Metabolomic fingerprinting and systemic inflammatory profiling of asthma COPD overlap (ACO).
Ghosh Nilanjana,Choudhury Priyanka,Kaushik Sandeep Rai,Arya Rakesh,Nanda Ranjan,Bhattacharyya Parthasarathi,Roychowdhury Sushmita,Banerjee Rintu,Chaudhury Koel
Respiratory research
BACKGROUND:Asthma-COPD overlap (ACO) refers to a group of poorly studied and characterised patients reporting with disease presentations of both asthma and COPD, thereby making both diagnosis and treatment challenging for the clinicians. They exhibit a higher burden in terms of both mortality and morbidity in comparison to patients with only asthma or COPD. The pathophysiology of the disease and its existence as a unique disease entity remains unclear. The present study aims to determine whether ACO has a distinct metabolic and immunological mediator profile in comparison to asthma and COPD. METHODS:Global metabolomic profiling using two different groups of patients [discovery (D) and validation (V)] were conducted. Serum samples obtained from moderate and severe asthma [n = 34(D); n = 32(V)], moderate and severe COPD [n = 30(D); 32(V)], ACO patients [n = 35(D); 40(V)] and healthy controls [n = 33(D)] were characterized using gas chromatography mass spectrometry (GC-MS). Multiplexed analysis of 25 immunological markers (IFN-γ (interferon gamma), TNF-α (tumor necrosis factor alpha), IL-12p70 (interleukin 12p70), IL-2, IL-4, IL-5, IL-13, IL-10, IL-1α, IL-1β, TGF-β (transforming growth factor), IL-6, IL-17E, IL-21, IL-23, eotaxin, GM-CSF (granulocyte macrophage-colony stimulating factor), IFN-α (interferon alpha), IL-18, NGAL (neutrophil gelatinase-associated lipocalin), periostin, TSLP (thymic stromal lymphopoietin), MCP-1 (monocyte chemoattractant protein- 1), YKL-40 (chitinase 3 like 1) and IL-8) was also performed in the discovery cohort. RESULTS:Eleven metabolites [serine, threonine, ethanolamine, glucose, cholesterol, 2-palmitoylglycerol, stearic acid, lactic acid, linoleic acid, D-mannose and succinic acid] were found to be significantly altered in ACO as compared with asthma and COPD. The levels and expression trends were successfully validated in a fresh cohort of subjects. Thirteen immunological mediators including TNFα, IL-1β, IL-17E, GM-CSF, IL-18, NGAL, IL-5, IL-10, MCP-1, YKL-40, IFN-γ, IL-6 and TGF-β showed distinct expression patterns in ACO. These markers and metabolites exhibited significant correlation with each other and also with lung function parameters. CONCLUSIONS:The energy metabolites, cholesterol and fatty acids correlated significantly with the immunological mediators, suggesting existence of a possible link between the inflammatory status of these patients and impaired metabolism. The present findings could be possibly extended to better define the ACO diagnostic criteria, management and tailoring therapies exclusively for the disease.
10.1186/s12931-020-01390-4
Dual action of neutrophil gelatinase-associated lipocalin.
Schmidt-Ott Kai M,Mori Kiyoshi,Li Jau Yi,Kalandadze Avtandil,Cohen David J,Devarajan Prasad,Barasch Jonathan
Journal of the American Society of Nephrology : JASN
Neutrophil gelatinase-associated lipocalin (NGAL) is expressed and secreted by immune cells, hepatocytes, and renal tubular cells in various pathologic states. NGAL exerts bacteriostatic effects, which are explained by its ability to capture and deplete siderophores, small iron-binding molecules that are synthesized by certain bacteria as a means of iron acquisition. Consistently, NGAL deficiency in genetically modified mice leads to an increased growth of bacteria. However, growing evidence suggests effects of the protein beyond fighting microorganisms. NGAL acts as a growth and differentiation factor in multiple cell types, including developing and mature renal epithelia, and some of this activity is enhanced in the presence of siderophore:iron complexes. This has led to the hypothesis that eukaryotes might synthesize siderophore-like molecules that bind NGAL. Accordingly, NGAL-mediated iron shuttling between the extracellular and intracellular spaces may explain some of the biologic activities of the protein. Interest in NGAL has been sparked by the observation that NGAL is massively upregulated after renal tubular injury and may participate in limiting kidney damage. This review summarizes the current knowledge about the dual effects of NGAL as a siderophore:iron-binding protein and as a growth factor and examines the role of these effects in renal injury.
10.1681/ASN.2006080882
Lipocalin 2: An Emerging Player in Iron Homeostasis and Inflammation.
Xiao Xia,Yeoh Beng San,Vijay-Kumar Matam
Annual review of nutrition
Lipocalin 2 (Lcn2), an innate immune protein, has emerged as a critical iron regulatory protein during physiological and inflammatory conditions. As a bacteriostatic factor, Lcn2 obstructs the siderophore iron-acquiring strategy of bacteria and thus inhibits bacterial growth. As part of host nutritional immunity, Lcn2 facilitates systemic, cellular, and mucosal hypoferremia during inflammation, in addition to stabilizing the siderophore-bound labile iron pool. In this review, we summarize recent advances in understanding the interaction between Lcn2 and iron, and its effects in various inflammatory diseases. Lcn2 exerts mostly a protective role in infectious and inflammatory bowel diseases, whereas both beneficial and detrimental functions have been documented in neurodegenerative diseases, metabolic syndrome, renal disorders, skin disorders, and cancer. Further animal and clinical studies are necessary to unveil the multifaceted roles of Lcn2 in iron dysregulation during inflammation and to explore its therapeutic potential for treating inflammatory diseases.
10.1146/annurev-nutr-071816-064559
The prevalence of undiagnosed renal failure in a cohort of COPD patients in western Norway.
Gjerde Bjarte,Bakke Per S,Ueland Thor,Hardie Jon A,Eagan Tomas M L
Respiratory medicine
Patients with COPD are at risk for other comorbid diseases, like heart failure, coronary heart disease, and depression. However, little is known about COPD phenotypes and prevalence of sub-clinical renal failure. 433 COPD patients and 233 subjects without COPD, from Western Norway, age 40-75, GOLD stage II-IV, were examined in 2006/07 upon entry to the Bergen COPD Cohort Study. Plasma creatinine was measured in 422 of the COPD patients. The Glomerular Flow Rate (GFR) was determined with the Cockcroft Gault formula, and having a GFR < 60 was defined as renal failure. Examined explanatory factors were sex, age, smoking habits, GOLD stage, hypoxemia, exacerbation history, cachexia, use of daily inhaled steroids, Charlson comorbidity score, use of ACE inhibitors and/or ARBs, and the inflammatory plasma markers C-reactive protein (CRP), soluble tumor necrosis factor receptor 1 (sTNF-R1) and neutrophil gelatinase associated lipocalin (NGAL). Associations between explanatory variables and renal failure were examined by a logistic regression analysis. The prevalence of having GFR < 60 was 9.6% in female COPD patients and 5.1% in male COPD patients (p = 0.08). In multivariable analysis, female sex, higher age, cachexia, and the inflammatory markers sTNF-R1 and NGAL were all independently associated with a higher risk for renal failure, whereas use of inhaled steroids, Charlson score, GOLD stage, respiratory failure, and exacerbation frequency were not. Undiagnosed renal failure is a concern particularly in elderly COPD patients and COPD patients with cachexia.
10.1016/j.rmed.2011.10.004
Relationship between Fractional Exhaled Nitric Oxide Level and Efficacy of Inhaled Corticosteroid in Asthma-COPD Overlap Syndrome Patients with Different Disease Severity.
