaiyang,Yu Rongguo,Zhu Pengli,Zhang Yingrui,Wang Ling,Xu Jingqing,Chen Kaihua
Medical science monitor : international medical journal of experimental and clinical research
BACKGROUND Sepsis combined with myocardial injury is an important cause of septic shock and multiple organ failure. However, the molecular mechanism of sepsis-induced myocardial dysfunction has not yet been thoroughly studied. Resveratrol has been an important research topic due its organ-protection function, but the specific mechanism is unclear. The purpose of this study was to explore the mechanism of organ injury in sepsis and to investigate the molecular mechanism of resveratrol in myocardial protection in sepsis. MATERIAL AND METHODS A classical Sprague-Dawley rat model of sepsis peritonitis was constructed for further experiments. The PI3K inhibitor LY294002 and resveratrol were used to intervene in a rat model of cardiomyopathy. HE staining was used to observe pathological changes. Cardiomyocyte apoptosis was detected by TUNEL assay. Western blot analysis was used to detect the level of maker proteins. RESULTS The PI3K inhibitors could promote cardiac abnormalities and apoptosis, but resveratrol showed the opposite effect. The upregulation function of the PI3K inhibitor on the expression of NF-kappaB, IL-6, IL-1ß, and TLR4 in LPS rats was not obvious, but the expression of TNF-a in LPS+LY294002 rats was increased by 22.85% compared with that in LPS rats (P<0.05). Compared with the LPS group, the expression of NF-kappaB, TNF-alpha, IL-6, IL-1ß, and TLR4 in the LPS+resveratrol group was decreased. The expression of p-PI3K, p-AKT, and p-mTOR in LPS+LY294002 was reduced. The expression p-PI3K, p-AKT, and p-mTOR in the myocardium of the LPS+resveratrol group was increased. CONCLUSIONS Resveratrol can protect the myocardium in sepsis by activating the PI3K/AKT/mTOR signaling pathway and inhibiting the NF-kappaB signaling pathway and related inflammatory factors.