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.
Protein S is an anticoagulant factor that also regulates inflammation and cell apoptosis. The effect of protein S on diabetes and its complications is unknown. This study compared the development of diabetes between wildtype and transgenic mice overexpressing human protein S and the development of diabetic glomerulosclerosis between mice treated with and without human protein S and between wild-type and protein S transgenic mice. Mice overexpressing protein S showed significant improvements in blood glucose level, glucose tolerance, insulin sensitivity, and insulin secretion compared with wild-type counterparts. Exogenous protein S improved insulin sensitivity in adipocytes, skeletal muscle, and liver cell lines in db/db mice compared with controls. Significant inhibition of apoptosis with increased expression of BIRC3 and Bcl-2 and enhanced activation of Akt/PKB was induced by protein S in islet b-cells compared with controls. Diabetic wild-type mice treated with protein S and diabetic protein S transgenic mice developed significantly less severe diabetic glomerulosclerosis than controls. Patients with type 2 diabetes had significantly lower circulating free protein S than healthy control subjects. This study shows that protein S attenuates diabetes by inhibiting apoptosis of b-cells and the development of diabetic nephropathy.
Pulmonary fibrosis is the terminal stage of a group of idiopathic interstitial pneumonias, of which idiopathic pulmonary fibrosis is the most frequent and fatal form. Recent studies have shown that recombinant human thrombomodulin (rhTM) improves exacerbation and clinical outcome of idiopathic pulmonary fibrosis, but the mechanism remains unknown. This study evaluated the mechanistic pathways of the inhibitory activity of rhTM in pulmonary fibrosis. Transgenic mice overexpressing human transforming growth factor-β1 that develop spontaneously pulmonary fibrosis, and wild-type mice treated with bleomycin were used as models of lung fibrosis. rhTM was administered to mice by i.p. injection or by the intranasal route. Therapy with rhTM significantly decreased the concentration of high mobility group box1, interferon-γ, and fibrinolytic markers, the expression of growth factors including transforming growth factor-β1, and the degree of lung fibrosis. rhTM significantly suppressed apoptosis of lung epithelial cells in in vivo and in vitro experiments. The results of the present study demonstrated that rhTM can inhibit bleomycin-induced pulmonary fibrosis and transforming growth factor-β1-driven exacerbation and progression of pulmonary fibrosis, and that apart from its well-recognized anticoagulant and anti-inflammatory properties, rhTM can also suppress apoptosis of lung epithelial cells.
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