Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown etiology; however, apoptosis of lung alveolar epithelial cells plays a role in disease progression. This intractable disease is associated with increased abundance of Staphylococcus and Streptococcus in the lungs, yet their roles in disease pathogenesis remain elusive. Here, we report that Staphylococcus nepalensis releases corisin, a peptide conserved in diverse staphylococci, to induce apoptosis of lung epithelial cells. The disease in mice exhibits acute exacerbation after intrapulmonary instillation of corisin or after lung infection with corisin-harboring S. nepalensis compared to untreated mice or mice infected with bacteria lacking corisin. Correspondingly, the lung corisin levels are significantly increased in human IPF patients with acute exacerbation compared to patients without disease exacerbation. Our results suggest that bacteria shedding corisin are involved in acute exacerbation of IPF, yielding insights to the molecular basis for the elevation of staphylococci in pulmonary fibrosis.
Background Bronchial asthma is a chronic disease characterized by inflammation, obstruction, and hyperresponsiveness of the airways. There is currently no curative therapy for asthma. Type 2 helper T cell response plays a critical role in the pathogenesis of the disease. Protein S is a glycoprotein endowed with anticoagulant, anti‐inflammatory, and anti‐apoptotic properties. Whether protein S can suppress bronchial asthma and be useful for its therapy is unknown. Methods To address this question here we compared the development of allergen‐associated bronchial asthma between wild type and protein S‐overexpressing transgenic mice. Mice were sensitized and challenged with ovalbumin. We also evaluated the circulating levels of total and active protein S in patients with bronchial asthma and healthy controls. Results The circulating level of total protein S and of its active form was significantly decreased in patients with bronchial asthma compared to controls. Allergic protein S transgenic mice showed a significant reduction of airway hyperresponsiveness, lung tissue inflammatory cell infiltration, lung levels of Th2 cytokines and IgE compared to their wild‐type counterparts. Administration of exogenous human protein S also decreased airway hyperresponsiveness and Th2‐mediated lung inflammation in allergic wild‐type mice compared with their untreated mouse counterparts. Human protein S significantly shifted the Th1/Th2 balance to Th1 and promoted the secretion of Th1 cytokines (IL‐12, tumor necrosis factor‐α) from dendritic cells. Conclusions These observations suggest the strong protective activity of protein S against the development of allergic bronchial asthma implicating its potential usefulness for the disease treatment.
Epithelial cell apoptosis is critical in the pathogenesis of idiopathic pulmonary fibrosis. Protein S, a circulating anticoagulant, inhibited apoptosis of lung epithelial cells. Overexpression of protein S in lung cells reduced bleomycin‐induced pulmonary fibrosis. Intranasal therapy with exogenous protein S ameliorated bleomycin‐induced pulmonary fibrosis. Summary BackgroundPulmonary fibrosis is the terminal stage of interstitial lung diseases, some of them being incurable and of unknown etiology. Apoptosis plays a critical role in lung fibrogenesis. Protein S is a plasma anticoagulant with potent antiapoptotic activity. The role of protein S in pulmonary fibrosis is unknown. ObjectivesTo evaluate the clinical relevance of protein S and its protective role in pulmonary fibrosis. Methods and ResultsThe circulating level of protein S was measured in patients with pulmonary fibrosis and controls by the use of enzyme immunoassays. Pulmonary fibrosis was induced with bleomycin in transgenic mice overexpressing human protein S and wild‐type mice, and exogenous protein S or vehicle was administered to wild‐type mice; fibrosis was then compared in both models. Patients with pulmonary fibrosis had reduced circulating levels of protein S as compared with controls. Inflammatory changes, the levels of profibrotic cytokines, fibrosis score, hydroxyproline content in the lungs and oxygen desaturation were significantly reduced in protein S‐transgenic mice as compared with wild‐type mice. Wild‐type mice treated with exogenous protein S showed significant decreases in the levels of inflammatory and profibrotic markers and fibrosis in the lungs as compared with untreated control mice. After bleomycin infusion, mice overexpressing human protein S showed significantly low caspase‐3 activity, enhanced expression of antiapoptotic molecules and enhanced Akt and Axl kinase phosphorylation as compared with wild‐type counterparts. Protein S also inhibited apoptosis of alveolar epithelial cells in vitro. ConclusionsThese observations suggest clinical relevance and a protective role of protein S in pulmonary fibrosis.
Summary Background Alcohol consumption is a major cause of liver injury but the mechanisms are not completely understood. Protein S (PS) is an anticoagulant glycoprotein with multiple functions. The role of PS in liver injury is unknown. Objectives This study investigated the role of PS in acute alcoholic hepatitis. Methods A mouse overexpressing human PS (hPS‐TG) was generated in which acute hepatitis was induced by intraperitoneal injection of ethanol. Results The levels of serum liver enzymes and liver tissue inflammatory cytokines and the degree of hepatic steatosis were significantly increased in hPS‐TG mice treated with ethanol compared with ethanol‐treated wild type (WT) mice. Cell expansion, activation and inhibition of apoptosis were significantly augmented in natural killer T (NKT) cells from hPS‐TG mice compared with WT mice. Liver mononuclear cells from hPS‐TG mice express higher levels of inflammatory cytokines than those from WT mice after stimulation with a specific stimulant of NKT cells in vitro. In a co‐culture system of hepatocytes and NKT cells, the effects of PS on ethanol‐mediated cell injury were suppressed by a CD1d neutralizing antibody. Alcoholic liver injury was significantly improved in mice pre‐treated with PS siRNA and anti‐protein S antibody compared with control mice. Patients with alcoholic hepatitis showed significantly increased plasma PS levels and enhanced liver expression of PS and CD1d compared with controls. Conclusions The results of this study suggest that PS exacerbates acute alcoholic hepatitis by inhibiting apoptosis of activated NKT cells.
Background and objective Activation of the blood coagulation system is a common observation in inflammatory diseases. The role of coagulation in COPD is underexplored. Methods The study included 413 COPD patients and 49 controls from the 3‐year Bergen COPD Cohort Study (BCCS). One hundred and forty‐eight COPD patients were also examined during AECOPD. The plasma markers of coagulation activation, TAT complex, APC–PCI complex and D‐dimer, were measured at baseline and during exacerbations by enzyme immunoassays. Differences in levels of the markers between stable COPD patients and controls, and between stable COPD and AECOPD were examined. The associations between coagulation markers and later AECOPD and mortality were examined by negative binomial and Cox regression analyses. Results TAT was significantly lower in stable COPD (1.03 ng/mL (0.76–1.44)) than in controls (1.28 (1.04–1.49), P = 0.002). During AECOPD, all markers were higher than in the stable state: TAT 2.56 versus 1.43 ng/mL, APC–PCI 489.3 versus 416.4 ng/mL and D‐dimer 763.5 versus 479.7 ng/mL (P < 0.001 for all). Higher D‐dimer in stable COPD predicted a higher mortality (HR: 1.60 (1.24–2.05), P < 0.001). Higher TAT was associated with both an increased risk of later exacerbations, with a yearly incidence rate ratio of 1.19 (1.04–1.37), and a faster time to the first exacerbation (HR: 1.25 (1.10–1.42), P = 0.001, all after adjustment). Conclusion Activation of the coagulation system is increased during COPD exacerbations. Coagulation markers are potential predictors of later COPD exacerbations and mortality.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.