Feng Jia Xi,Lin Yun,Lin Jian,He Su Su,Chen Mei Fang,Wu Xiao Mai,Xu You Zu
Journal of Korean medical science
This study explored the relationship between the fractional exhaled nitric oxide (FeNO) level and the efficacy of inhaled corticosteroid (ICS) in asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) patients with different disease severity. A total of 127 ACOS patients with ACOS (case group) and 131 healthy people (control group) were enrolled in this study. Based on the severity of COPD, the ACOS patients were divided into: mild ACOS; moderate ACOS; severe ACOS; and extremely severe ACOS groups. We compared FeNO levels, pulmonary function parameters including percentage of forced expiratory volume in 1 second (FEV1) to predicted value (FEV1%pred), ratio of FEV1 to forced vital capacity (FEV1/FVC), inspiratory capacity to total lung capacity (IC/TLC) and residual volume to total lung capacity (RV/TLC), arterial blood gas parameters, including PH, arterial partial pressure of oxygen (PaO₂) and arterial partial pressure of carbon dioxide (PaCO₂), total serum immunoglobulin E (IgE), induced sputum eosinophil (EOS), plasma surfactant protein A (SP-A), plasma soluble receptor for advanced glycation end products (sRAGE), sputum myeloperoxidase (MPO), sputum neutrophil gelatinase-associated lipocalin (NGAL) and Asthma Control Test (ACT) scores, and COPD Assessment Test (CAT) scores. Compared with pre-treatment parameters, the FeNO levels, RV/TLC, PaCO₂, total serum IgE, induced sputum EOS, plasma SP-A, sputum MPO, sputum NGAL, and CAT scores were significantly decreased after 6 months of ICS treatment, while FEV1%pred, FEV1/FVC, IC/TLC, PH, PaO2, plasma sRAGE, and ACT scores were significantly increased in ACOS patients with different disease severity after 6 months of ICS treatment. This finding suggests that the FeNO level may accurately predict the efficacy of ICS in the treatment of ACOS patients.
10.3346/jkms.2017.32.3.439
Predictors of exacerbations in chronic obstructive pulmonary disease--results from the Bergen COPD cohort study.
Husebø Gunnar R,Bakke Per S,Aanerud Marianne,Hardie Jon A,Ueland Thor,Grønseth Rune,Persson Louise J P,Aukrust Pål,Eagan Tomas M
PloS one
BACKGROUND:COPD exacerbations accelerate disease progression. AIMS:To examine if COPD characteristics and systemic inflammatory markers predict the risk for acute COPD exacerbation (AECOPD) frequency and duration. METHODS:403 COPD patients, GOLD stage II-IV, aged 44-76 years were included in the Bergen COPD Cohort Study in 2006/07, and followed for 3 years. Examined baseline predictors were sex, age, body composition, smoking, AECOPD the last year, GOLD stage, Charlson comorbidity score (CCS), hypoxemia (PaO2<8 kPa), cough, use of inhaled steroids, and the inflammatory markers leucocytes, C-reactive protein (CRP), neutrophil gelatinase associated lipocalin (NGAL), soluble tumor necrosis factor receptor 1 (sTNF-R1), and osteoprotegrin (OPG). Negative binomial models with random effects were fitted to estimate the annual incidence rate ratios (IRR). For analysis of AECOPD duration, a generalized estimation equation logistic regression model was fitted, also adjusting for season, time since inclusion and AECOPD severity. RESULTS:After multivariate adjustment, significant predictors of AECOPD were: female sex [IRR 1.45 (1.14-1.84)], age per 10 year increase [1.23 (1.03-1.47)], >1 AECOPD last year before baseline [1.65 (1.24-2.21)], GOLD III [1.36 (1.07-1.74)], GOLD IV [2.90 (1.98-4.25)], chronic cough [1.64 (1.30-2.06)] and use of inhaled steroids [1.57 (1.21-2.05)]. For AECOPD duration more than three weeks, significant predictors after adjustment were: hypoxemia [0.60 (0.39-0.92)], years since inclusion [1.19 (1.03-1.37)], AECOPD severity; moderate [OR 1.58 (1.14-2.18)] and severe [2.34 (1.58-3.49)], season; winter [1.51 (1.08-2.12)], spring [1.45 (1.02-2.05)] and sTNF-R1 per SD increase [1.16 (1.00-1.35)]. CONCLUSION:Several COPD characteristics were independent predictors of both AECOPD frequency and duration.
10.1371/journal.pone.0109721
IL-10 Combined with NGAL Has Diagnostic Value for AECOPD Combined with AKI.
International journal of chronic obstructive pulmonary disease
Background:In patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) complicated by acute kidney injury (AKI) has an acute onset and seriously affects the prognosis of patients. The inflammatory factors are still in doubt in the diagnosis of AECOPD with AKI. Material and Methods:This study is a retrospective study. By collecting the plasma concentrations of inflammatory factors IFN-γ, IL-2, IL-4, IL-10, IL-17, and NGAL in patients with AECOPD group, AECOPD plus AKI group, and control group. The expression level of each factor among the three different groups was analyzed, and the correlation of each factor was analyzed. The diagnostic value of each factor in patients with AECOPD combined with AKI was tested. Results:A total of 245 cases of AECOPD, 69 cases of AECOPD with AKI, and 50 healthy control group were included in this study. IFN-γ and IL-4 were differentially expressed among the three groups (P <0.001). However, there was no difference between the AECOPD group and the AECOPD + AKI group (P = 0.153, and 0.070, respectively). The expression of IL-2, IL-10, IL-17, and NGAL in the three groups were different, and there are statistical differences in pairwise comparisons. (all P values are <0.001). The univariate analysis showed that NGAL and IL-10 with the best correlation (r = 0.696). The ROC curve shows that IL-10 and NGAL have better diagnostic value for AECOPD with AKI. Conclusion:The inflammatory factor IL-10 combined with NGAL has a better diagnostic value for AECOPD with AKI.
10.2147/COPD.S245541
Serum Neutrophil Gelatinase-associated Lipocalin (NGAL) Is Elevated in Patients with Asthma and Airway Obstruction.
Kawagoe Junichiro,Kono Yuta,Togashi Yuki,Ishiwari Mayuko,Toriyama Kazutoshi,Yajima Chika,Nakayama Hideaki,Kasagi Satoshi,Abe Shinji,Setoguchi Yasuhiro
Current medical science
Neutrophilic airway inflammation is one of the features of severe asthma. Neutrophil gelatinase-associated lipocalin (NGAL), or lipocalin-2, is a glycoprotein associated with neutrophilic inflammation and can be detected in blood. Recently, blood NGAL levels have been reported to be elevated in chronic obstructive pulmonary disease. However, the clinical significance of serum NGAL levels in patients with asthma has not been elucidated. The aim of this study was to explore the association between serum NGAL level and clinical parameters in patients with asthma. Sixty-one non-smoking people with stable asthma were enrolled in this study. All patients underwent blood collection and pulmonary function tests. The associations between serum NGAL levels and clinical parameters were analyzed retrospectively. Serum NGAL levels in patients with asthma and obstructive ventilatory defect were higher than those in patients with asthma without obstructive ventilatory defect (76.4±51.4 ng/mL vs. 39.3±27.4 ng/mL, P=0.0019). Serum NGAL levels were correlated with forced expired flow at 50% of vital capacity %predicted and forced expired flow at 75% of vital capacity %predicted (r=-0.3373, P=0.0078 and r=-0.2900, P=0.0234, respectively). Results of a multiple regression analysis demonstrated that serum NGAL level was independently associated with obstructive ventilatory defect. Serum NGAL levels were elevated in patients with asthma and obstructive ventilatory defect. NGAL may be involved in airway remodeling possibly mediated by neutrophilic inflammation in asthma.
10.1007/s11596-021-2350-1
Neutrophil gelatinase-associated lipocalin as a complementary biomarker for the asthma-chronic obstructive pulmonary disease overlap.
Jo Yong Suk,Kwon Sung Ok,Kim Jeeyoung,Kim Woo Jin
Journal of thoracic disease
BACKGROUND:There is no standardized definition of the asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO). Although the blood eosinophil count is regarded as a biomarker for identifying ACO, it has no distinct value. This study aimed to measure plasma levels of neutrophil gelatinase-associated lipocalin (NGAL), a potential biomarker for distinguishing between ACO and non-ACO COPD. METHODS:We used the Korean cohort in the COPD in dusty area (CODA) study which included 137 subjects with COPD confirmed by spirometry. We defined ACO by a positive bronchodilator response (forced expiratory volume in 1 s, FEV >12% and >200 mL from baseline) or based on a previous history of asthma. Plasma levels of NGAL were determined by enzyme immunoassay. RESULTS:Among the 137 subjects, 77 were ACO and 60 were non-ACO COPD. Overall, the plasma NGAL levels were 15.9±7.9 and 15.6±6.6 ng/mL for non-ACO and ACO subjects respectively, and not significantly different. However, NGAL levels were significantly higher in female subjects with ACO (17.0±6.4 11.1±4.5, P=0.01). In female subjects, NGAL levels showed a good predictive ability to discriminate between ACO and non-ACO COPD [area under the receiver operating characteristic curve (AUROC), 0.77]; the predictive ability was similar to that of the blood eosinophil count (AUROC, 0.79). There was a higher probability of discriminating ACO from non-ACO among subjects in the highest tertile of NGAL levels (odds ratio, 1.72; 95% confidence interval, 0.69-4.28; P for trend =0.01). CONCLUSIONS:NGAL levels were significantly higher in ACO compared to non-ACO COPD in female subjects. After adjusting for gender as a confounding factor, the ability to distinguish ACO was better at higher levels of NGAL.
