Effect Of α7 NAChR On Bleomycin - Induced Pulmonary Fibrosis

Introduction Pulmonary fibrosis(PF) is an interstitial lung disease which is characterized by the destruction of pulmonary parenchyma together with deposition of extracel ular matrix(ECM) in the interstitial and alveolar spaces. Recently, one study has demonstrated that unilateral vagotomy could attenuate lung collagen deposition. Vagus nerve through α7 nicotinic acetylcholine receptor(α7 n ACh R) could modulate lung infection, inflammation, and immunity; however, the role of α7 n ACh R in the development of BLM-induced lung inflammation and fibrosis remains unclear.Objective We aimed to test whether α7 n ACh R would play an important role in regulating pulmonary inflammation and fibrosis.Methods Wildtype and α7 n ACh R deficient mice were intratrachealy chalenged with bleomycin(BLM at 3 mg/kg to induce acute lung inflammation for 7 days; at 1.5 mg/kg for 14 days, especially 0.5 mg/kg for 21 days to elicit lung fibrosis) to measure the changes of body weights and lung fibrogenic genes(Acta2, Col1a1, Fsp1, and Fstl1). Histologically, Masson’s Trichrome and immunohistochemistry staining were performed for evaluating severity of lung fibrosis. Fibroblasts were also pretreated with α7 n ACh R agonist GTS-21 to study TGF-β1 signaling and its downstream profibrotic profiles.Results During BLM-induced lung inflammation and injury, Chrna7 expression was 12-fold increased. Deletion of Chrna7 prevented body weight loss and reduced lung fibrogenic genes(Acta2, Col1a1, Fsp1, and Fstl1) compared to wildtype in BLM-induced lung fibrosis. Knockout of Chrna7 do not affect BLM-elicited lung inflammation, but attenuated intensity of Masson’s Trichrome, and Collagen 1 immunohistochemistry staining, and hydroxyproline levels. Mechanistical y, activation of α7 n ACh R in fibroblasts increased rh TGF-β1 induced phosphorylation of Smad2/3 and transcription and translation of fibrogenic gene(Acta2, Col1a1) in a PTP1B-dependent manner.Conclusion Deficiency of Chrna7 attenuates bleomycin-induced lung fibrosis. Activation of α7 n ACh R increases TGF-β signaling in fibroblasts. This study indicates α7 n ACh R is a novel therapeutic target for pulmonary fibrosis.