Receptor for advanced glycation end products (RAGE) is implicated in inflammatory responses in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), but its role in pulmonary edema formation remains unclear, especially in infection-related ARDS mainly caused by pneumonia or sepsis. In this study, we investigated the role of RAGE in alveolar fluid regulation by using RAGE gene knockout (RAGE) mice in a murine ALI model induced by lipopolysaccharide (LPS), and by comparing soluble RAGE (sRAGE) levels in serum and bronchial alveolar lavage fluid between ARDS patients and control subjects. We found that RAGE knockout significantly improved alveolar fluid clearance and reduced pulmonary vascular albumin leakage upon LPS challenge. Furthermore, LPS-induced substantial decrease in lung expression of sodium-potassium ATPase (Na,K-ATPase), epithelial sodium channel, and zonula occluden-1 (ZO-1) were fully or partially restored by the deletion of RAGE. In addition to this, LPS-induced lung leukocyte infiltration and inflammatory cytokine and chemokine release were all attenuated in RAGE mice as compared to wide-type mice. In infection-related ARDS patients, both serum and bronchial alveolar lavage fluid levels of the sRAGE were much higher than those in control subjects, and they were positively correlated with pulmonary vascular permeability and levels of interleukin (IL)-6, IL-8, and macrophage inflammatory protein (MIP)-2. Taken together, we provided the first direct evidence for the essential role of RAGE in regulating lung fluid balance in infection-related ARDS/ALI. The underlying mechanisms may involve the downregulation of both ion-channel and tight junction proteins mediated by RAGE signaling in bacterial endotoxin-induced lung injury.
Acute lung injury (ALI) is characterized by alveolar epithelial damage and uncontrolled pulmonary inflammation. Mitochondrial damage-associated molecular patterns (DAMPs), including mitochondrial peptides (N-formyl peptides, NFPs), are released during cell injury and death and induce inflammation by unclear mechanisms. In this study, we have investigated the role of mitochondrial DAMPs (MTDs), especially NFPs, in alveolar epithelial injury and lung inflammation. In murine models of ALI, high levels of mitochondrial NADH dehydrogenase 1 in bronchoalveolar lavage fluid (BALF) were associated with lung injury scores and increased formyl peptide receptor (FPR)-1 expression in the alveolar epithelium. Cyclosporin H (CsH), a specific inhibitor of FPR1, inhibited lung inflammation in the ALI models. Both MTDs and NFPs upon intratracheal challenge caused accumulation of neutrophils into the alveolar space with elevated BALF levels of mouse chemokine KC, interleukin-1β and nitric-oxide and increased pulmonary FPR-1 levels. CsH significantly attenuated MTDs or NFP-induced inflammatory lung injury and activation of MAPKs and AKT pathways. FPR1 expression was present in rat primary alveolar epithelial type II cells (AECIIs) and was increased by MTDs. CsH inhibited MTDs or NFP-induced CINC-1/IL-8 release and phosphorylation of p38, JNK, and AKT in rat AECII and human cell line A549. Inhibitors of MAPKs and AKT also suppressed MTD-induced IL-8 release and NF-κB activation. Collectively, our data indicate an important role of the alveolar epithelium in initiating immune responses to MTDs released during ALI. The potential mechanism may involve increase of IL-8 production in MTD-activated AECII through FPR-1 and its downstream MAPKs, AKT, and NF-κB pathways.
BackgroundEndocan is thought to be a novel inflammatory marker that is associated with a variety of inflammatory diseases. However, its role in the pathogenesis of COPD remains unclear. This study aims to explore the potential role of endocan in COPD.MethodsIn total, 27 healthy volunteers, 55 COPD patients and 36 acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients were included in the study. Basic demographic characteristics, clinical features and blood samples were collected. Magnetic luminex screening assays were used to detect the concentration of endocan, Fas and Fas ligand (Fas-L) in plasma. Differences between groups were compared using an Independent sample t-test, Welch’s t-test, chi-squared test and Wilcoxon rank sum test. The correlations of plasma endocan with lung function parameters, Fas and Fas-L were analyzed by Pearson’s partial correlation test (adjusted for age, gender, body mass index and smoking history) and multiple linear regression.ResultsPlasma endocan levels in COPD patients were significantly higher than those in healthy volunteers (509.7±18.25 pg/mL vs 434.8±18.98 pg/mL (P=0.0124)), and AECOPD patients had the highest levels of endocan (524.7±27.18 pg/mL). Correlation analysis showed that circulating endocan had a negative correlation to FEV1/FVC, FEV1/predictive and FVC (adjusted r=−0.213, P=0.03; adjusted r=−0.209, P=0.034; and adjusted r=−0.300, P=0.002, respectively), and had a positive correlation to Fas (adjusted r=0.280, P=0.004).ConclusionOur study shows that elevated circulating endocan levels are associated with reduced lung ventilation function in COPD and AECOPD patients. In addition, endocan may influence apoptosis in COPD, suggesting that endocan may play a role in COPD pathogenesis.
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