10.21037/jtd.2018.07.86
Increased neutrophil gelatinase-associated lipocalin (NGAL) promotes airway remodelling in chronic obstructive pulmonary disease.
Wang Yujie,Jia Man,Yan Xiaoyi,Cao Limin,Barnes Peter J,Adcock Ian M,Huang Mao,Yao Xin
Clinical science (London, England : 1979)
Airway remodelling is an important component of chronic obstructive pulmonary disease (COPD). Neutrophil gelatinase-associated lipocalin (NGAL) from neutrophils may drive COPD epithelial-mesenchymal transition (EMT). NGAL expression was quantified in the lungs of COPD patients and bronchoalveolar lavage fluid (BALF) of ozone-treated mice. Reticular basement membrane (RBM) thickness and E-cadherin and α-smooth muscle actin (α-SMA) expression were determined in mice airways. Effects of cigarette smoke extract (CSE) and inflammatory factors on NGAL expression in human neutrophils as well as the effects of NGAL on airway structural cells was assessed. NGAL was mainly distributed in neutrophils and enhanced in lung tissues of both COPD patients and BALF of ozone-treated mice. We showed decreased E-cadherin and increased α-SMA expression in bronchial epithelium and increased RBM thickness in ozone-treated animals. , CSE, IL-1β and IL-17 enhanced mRNA expression in human neutrophils. NGAL, in turn, down-regulated the expression of E-cadherin and up-regulated α-SMA expression in 16HBE cells via the WNT/glycogensynthase kinase-3β (GSK-3β) pathway. Furthermore, NGAL promoted the proliferation and migration of human bronchial smooth muscle cells (HASMCs). The present study suggests that elevated NGAL promotes COPD airway remodelling possibly through altered EMT. NGAL may be a potential target for reversing airway obstruction and remodelling in COPD.
10.1042/CS20170096
Human neutrophil lipocalin, a highly specific marker for acute exacerbation in cystic fibrosis.
Eichler I,Nilsson M,Rath R,Enander I,Venge P,Koller D Y
The European respiratory journal
Cystic fibrosis (CF) is characterized by the production of abnormally thick secretions in the airways, chronic bacterial endobronchial infections and a chronic, predominantly neutrophilic inflammatory response. Therefore, myeloperoxidase (MPO) and lactoferrin are frequently used as inflammatory markers. Recently, a new protein in the neutrophil granules, human neutrophil lipocalin (HNL) has been discovered. The aim of the present study was to investigate HNL in sera of patients with CF and its relation to MPO and lactoferrin as well as to acute pulmonary exacerbation. Serum concentrations of HNL, MPO and lactoferrin were determined in 42 patients with CF and in 25 healthy subjects. Patients with CF were divided into groups with and without acute pulmonary exacerbation (APE) and also with and without colonization with Pseudomonas aeruginosa (Pa). Median serum levels of HNL (200.5 microg x L(-1)), MPO (595 microg x L(-1)) and lactoferrin (1,356.5 microg x L(-1)) were significantly increased in patients with CF compared to control subjects (57.7, 178 and 478 microg x L(-1), respectively; p<0.0001). CF patients with APE had significantly increased serum concentrations of HNL (321 versus 97.7 microg x L(-1); p<0.0001), MPO (1,125 versus 300 microg x L(-1); p<0.005) and lactoferrin (4,936 versus 980 microg x L(-1); p<0.001) compared with patients in stable clinical condition. Similarly, patients colonized with Pa had significantly higher concentrations of HNL, MPO and lactoferrin than Pa negative patients. These results indicate that in patients with cystic fibrosis, serum concentrations of human neutrophil lipocalin are markedly increased with a strong relationship to myeloperoxidase and lactoferrin. Thus, determination of serum human neutrophil lipocalin concentrations may be another useful diagnostic tool to monitor neutrophil inflammation in cystic fibrosis. The more marked difference in human neutrophil lipocalin compared with myeloperoxidase concentrations with no overlap between patients with acute pulmonary exacerbation and those in stable condition even suggests that human neutrophil lipocalin may be a more sensitive and specific discriminator.
Impact of vitamin D supplementation on markers of inflammation in adults with cystic fibrosis hospitalized for a pulmonary exacerbation.
Grossmann R E,Zughaier S M,Liu S,Lyles R H,Tangpricha V
European journal of clinical nutrition
Patients with cystic fibrosis (CF) suffer from chronic lung infection and inflammation leading to respiratory failure. Vitamin D deficiency is common in patients with CF, and correction of vitamin D deficiency may improve innate immunity and reduce inflammation in patients with CF. We conducted a double-blinded, placebo-controlled, randomized clinical trial of high-dose vitamin D to assess the impact of vitamin D therapy on antimicrobial peptide concentrations and markers of inflammation. We randomized 30 adults with CF hospitalized with a pulmonary exacerbation to 250,000 IU of cholecalciferol or placebo, and evaluated changes in plasma concentrations of inflammatory markers and the antimicrobial peptide LL-37 at baseline and 12 weeks post intervention. In the vitamin D group, there was a 50.4% reduction in tumor necrosis factor-α (TNF-α) at 12 weeks (P<0.01), and there was a trend for a 64.5% reduction in interleukin-6 (IL-6) (P=0.09). There were no significant changes in IL-1β, IL-8, IL-10, IL-18BP and NGAL (neutrophil gelatinase-associated lipocalin). We conclude that a large bolus dose of vitamin D is associated with reductions in two inflammatory cytokines, IL-6 and TNF-α. This study supports the concept that vitamin D may help regulate inflammation in CF, and that further research is needed to elucidate the potential mechanisms involved and the impact on clinical outcomes.
10.1038/ejcn.2012.82
Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL) in Patients with Obstructive Sleep Apnea.
Maski Manish R,Thomas Robert J,Karumanchi S Ananth,Parikh Samir M
PloS one
BACKGROUND:Obstructive sleep apnea (OSA) is a well-established risk factor for hypertension and cardiovascular morbidity and mortality. More recently, OSA has been implicated as an independent risk factor for chronic kidney disease. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a well-accepted early biomarker of subclinical kidney tubular injury, preceding an increase in serum creatinine. The goal of this study was to determine if an association exists between OSA and increased urinary NGAL levels. METHODS:We prospectively enrolled adult patients from the sleep clinic of an academic medical center. Each underwent polysomnography and submitted a urine specimen upon enrollment. We measured NGAL and creatinine levels on all urine samples before participants received treatment with continuous positive airway pressure (CPAP), and, in a subset of OSA patients, after CPAP therapy. We compared the urinary NGAL/creatinine ratio between untreated participants with and without OSA, and within a subset of 11 OSA patients also after CPAP therapy. RESULTS:A total of 49 subjects were enrolled: 16 controls based on an apnea-hypopnea index (events with at least 4% oxygen desaturation; AHI-4%) <5 events/hour (mean AHI-4% = 0.59 +/- 0.60); 33 OSA patients based on an AHI-4% >5 events/hour (mean AHI-4% = 43.3 +/- 28.1). OSA patients had a higher mean body-mass index than the control group (36.58 +/- 11.02 kg/m2 vs. 26.81 +/- 6.55 kg/m2, respectively; p = 0.0005) and were more likely to be treated for hypertension (54.5% vs. 6.25% of group members, respectively; p = 0.0014). The groups were otherwise similar in demographics, and there was no difference in the number of diabetic subjects or in the mean serum creatinine concentration (control = 0.86 +/- 0.15 mg/dl, OSA = 0.87 +/- 0.19 mg/dl; p = 0.7956). We found no difference between the urinary NGAL-to-creatinine ratios among untreated OSA patients versus control subjects (median NGAL/creatinine = 6.34 ng/mg vs. 6.41 ng/mg, respectively; p = 0.4148). Furthermore, CPAP therapy did not affect the urinary NGAL-to-creatinine ratio (p = 0.7758 for two-tailed, paired t-test). CONCLUSIONS:In this prospective case-control study comparing patients with severe, hypoxic OSA to control subjects, all with normal serum creatinine, we found no difference between urinary levels of NGAL. Furthermore, CPAP therapy did not change these levels pre- and post-treatment.
