Inhibition of angiotensin II and calpain attenuates pleural fibrosis. (February 2018) - Song, Lin-Jie
Abstract: Pleural fibrosis is associated with various inflammatory processes such as tuberculous pleurisy and bacterial empyema. There is currently no ideal therapeutic to attenuate pleural fibrosis. Some pro-fibrogenic mediators induce fibrosis through inflammatory processes, suggesting that blockage of these mediators might prevent pleural fibrosis. The MeT-5A human pleural mesothelial cell line (PMC) was used in this study as an in vitro model of fibrosis; and intra-pleural injection of bleomycin with carbon particles was used as an in vivo mouse model of pleural fibrosis. Calpain knockout mice, calpain inhibitor (calpeptin), and angiotensin (Ang) II type 1 receptor (AT1 R) antagonist (losartan) were evaluated in prevention of experimental pleural fibrosis. We found that bleomycin and carbon particles induced calpain activation in cultured PMCs. This in vitro response was associated with increased collagen-I synthesis, and was blocked by calpain inhibitor or AT1 R antagonist. Calpain genetic or treatment with calpeptin or losartan prevented pleural fibrosis in a mouse model induced by bleomycin and carbon particles. Our findings indicate that Ang II signaling and calpain activation induce collagen-I synthesis and contribute to fibrotic alterations in pleural fibrosis. Inhibition of Ang II and calpain might therefore be a novel strategy in treatment of pleural fibrosis. Highlights: Bleomycin and carbon induces calpain activation in pleural mesothelial cells (PMCs). Calpain is activated in PMCs through angiotensin II type 1 receptor (AT1 R). Calpain inhibitor or AT1 R antagonist prevents collagen-I synthesis in PMCs. Calpain knockout attenuates bleomycin and carbon induced experimental pleural fibrosis. Calpain inhibitor or AT1 R antagonist also attenuates experimental pleural fibrosis.