Contraction-dependent TGF-β1 activation is required for thrombin-induced remodeling in human airway smooth muscle cells

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Aims:Thrombin is a serine proteinase that is not only involved in coagulation cascade, but also mediates a number of biological responses relevant to tissues repair, and induces bronchoconstriction. TGF-β plays a pivotal role in airway remodeling due to its effects on airway smooth muscle proliferation and extracellular matrix (ECM) deposition. Recently, bronchoconstriction itself is found to constitute a form of strain and is highly relevant to asthmatic airway remodeling. However, the underlying mechanisms remain unknown. Here, we investigated the role of contraction- dependent TGF-β activation in thrombin-induced remodeling in human airway smooth muscle (HASM) cells.Materials and methods:Primary HASM cells were treated with or without thrombin in the absence or presence of anti-TGF-β antibody, cytochalasin D and formoterol. CFSE labeling index or CCK-8 assay were performed to test cell proliferation. RT-PCR and Western blotting were used to examined ECM mRNA level and collagen Iα1, α-actin protein expression, respectively. Immunofluorescence was also used to confirm contraction induced by thrombin in HASM cells.Key finding:Thrombin stimulation enhanced HASM cells proliferation and activated TGF-β signaling. Thrombin induced ECM mRNA and collagen Iα1 protein expression, and these effects are mediated by TGF-β. Abrogation of TGF-β activation by contraction inhibitors cytochalasin D and formoterol prevents the thrombin-induced effects.Significance:These findings suggest that contraction-dependent TGF-β activation could be a mechanism by which thrombin leads to the development of asthmatic airway remodeling. Blocking physical forces with bronchodilator would be an intriguing way in reducing airway remodeling in asthma.

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