10.1371/journal.pone.0154503
Neutrophil-associated activation markers in healthy smokers relates to a fall in DL(CO) and to emphysematous changes on high resolution CT.
Ekberg-Jansson A,Andersson B,Bake B,Boijsen M,Enanden I,Rosengren A,Skoogh B E,Tylén U,Venge P,Löfdahl C G
Respiratory medicine
Smoking is a risk factor for developing chronic obstructive pulmonary disease (COPD), but there are no good indicators for early identification of subjects who will develop symptomatic COPD. The aim of this study was to investigate inflammatory mechanisms related to changes in lung function and emphysematous changes on high resolution computed tomography (HRCT) in 'healthy' smokers. Subjects were 60-year-old men from a population study. Bronchoscopy was performed in 30 smokers and 18 who had never smoked. Blood tests, lung function measurements and HRCT were carried out in 58 and 34 subjects, respectively. In comparison with never-smokers, smokers had higher levels of myeloperoxidase (MPO), human neutrophil lipocalin (HNL), eosinophil cationic protein (ECP) and lysozyme in blood, higher levels of MPO, interleukin-8 (IL-8) and HNL in bronchial lavage (BL), and of IL-8, HNL and interleukin-lbeta (IL-1beta) in bronchoalveolar lavage (BAL). Smokers also had lower levels of Clara cell protein 16 (CC-16) in blood. HNL in BL and BAL showed strong correlations to other inflammatory markers (MPO, IL-8, IL-1beta). The variations in MPO in BL were explained by variations in HNL (R2 =0.69), while these variations in BAL were explained by variations in HNL and IL-1beta (R2 = 0.76). DL(CO) was the lung function variable most closely related to MPO and IL-8 in BL and BAL and to IL-1beta in BAL. In a multiple regression analysis, MPO, IL-1beta, IL-8 and CC-16 in BL and MPO in BAL contributed to the explanation of variations in DL(CO) to 41% and 22%. respectively, independent of smoking habits. In smokers with emphysematous lesions on HRCT, HNL in BAL correlated to emphysema score (r(s) = 0.71). We conclude that 'healthy' smoking men with a near normal FEV1 show signs of inflammation in the lower airways that are related to a decrease in DL(CO) and to emphysematous lesions on HRCT. This inflammation seems to be the result of both monocyte/macrophage and neutrophil activation.
10.1053/rmed.2001.1050
Myeloperoxidase as a marker of increasing systemic inflammation in smokers without severe airway symptoms.
Andelid Kristina,Bake Björn,Rak Sabina,Lindén Anders,Rosengren Annika,Ekberg-Jansson Ann
Respiratory medicine
BACKGROUND:There is increasing evidence of systemic inflammation in patients with chronic obstructive pulmonary disease (COPD), but there is very little information on the development of systemic inflammation in smokers without severe airway symptoms. In this longitudinal study, we examined whether smokers with mild or no airway symptoms develop signs of systemic inflammation by assessing inflammatory markers in blood over a 6-year period. METHODS:Forty smokers and 28 male never-smokers were investigated in 1995 (year 0) and 6 years later (year 6). At year 6, 11 smokers had stopped smoking (quitters); these subjects were analysed as a separate group. At year 0 and 6, we measured serum levels of myeloperoxidase (MPO), lysozyme and human neutrophil lipocalin (HNL), regarded as markers of activity in neutrophils plus monocyte-lineage cells, monocyte-lineage cells only and neutrophils only. RESULTS:All systemic markers of inflammation (MPO, HNL and lysozyme) were significantly higher in smokers than in never smokers at year 6. For MPO alone, smokers only displayed a unique pattern compared with the other groups; the concentration of MPO in blood increased among smokers during the 6-year period, and this increase was statistically significant compared with that observed in never-smokers. Even though quitters did not display any clear change in MPO, we observed a statistically significant negative correlation between the change in blood MPO and the duration of smoking cessation in this group. For HNL and lysozyme, the changes over time were similar in smokers and never-smokers, with no statistically significant difference compared with quitters. CONCLUSION:This study provides evidence that male smokers without severe airway symptoms develop an increasing systemic inflammation during a 6-year period. The study forwards both direct and indirect evidence that MPO may be an early marker of this systemic inflammation. However, our study also forwards indirect evidence that ongoing tobacco smoking may "drive" the level of systemic HNL and lysozyme. The origin of the increased MPO and its value as an easily measured predictor for future COPD deserves to be further evaluated.
10.1016/j.rmed.2006.09.023
Granulocyte markers in induced sputum in patients with respiratory disorders and healthy persons obtained by two sputum-processing methods.
Metso T,Rytilä P,Peterson C,Haahtela T
Respiratory medicine
Induced sputum is increasingly used to detect and monitor airway inflammation in respiratory diseases. However, the processing of sputum has been rather laborious for clinical practice. The aim of this study was to improve the practicality of induced-sputum studies by simplifying sample processing. Eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), neutrophil lipocalin (HNL) and myeloperoxidase (MPO) were used as biochemical markers of airway inflammation and the results of the study method were compared with a previously validated (reference) method. Induced sputum was obtained from 42 healthy controls, 10 subjects with acute respiratory infection, eight patients with chronic obstructive pulmonary disease (COPD) and 17 asthmatics. The sputum sample was divided into two parts and treated either: (i) by the reference method (released markers), where sputum was homogenized with dithiotreitol and centrifuged to yield cell-free supernatant and a cell pellet, or (ii) by the study method (total markers), where the cells were lysed after homogenization so that cell-associated markers were released and solubilized. For comparison, the four biochemical markers were measured in sputum supernatant and in sputum lysate. The differential cell count was performed from the cell pellet in the reference method. Repeatability was assessed in a group of 16 subjects. The effect of reagents and the recovery of assays were also evaluated. Released and total markers correlated well (ECP r(s)=0.80, P<0.0001; EPO r(s)=0.49, P<0.0001; HNL r(s)=0.87, P<0.0001; MPO r(s)=0.71, P<0.0001). Incubation with dithiotreitol and lysis reagent had no negative influence on marker assays. The within-subject variability of total ECP, MPO and HNL in both methods was small in two measurements taken I week apart. The study method, measuring total inflammatory markers, gave comparable results to the reference method, measuring released markers. In the study method the sputum processing was simplified, which may improve its applicability.
Peripheral monocytes derived from patients with cystic fibrosis and healthy donors secrete NGAL in response to Pseudomonas aeruginosa infection.
Zughaier Susu M,Tangpricha Vin,Leong Traci,Stecenko Arlene A,McCarty Nael A
Journal of investigative medicine : the official publication of the American Federation for Clinical Research
BACKGROUND:Patients with cystic fibrosis (CF) develop chronic bacterial infections in the respiratory tract, reflecting dysfunctional innate immunity. Neutrophil gelatinase-associated lipocalin (NGAL) has 2 functions: one as an antibacterial host defense protein and the other as a physiological iron carrier. Neutrophil gelatinase-associated lipocalin (NGAL) has been validated as a biomarker for early kidney disease. The aim of this study was to determine whether NGAL could serve as a marker of acute pulmonary exacerbations in CF by measuring NGAL levels in serum samples from subjects with CF during stable clinic visits and during hospitalization for pulmonary exacerbations and comparing these levels to healthy controls and to patients without CF with significant infection. In addition, we aimed to determine if innate immunity cells other than neutrophils act as a source of NGAL. METHODS:Circulating NGAL levels were measured by enzyme-linked immunosorbent assay in serum samples from 30 subjects with CF when hospitalized for an acute pulmonary exacerbation, 33 subjects with CF during stable clinic visits, 33 patients with sepsis, and 21 healthy controls. Secreted NGAL from CF and healthy control peripheral monocytes infected with Pseudomonas aeruginosa was also measured by enzyme-linked immunosorbent assay. RESULTS:Serum NGAL levels were elevated in the patients with CF compared to the healthy controls (P < 0.001). However, no difference in serum NGAL levels was found between subjects with CF with stable disease compared to subjects with CF undergoing pulmonary exacerbation. Furthermore, peripheral monocytes from CF and subjects without CF secreted NGAL upon infection with Pseudomonas aeruginosa and thereby may be contributing to the circulating NGAL levels observed. CONCLUSIONS:Our data show that peripheral monocytes secrete NGAL, and serum NGAL levels are widely distributed among subjects with CF, being elevated both when clinically stable and during a pulmonary exacerbation and thus NGAL is not a sensitive biomarker for pulmonary exacerbations.
