Exercise training ameliorates bleomycin-induced epithelial mesenchymal transition and lung fibrosis through restoration of H2 S synthesis.

AIMS: Clinical trials have shown the beneficial effects of exercise training against pulmonary fibrosis. This study aimed to investigate whether prophylactic intervention with exercise training attenuates lung fibrosis via modulating endogenous hydrogen sulphde (H2 S) generation. METHODS: First, ICR mice were allocated to Control, Bleomycin, Exercise, and Bleomycin + Exercise groups. Treadmill exercise began on day 1 and continued for 4 weeks. A single intratracheal dose of bleomycin (3 mg/kg) was administered on day 15. Second, ICR mice were allocated to Control, Bleomycin, H2 S, and Bleomycin + H2 S groups. H2 S donor NaHS (28 µmol/kg) was intraperitoneally injected once daily for 2 weeks. RESULTS: Bleomycin-treated mice exhibited increased levels of collagen deposition, hydroxyproline, collagen I, transforming growth factor (TGF)-ß1, Smad2/Smad3/low-density lipoprotein receptor-related proteins (LRP-6)/glycogen synthase kinase-3ß (GSK-3ß) phosphorylation, and Smad4/ß-catenin expression in lung tissues (P < 0.01), which was alleviated by exercise training (P < 0.01 except for Smad4 and phosphorylated GSK-3ß: P < 0.05). Bleomycin-induced lung fibrosis was associated with increased α smooth muscle actin (α-SMA) and decreased E-cadherin expression (P < 0.01). Double immunofluorescence staining showed the co-localization of E-cadherin/α-SMA, indicating epithelial-mesenchymal transition (EMT) formation, which was ameliorated by exercise training. Moreover, exercise training restored bleomycin-induced downregulation of cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE) expression, as well as H2 S generation in lung tissue (P < 0.01). NaHS treatment attenuated bleomycin-induced TGF-ß1 production, activation of LRP-6/ß-catenin signalling, EMT and lung fibrosis (P < 0.01 except for ß-catenin: P < 0.05). CONCLUSION: Exercise training restores bleomycin-induced downregulation of pulmonary CBS/CSE expression, thus contributing to the increased H2 S generation and suppression of TGF-ß1/Smad and LRP-6/ß-catenin signalling pathways, EMT and lung fibrosis.

In obese mice, exercise training increases 11ß-HSD1 expression, contributing to glucocorticoid activation and suppression of pulmonary inflammation.

Exercise training is advocated for treating chronic inflammation and obesity-related metabolic syndromes. Glucocorticoids (GCs), the anti-inflammatory hormones, are synthesized or metabolized in extra-adrenal organs. This study aims to examine whether exercise training affects obesity-associated pulmonary inflammation by regulating local GC synthesis or metabolism. We found that sedentary obese (ob/ob) mice exhibited increased levels of interleukin (IL)-1ß, IL-18, monocyte chemotactic protein (MCP)-1, and leukocyte infiltration in lung tissues compared with lean mice, which was alleviated by 6 wk of exercise training. Pulmonary corticosterone levels were decreased in ob/ob mice. Exercise training increased pulmonary corticosterone levels in both lean and ob/ob mice. Pulmonary corticosterone levels were negatively correlated with IL-1ß, IL-18, and MCP-1. Immunohistochemical staining of the adult mouse lung sections revealed positive immunoreactivities for the steroidogenic acute regulatory protein, the cholesterol side-chain cleavage enzyme (CYP11A1), the steroid 21-hydroxylase (CYP21), 3ß-hydroxysteroid dehydrogenase (3ß-HSD), and type 1 and type 2 11ß-hydroxysteroid dehydrogenase (11ß-HSD) but not for 11ß-hydroxylase (CYP11B1). Exercise training significantly increased pulmonary 11ß-HSD1 expression in both lean and ob/ob mice. In contrast, exercise training per se had no effect on pulmonary 11ß-HSD2 expression, although pulmonary 11ß-HSD2 levels in ob/ob mice were significantly higher than in lean mice. RU486, a glucocorticoid receptor antagonist, blocked the anti-inflammatory effects of exercise training in lung tissues of obese mice and increased inflammatory cytokines in lean exercised mice. These findings indicate that exercise training increases pulmonary expression of 11ß-HSD1, thus contributing to local GC activation and suppression of pulmonary inflammation in obese mice.NEW & NOTEWORTHY Treadmill training leads to a significant increase in pulmonary corticosterone levels in ob/ob mice, which is in parallel with the favorable effects of exercise on obesity-associated pulmonary inflammation. Exercise training increases pulmonary 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) expression but has no significant effect on 11ß-HSD2 expression in both lean and ob/ob mice. These findings indicate that exercise training increases pulmonary expression of 11ß-HSD1, thus contributing to local glucocorticoid activation and suppression of pulmonary inflammation in obese mice.