10.2310/JIM.0b013e31829cbd14
Neutrophil gelatinase-associated lipocalin: a biomarker in COPD.
Eagan Tomas M,Damås Jan K,Ueland Thor,Voll-Aanerud Marianne,Mollnes Tom E,Hardie Jon A,Bakke Per S,Aukrust Pål
Chest
BACKGROUND:Neutrophil gelatinase-associated lipocalin (NGAL) is an antimicrobial peptide that could be involved in the pathogenesis of COPD. This study aimed to measure the plasma levels of NGAL in a large cohort of patients with COPD and control subjects and examine the levels of NGAL by COPD characteristics. METHODS:The study included 402 patients with COPD and 229 control subjects aged 40 to 76 years from the Bergen COPD Cohort Study. All patients with COPD had an FEV(1)/FVC ratio of < 0.7, an FEV(1) < 80% predicted, and a smoking history of ≥ 10 pack-years. Plasma levels of NGAL were determined by enzyme immunoassay. Linear regression models were fitted with NGAL as the outcome variable. Confounders examined were sex, age, smoking, Charlson comorbidity score, use of inhaled steroids, neutrophil cell count, plasma creatinine and ferritin, and C-reactive protein. RESULTS:Mean ± SD plasma concentrations of NGAL were 75.1 ± 31.8 ng/mL in patients with COPD and 56.5 ± 22.0 ng/mL in control subjects (P < .01). NGAL levels were bivariately associated with age, smoking, body composition, Charlson comorbidity score, neutrophil blood count, creatinine, and C-reactive protein but were significantly elevated in patients with COPD, even after adjustment for confounders. Frequent exacerbations and hypoxemia was associated with higher levels of NGAL, whereas increasing Global Initiative for Chronic Obstructive Lung Disease stage was associated with lower levels of NGAL among patients with COPD. CONCLUSIONS:Plasma levels of NGAL were significantly higher in patients with COPD compared with control subjects. NGAL was related to important COPD characteristics.
10.1378/chest.09-2718
Biomarkers of disease and treatment in murine and cynomolgus models of chronic asthma.
Louten Jennifer,Mattson Jeanine D,Malinao Maria-Christina,Li Ying,Emson Claire,Vega Felix,Wardle Robert L,Van Scott Michael R,Fick Robert B,McClanahan Terrill K,de Waal Malefyt Rene,Beaumont Maribel
Biomarker insights
BACKGROUND:Biomarkers facilitate early detection of disease and measurement of therapeutic efficacy, both at clinical and experimental levels. Recent advances in analytics and disease models allow comprehensive screening for biomarkers in complex diseases, such as asthma, that was previously not feasible. OBJECTIVE:Using murine and nonhuman primate (NHP) models of asthma, identify biomarkers associated with early and chronic stages of asthma and responses to steroid treatment. METHODS:The total protein content from thymic stromal lymphopoietin transgenic (TSLP Tg) mouse BAL fluid was ascertained by shotgun proteomics analysis. A subset of these potential markers was further analyzed in BAL fluid, BAL cell mRNA, and lung tissue mRNA during the stages of asthma and following corticosteroid treatment. Validation was conducted in murine and NHP models of allergic asthma. RESULTS:Over 40 proteins were increased in the BAL fluid of TSLP Tg mice that were also detected by qRT-PCR in lung tissue and BAL cells, as well as in OVA-sensitive mice and house dust mite-sensitive NHP. Previously undescribed as asthma biomarkers, KLK1, Reg3γ, ITLN2, and LTF were modulated in asthmatic mice, and Clca3, Chi3l4 (YM2), and Ear11 were the first lung biomarkers to increase during disease and the last biomarkers to decline in response to therapy. In contrast, GP-39, LCN2, sICAM-1, YM1, Epx, Mmp12, and Klk1 were good indicators of early therapeutic intervention. In NHP, AMCase, sICAM-1, CLCA1, and GP-39 were reduced upon treatment with corticosteroids. CONCLUSIONS AND CLINICAL RELEVANCE:These results significantly advance our understanding of the biomarkers present in various tissue compartments in animal models of asthma, including those induced early during asthma and modulated with therapeutic intervention, and show that BAL cells (or their surrogate, induced sputum cells) are a viable choice for biomarker examination.
10.4137/BMI.S9776
Nicotine promotes breast cancer metastasis by stimulating N2 neutrophils and generating pre-metastatic niche in lung.
Tyagi Abhishek,Sharma Sambad,Wu Kerui,Wu Shih-Ying,Xing Fei,Liu Yin,Zhao Dan,Deshpande Ravindra Pramod,D'Agostino Ralph B,Watabe Kounosuke
Nature communications
Smoking has a profound impact on tumor immunity, and nicotine, which is the major addictive component of smoke, is known to promote tumor progression despite being a non-carcinogen. In this study, we demonstrate that chronic exposure of nicotine plays a critical role in the formation of pre-metastatic niche within the lungs by recruiting pro-tumor N2-neutrophils. This pre-metastatic niche promotes the release of STAT3-activated lipocalin 2 (LCN2), a secretory glycoprotein from the N2-neutrophils, and induces mesenchymal-epithelial transition of tumor cells thereby facilitating colonization and metastatic outgrowth. Elevated levels of serum and urine LCN2 is elevated in early-stage breast cancer patients and cancer-free females with smoking history, suggesting that LCN2 serve as a promising prognostic biomarker for predicting increased risk of metastatic disease in female smoker(s). Moreover, natural compound, salidroside effectively abrogates nicotine-induced neutrophil polarization and consequently reduced lung metastasis of hormone receptor-negative breast cancer cells. Our findings suggest a pro-metastatic role of nicotine-induced N2-neutrophils for cancer cell colonization in the lungs and illuminate the therapeutic use of salidroside to enhance the anti-tumor activity of neutrophils in breast cancer patients.
10.1038/s41467-020-20733-9
Lipocalin2 protects against airway inflammation and hyperresponsiveness in a murine model of allergic airway disease.
Dittrich A M,Krokowski M,Meyer H-A,Quarcoo D,Avagyan A,Ahrens B,Kube S M,Witzenrath M,Loddenkemper C,Cowland J B,Hamelmann E
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
BACKGROUND:Allergen-induced bronchial asthma is a chronic airway disease that involves the interplay of various genes with environmental factors triggering different inflammatory pathways. OBJECTIVE:The aim of this study was to identify possible mediators of airway inflammation (AI) in a model of allergic AI via microarray comparisons and to analyse one of these mediators, Lipocalin2 (Lcn2), for its role in a murine model of allergic airway disease. METHODS:Gene microarrays were used to identify genes with at least a twofold increase in gene expression in the lungs of two separate mouse strains with high and low allergic susceptibility, respectively. Validation of mRNA data was obtained by Western blotting, followed by functional analysis of one of the identified genes, Lcn2, in mice with targeted disruption of specific gene expression. Epithelial cell cultures were undertaken to define induction requirements and possible mechanistic basis of the results observed in the Lcn2 knock-out mice. RESULTS:Lcn2 was up-regulated upon allergen sensitization and airway challenges in lung tissues of both mouse strains and retraced on the protein level in bronchoalveolar lavage fluids. Functional relevance was assessed in mice genetically deficient for Lcn2, which showed enhanced airway resistance and increased AI associated with decreased apoptosis of lung inflammatory cells, compared with wild-type controls. Similarly, application of Lcn2-blocking antibodies before airway challenges resulted in increased inflammation and reduced apoptosis. CONCLUSION:These data indicate a protective role for Lcn2 in allergic airway disease, suggesting a pro-apoptotic effect as the underlying mechanism.
10.1111/j.1365-2222.2010.03508.x
Associations Between Neutrophil Gelatinase Associated Lipocalin, Neutrophil-to-Lymphocyte Ratio, Atrial Fibrillation and Renal Dysfunction in Chronic Heart Failure.
Argan Onur,Ural Dilek,Kozdag Guliz,Sahin Tayfun,Bozyel Serdar,Aktas Mujdat,Karauzum Kurtulus,Yilmaz Irem,Dervis Emir,Agir Aysen
Medical science monitor : international medical journal of experimental and clinical research
BACKGROUND Atrial fibrillation (AF) and renal dysfunction are two common comorbidities in patients with chronic heart failure with reduced ejection fraction (HFrEF). This study evaluated the effect of permanent AF on renal function in HFrEF and investigated the associations of atrial fibrillation, neutrophil gelatinase-associated lipocalin (NGAL), and neutrophil-to-lymphocyte ratio (NLR) with adverse clinical outcome. MATERIAL AND METHODS Serum NGAL levels measured by ELISA and NLR were compared between patients with sinus rhythm (HFrEF-SR, n=68), with permanent AF (HFrEF-AF, n=62), and a healthy control group (n=50). RESULTS Mean eGFR levels were significantly lower, and NLR and NGAL levels were significantly higher in the HFrEF patients than in the control patients but the difference between HFrEF-SR and HFrEF-AF was not statistically significant (NGAL: 95 ng/mL in HFrEF-SR, 113 ng/mL in HFrEF-AF and 84 ng/mL in the control group; p<0.001). Independent associates of baseline eGFR were age, hemoglobin, NLR, triiodothyronine, and pulmonary artery systolic pressure. In a mean 16 months follow-up, adverse clinical outcome defined as progression of kidney dysfunction and composite of all-cause mortality and re-hospitalization were not different between HFrEF-SR and HFrEF-AF patients. Although NGAL was associated with clinical endpoints in the univariate analysis, Cox regression analysis showed that independent predictors of increased events were the presence of signs right heart failure, C-reactive protein, NLR, triiodothyronine, and hemoglobin. In ROC analysis, a NLR >3 had a 68% sensitivity and 75% specificity to predict progression of kidney disease (AUC=0.72, 95% CI 0.58-0.85, p=0.001). CONCLUSIONS Presence of AF in patients with HFrEF was not an independent contributor of adverse clinical outcome (i.e., all-cause death, re-hospitalization) or progression of renal dysfunction. Renal dysfunction in HFrEF was associated with both NLR and NGAL levels, but systemic inflammation reflected by NLR seemed to be a more important determinant of progression of kidney dysfunction.
10.12659/msm.898608
Systemic biomarkers of neutrophilic inflammation, tissue injury and repair in COPD patients with differing levels of disease severity.
PloS one
The identification and validation of biomarkers to support the assessment of novel therapeutics for COPD continues to be an important area of research. The aim of the current study was to identify systemic protein biomarkers correlated with measures of COPD severity, as well as specific protein signatures associated with comorbidities such as metabolic syndrome. 142 protein analytes were measured in serum of 140 patients with stable COPD, 15 smokers without COPD and 30 non-smoking controls. Seven analytes (sRAGE, EN-RAGE, NGAL, Fibrinogen, MPO, TGF-α and HB-EGF) showed significant differences between severe/very severe COPD, mild/moderate COPD, smoking and non-smoking control groups. Within the COPD subjects, univariate and multivariate analyses identified analytes significantly associated with FEV(1), FEV(1)/FVC and DLCO. Most notably, a set of 5 analytes (HB-EGF, Fibrinogen, MCP-4, sRAGE and Sortilin) predicted 21% of the variability in DLCO values. To determine common functions/pathways, analytes were clustered in a correlation network by similarity of expression profile. While analytes related to neutrophil function (EN-RAGE, NGAL, MPO) grouped together to form a cluster associated with FEV(1) related parameters, analytes related to the EGFR pathway (HB-EGF, TGF-α) formed another cluster associated with both DLCO and FEV(1) related parameters. Associations of Fibrinogen with DLCO and MPO with FEV(1)/FVC were stronger in patients without metabolic syndrome (r = -0.52, p = 0.005 and r = -0.61, p = 0.023, respectively) compared to patients with coexisting metabolic syndrome (r = -0.25, p = 0.47 and r = -0.15, p = 0.96, respectively), and may be driving overall associations in the general cohort. In summary, our study has identified known and novel serum protein biomarkers and has demonstrated specific associations with COPD disease severity, FEV(1), FEV(1)/FVC and DLCO. These data highlight systemic inflammatory pathways, neutrophil activation and epithelial tissue injury/repair processes as key pathways associated with COPD.
10.1371/journal.pone.0038629
Differences in plasma and sputum biomarkers between COPD and COPD-asthma overlap.
Iwamoto Hiroshi,Gao Jing,Koskela Jukka,Kinnula Vuokko,Kobayashi Hideo,Laitinen Tarja,Mazur Witold
The European respiratory journal
The pathophysiological features of chronic obstructive pulmonary disease (COPD)-asthma overlap are poorly understood and there has been no study of plasma or sputum biomarkers in overlap patients. In order to clarify the similarity and differences between overlap and COPD or asthma, we have investigated four potential biomarkers of COPD: surfactant protein A (SP-A), soluble receptor for advanced glycation end-products (sRAGE), myeloperoxidase (MPO) and neutrophil gelatinase-associated lipocalin (NGAL). SP-A and sRAGE are pneumocyte-derived markers. MPO and NGAL are neutrophil-derived molecules, but NGAL can also be expressed by respiratory epithelial cells. Plasma levels of SP-A and sRAGE and induced sputum levels of MPO and NGAL were measured by enzyme immunoassay/ELISA in 134 subjects: nonsmokers (n=26), smokers (n=23), asthma (n=32), COPD (n=39) and COPD-asthma overlap patients (n=14). In patients with COPD-asthma overlap, sputum MPO and plasma SP-A were significantly elevated whereas plasma sRAGE levels were reduced compared with asthma patients. Only sputum NGAL was significantly elevated in COPD-asthma overlap compared with COPD (p=0.00016) and could be used to differentiate patients with overlap from those with COPD. Increased induced sputum levels of NGAL might be a characteristic feature of overlap, suggesting enhanced neutrophilic airway inflammation and/or airway epithelial injury in COPD-asthma overlap.
10.1183/09031936.00024313
Detection of high-sensitivity troponin in outpatients with stable pulmonary hypertension identifies a subgroup at higher risk of adverse outcomes.
Roy Andrew K,McCullagh Brian N,Segurado Ricardo,McGorrian Catherine,Keane Elizabeth,Keaney John,Fitzgibbon Maria N,Mahon Niall G,Murray Patrick T,Gaine Sean P
Journal of cardiac failure
BACKGROUND:The detection of elevations in cardiorenal biomarkers, such as troponins, B-type natriuretic peptides (BNPs), and neutrophil gelatinase-associated lipocalins, are associated with poor outcomes in patients hospitalized with acute heart failure. Less is known about the association of these markers with adverse events in chronic right ventricular dysfunction due to pulmonary hypertension, or whether their measurement may improve risk assessment in the outpatient setting. METHODS AND RESULTS:We performed a cohort study of 108 patients attending the National Pulmonary Hypertension Unit in Dublin, Ireland, from 2007 to 2009. Cox proportional hazards analysis and receiver operating characteristic curves were used to determine predictors of mortality and hospitalization. Death or hospitalization occurred in 50 patients (46.3%) during the median study period of 4.1 years. Independent predictors of mortality were: 1) decreasing 6-minute walk test (6MWT; hazard ratio [HR] 12.8; P < .001); 2) BNP (HR 6.68; P < .001); and 3) highly sensitive troponin (hsTnT; HR 5.48; P < .001). Adjusted hazard analyses remained significant when hsTnT was added to a model with BNP and 6MWT (HR 9.26, 95% CI 3.61-23.79), as did the predictive ability of the model for death and rehospitalization (area under the receiver operating characteristic curve 0.81, 95% CI 0.73-0.90). CONCLUSIONS:Detection of troponin using a highly sensitive assay identifies a pulmonary hypertension subgroup with a poorer prognosis. hsTnT may also be used in a risk prediction model to identify patients at higher risk who may require escalation of targeted pulmonary vasodilator therapies and closer clinical surveillance.
10.1016/j.cardfail.2013.12.001
Changes in inflammatory markers following treatment of acute exacerbations of obstructive pulmonary disease.
Dahlén I,Janson C,Björnsson E,Stålenheim G,Peterson C G,Venge P
Respiratory medicine
The aim ofthe study was to investigate changes in inflammatory markers following emergency treatment of obstructive pulmonary disease. The study comprised 43 patients. After acute treatment, they were given either 30 mg of prednisolone p.o. or 1600 microg of inhaled budeson de daily for 1 week. Over the following 3 weeks, all the patients were given 1600 microg of inhaled budesonide daily. Blood samples for measurements of eosinophil cationic protein (S-ECP), eosinophil peroxidase (S-EPO), total eos nophil count (B-Eos), myeloperoxidase (S-MPO) and human neutrophil lipocaline (HNL) were taken and spirometry was performed before emergency treatment and after 1 and 4 weeks. There was no difference in the improvement in forced expiratory volume in 1 sec (FEV1) between patients given prednisolone or budesonide. Patients with an improvement in FEV1 of >20% of baseline after 1 and 4 weeks displayed a larger decrease in eosinophil markers. The correlation between deltaFEV1 and deltaS-ECP was r= -0.37, P < 0.05, deltaS-EPO -0.40, P < 0.01 and deltaB-Eos -0.44, P < 0.01, after 4 weeks. This correlation was highly significant in patients who had smoked < or = 5 pack-years, while the correlation was not significant in patients with a longer smoking history and chronic airflow limitation (best FEV <80% of predicted). We conclude that the change in eosinophil markers is correlated to the improvement in lung function in non-smokers or short-term smokers following the emergency treatment of obstructive pulmonary disease. This study indicates that following eosinophil markers is more useful in patients with asthma than patients with COPD.
10.1053/rmed.2001.1179
Plasma YKL-40 and NGAL are useful in distinguishing ACO from asthma and COPD.
Respiratory research
BACKGROUND:Asthma-chronic obstructive pulmonary disorder (COPD) overlap (ACO) is characterized by the coexistence of features of both asthma and COPD and is associated with rapid progress and a poor prognosis. Thus, the early recognition of ACO is crucial. OBJECTIVES:We sought to explore the plasma levels of biomarkers associated with asthma (periostin, TSLP and YKL-40), COPD (NGAL) and their possible correlation with lung function, the bronchodilator response and radiographic imaging in patients with asthma, COPD and with features of ACO. METHODS:We enrolled 423 subjects from 6 clinical centers. All participants underwent blood collection, lung function measurements, bronchodilator response tests and high-resolution CT. Correlations of the plasma biomarkers with lung function, the bronchodilator response and percentemphysema were calculated by Spearman's rank correlation and multivariate stepwise regressionanalysis. RESULTS:1) Patients with features of ACO had lower plasma YKL-40 than COPD patients and a moderate elevated plasma level of NGAL compared with asthma patients. 2) Patients with features of ACO had an intermediate degree of airflow obstruction, the bronchodilator response and emphysema between patients with COPD and asthma. 3) Plasma YKL-40 was negatively correlated with lung function and with the bronchodilator response, and plasma NGAL was positively correlated with the extent of emphysema. CONCLUSIONS:Plasma YKL-40 is a promising candidate for distinguishing between patients with features of ACO and COPD patients, while plasma NGAL may be a valuable biomarker for differentiating between patients with features of ACO and asthma patients. CLINICAL TRIAL REGISTRATION:ChiCTR-OOC-16009221.
10.1186/s12931-018-0755-6
Characterization of sputum biomarkers for asthma-COPD overlap syndrome.
Gao Jing,Iwamoto Hiroshi,Koskela Jukka,Alenius Harri,Hattori Noboru,Kohno Nobuoki,Laitinen Tarja,Mazur Witold,Pulkkinen Ville
International journal of chronic obstructive pulmonary disease
Asthma-COPD overlap syndrome (ACOS) is a commonly encountered chronic airway disease. However, ACOS is still a consensus-based clinical phenotype and the underlying inflammatory mechanisms are inadequately characterized. To clarify the inflammatory mediatypical for ACOS, five biomarkers, namely interleukin (IL)-13, myeloperoxidase (MPO), neutrophil gelatinase-associated lipocalin (NGAL), chitinase-like protein (YKL-40), and IL-6, were selected. This study hypothesized that sputum biomarkers relevant for airway inflammation in asthma (IL-13), COPD (MPO, NGAL), or in both asthma and COPD (YKL-40, IL-6) could be used to differentiate ACOS from COPD and asthma. The aim of this study was to characterize the inflammatory profile and improve the recognition of ACOS. Induced sputum levels of IL-13, MPO, NGAL, YKL-40, and IL-6 were measured by enzyme-linked immunosorbent assay/Luminex assay in a Finnish discovery cohort (n=90) of nonsmokers, smokers, and patients with asthma, COPD, and ACOS and validated in a Japanese cohort (n=135). The classification accuracy of potential biomarkers was compared with area under the receiver operating characteristic curves. Only sputum NGAL levels could differentiate ACOS from asthma (<0.001 and <0.001) and COPD (<0.05 and =0.002) in the discovery and replication cohorts, respectively. Sputum NGAL levels were independently correlated with the percentage of pre-bronchodilator forced expiratory volume in 1 second predicted in multivariate analysis in the discovery and replication cohorts (=0.001 and =0.002, respectively). In conclusion, sputum biomarkers reflecting both airway inflammation and remodeling of the tissue show potential in differentiation between asthma, COPD, and ACOS.
10.2147/COPD.S113484
Integration of transcriptomics, proteomics and metabolomics identifies biomarkers for pulmonary injury by polyhexamethylene guanidine phosphate (PHMG-p), a humidifier disinfectant, in rats.
Lee Jung Dae,Kim Hyang Yeon,Kang Keunsoo,Jeong Hye Gwang,Song Mi-Kyung,Tae In Hwan,Lee Su Hyun,Kim Hae Ri,Lee Kyuhong,Chae Sehyun,Hwang Daehee,Kim Suhkmann,Kim Hyung Sik,Kim Kyu-Bong,Lee Byung-Mu
Archives of toxicology
Polyhexamethylene guanidine phosphate (PHMG-p) was used as a humidifier disinfectant in Korea. PHMG induced severe pulmonary fibrosis in Koreans. The objective of this study was to elucidate mechanism of pulmonary toxicity caused by PHMG-p in rats using multi-omics analysis. Wistar rats were intratracheally instilled with PHMG-p by single (1.5 mg/kg) administration or 4-week (0.1 mg/kg, 2 times/week) repeated administration. Histopathologic examination was performed with hematoxylin and eosin staining. Alveolar macrophage aggregation and granulomatous inflammation were observed in rats treated with single dose of PHMG-p. Pulmonary fibrosis, chronic inflammation, bronchiol-alveolar fibrosis, and metaplasia of squamous cell were observed in repeated dose group. Next generation sequencing (NGS) was performed for transcriptome profiling after mRNA isolation from bronchiol-alveoli. Bronchiol-alveoli proteomic profiling was performed using an Orbitrap Q-exactive mass spectrometer. Serum and urinary metabolites were determined using H-NMR. Among 418 differentially expressed genes (DEGs) and 67 differentially expressed proteins (DEPs), changes of 16 mRNA levels were significantly correlated with changes of their protein levels in both single and repeated dose groups. Remarkable biological processes represented by both DEGs and DEPs were defense response, inflammatory response, response to stress, and immune response. Arginase 1 (Arg1) and lipocalin 2 (Lcn2) were identified to be major regulators for PHMG-p-induced pulmonary toxicity based on merged analysis using DEGs and DEPs. In metabolomics study, 52 metabolites (VIP > 0.5) were determined in serum and urine of single and repeated-dose groups. Glutamate and choline were selected as major metabolites. They were found to be major factors affecting inflammatory response in association with DEGs and DEPs. Arg1 and Lcn2 were suggested to be major gene and protein related to pulmonary damage by PHMG-p while serum or urinary glutamate and choline were endogenous metabolites related to pulmonary damage by PHMG-p.
10.1007/s00204-020-02657-x
Identification of proteomic signatures associated with lung cancer and COPD.
Pastor M D,Nogal A,Molina-Pinelo S,Meléndez R,Salinas A,González De la Peña M,Martín-Juan J,Corral J,García-Carbonero R,Carnero A,Paz-Ares L
Journal of proteomics
Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) commonly coexist in smokers, and the presence of COPD increases the risk of developing LC. The aim of this study was to identify distinct proteomic profiles able to discriminate these two pathological entities. Protein content was assessed in the bronchoalveolar lavage (BAL) of 60 patients classified in four groups: COPD, COPD and LC, LC without COPD, and control with neither COPD nor LC. Proteins were separated into spots by bidimensional polyacrylamide gel electrophoresis (2D-PAGE) and examined by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF). A total of 40 proteins were differentially expressed in the LC and/or COPD groups as compared with the control group. Distinct protein profiles were identified and validated for each pathological entity (LC and COPD). The main networks involved were related to inflammatory signalling, free radical scavenging and oxidative stress response, and glycolysis and gluconeogenesis pathways. The most relevant signalling link between LC and COPD was through the NF-κB pathway. In conclusion, the protein profiles identified contribute to elucidate the underlying pathogenic pathways of both diseases, and provide new tools of potential use as biomarkers for the early diagnosis of LC. BIOLOGICAL SIGNIFICANCE:Sequence coverage. The protein sequence coverage (95%) was estimated for specific proteins by the percentage of matching amino acids from the identified peptides having confidence greater than or equal to 95% divided by the total number of amino acids in the sequence. Ingenuity Pathways Analysis. Mapping of our proteins onto biological pathways and disease networks demonstrated that 22 proteins were linked to inflammatory signalling (p-value: 1.35 10(-08)-1.42 10(-02)), 15 proteins were associated with free radical scavenging and oxidative stress response (p-value: 4.93 10(-11)-1.27 10(-02)), and 9 proteins were related with glycolysis and gluconeogenesis pathways (p-value: 7.39 10(-09)-1.58 10(-02)).
10.1016/j.jprot.2013.04.037
Concomitant elevations of MMP-9, NGAL, proMMP-9/NGAL and neutrophil elastase in serum of smokers with chronic obstructive pulmonary disease.
Bchir Sarra,Nasr Hela Ben,Bouchet Sandrine,Benzarti Mohamed,Garrouch Abdelhamid,Tabka Zouhair,Susin Santos,Chahed Karim,Bauvois Brigitte
Journal of cellular and molecular medicine
A growing body of evidence points towards smoking-related phenotypic differences in chronic obstructive pulmonary disease (COPD). As COPD is associated with systemic inflammation, we determined whether smoking status is related to serum levels of matrix metalloproteinase-9 (pro- and active MMP-9), neutrophil gelatinase-associated lipocalin (NGAL) and the proMMP-9/NGAL complex in patients with COPD. Serum samples were collected in 100 stable-phase COPD patients (82 smokers, 18 never-smokers) and 28 healthy adults (21 smokers, 7 never-smokers). Serum levels of studied factors were measured in ELISA. Our data provide the first evidence of simultaneously elevated serum levels of MMP-9, NGAL and proMMP-9/NGAL in COPD smokers. While the triad discriminated between smokers and non-smokers in the COPD group, MMP-9 and proMMP-9/NGAL (but not NGAL) discriminated between smokers with and without COPD. Adjustment for age and smoking pack-years did not alter the findings. Serum MMP-9, NGAL and proMMP-9/NGAL levels were not correlated with the GOLD stage or FEV1 decline. Furthermore, serum levels of neutrophil elastase (NE) and MMP-3 (but not of IL-6 and MMP-12) were also higher in COPD smokers than in healthy smokers before and after adjustment for age and pack-years. Among COPD smokers, levels of MMP-9, NGAL and proMMP-9/NGAL were positively correlated with NE (P < 0.0001) but not with the remaining factors. Gelatin zymography detected proMMP-9 in serum samples of healthy and COPD smoking groups. Our results suggest that associated serum levels of proMMP-9, NGAL, proMMP-9/NGAL and NE may reflect the state of systemic inflammation in COPD related to cigarette smoking.
10.1111/jcmm.13057
Increased serum levels of lipocalin-1 and -2 in patients with stable chronic obstructive pulmonary disease.
Wang Xiao-ru,Li Yong-pu,Gao Shui,Xia Wei,Gao Kun,Kong Qing-hua,Qi Hui,Wu Ling,Zhang Jing,Qu Jie-ming,Bai Chun-xue
International journal of chronic obstructive pulmonary disease
Despite a number of studies on biomarkers in chronic obstructive pulmonary disease (COPD), only a few disease-related markers have been identified, yet we still have no satisfactory markers specific to innate immune system and neutrophil activation, which is essential in airway inflammation in COPD. Recent biological studies indicated that lipocalins (LCNs) might be involved in airway inflammation and innate immunity; however, results from available studies on the association of LCNs with COPD are not consistent. We carried out a multicenter prospective observational cohort study to investigate the differences in serum levels of LCN1 and LCN2 between subjects with COPD (n=58) and healthy controls (n=29). Several validated inflammatory markers, including C-reactive protein, tumor necrosis factor-α, interleukin-6, and interleukin-8, were measured. The correlation of LCN1 and LCN2 with clinical features such as smoking habits, lung function, symptoms, and disease category was also analyzed. When comparing with healthy controls, serum levels of LCN1 (66.35±20.26 ng/mL versus 41.16±24.19 ng/mL, P<0.001) and LCN2 (11.29±3.92 ng/mL versus 6.09±5.13 ng/mL, P<0.001) were both elevated in subjects with COPD after adjusting for age, sex, smoking habits, and inflammatory biomarkers. Smoking history and tobacco exposure, as quantified by pack-year, had no impact on systemic expressions of LCN1 and LCN2 in our study. Blood levels of LCN1 and LCN2, respectively, were negatively correlated to COPD Assessment Test and Modified Medical British Research Council score (P<0.001). Disease category by Global Initiative for Chronic Obstructive Lung Disease grade 1-4 or group A-D was not associated with levels of LCNs. Patient-reported exacerbations and body mass index were also tested, but no relationship with LCNs was found. In summary, serum concentrations of LCN1 and LCN2 were both elevated in patients with COPD, with their levels correlating to COPD Assessment Test and Modified Medical British Research Council score. These findings warrant large-scale and longitudinal studies to validate LCNs as circulating biomarkers for COPD.
10.2147/COPD.S62700
Augmented Lipocalin-2 Is Associated with Chronic Obstructive Pulmonary Disease and Counteracts Lung Adenocarcinoma Development.
Treekitkarnmongkol Warapen,Hassane Maya,Sinjab Ansam,Chang Kyle,Hara Kieko,Rahal Zahraa,Zhang Jiexin,Lu Wei,Sivakumar Smruthy,McDowell Tina L,Kantrowitz Jacob,Zhou Jianling,Lang Wenhua,Xu Li,Ochieng Joshua K,Nunomura-Nakamura Sayuri,Deng Shanshan,Behrens Carmen,Raso Maria Gabriela,Fukuoka Junya,Reuben Alexandre,Ostrin Edwin J,Parra Edwin,Solis Luisa M,Spira Avrum E,McAllister Florencia,Cascone Tina,Wistuba Ignacio I,Moghaddam Seyed Javad,Scheet Paul A,Fujimoto Junya,Kadara Humam
American journal of respiratory and critical care medicine
Early pathogenesis of lung adenocarcinoma (LUAD) remains largely unknown. We found that, relative to wild-type littermates, the innate immunomodulator (lipocalin-2) was increased in normal airways from mice with knockout of the airway lineage gene () and that are prone to developing inflammation and LUAD. Yet, the role of LCN2 in lung inflammation and LUAD is poorly understood. Delineate the role of induction in LUAD pathogenesis. Normal airway brushings, uninvolved lung tissues, and tumors from mice before and after tobacco carcinogen exposure were analyzed by RNA sequencing. mRNA was analyzed in public and in-house data sets of LUAD, lung squamous cancer (LUSC), chronic obstructive pulmonary disease (COPD), and LUAD/LUSC with COPD. LCN2 protein was immunohistochemically analyzed in a tissue microarray of 510 tumors. Temporal lung tumor development, gene expression programs, and host immune responses were compared between and / littermates. was progressively elevated during LUAD development and positively correlated with proinflammatory cytokines and inflammation gene sets. was distinctively elevated in human LUADs, but not in LUSCs, relative to normal lungs and was associated with COPD among smokers and patients with LUAD. Relative to mice, / littermates exhibited significantly increased lung tumor development concomitant with reduced T-cell abundance (CD4) and richness, attenuated antitumor immune gene programs, and increased immune cell expression of protumor inflammatory cytokines. Augmented LCN2 expression is a molecular feature of COPD-associated LUAD and counteracts LUAD development by maintaining antitumor immunity.
10.1164/rccm.202004-1079OC