title: Deficiency of α7 nicotinic acetylcholine receptor attenuates bleomycin-induced lung fibrosis in mice.
abstract: α7 nicotinic acetylcholine receptor (α7 nAChR, coded byChrna7) is indispensible in dampening proinflammatory responses. However, whether α7 nAChR would play a role in regulating bleomycin (BLM)-induced lung fibrosis is less investigated. Here, we intratracheally challenged wildtype andChrna7-/-mice with BLM to elicit lung fibrosis. Taken advantage of this model, we measured body weight loss, lung fibrogenic genes (Acta2,Col1a1,Fsp1, andFstl1), histology, Masson's trichrome staining, hydroxyproline levels, and expression of α-SMA at protein levels in the BLM-challenged lung for evaluating severity of lung fibrosis. We also pretreated human fibroblasts (MRC5 cell line) and isolated mouse lung fibroblasts with GTS-21 (an α7 nAChR agonist) to study its effects on TGF-β-stimulated profibrotic profiles. We found that lungChrna7expression and CD4+CHAT+(Choline acetyltransferase, an enzyme for local acetylcholine synthesis) cells were 12-fold and 4.5-fold respectively elevated in the early stage of lung fibrosis. Deletion ofChrna7prevented body weight loss and reduced lung fibrogenic genes (Acta2,Col1a1,Fsp1, andFstl1) andArg 1(coding arginase 1). Deletion ofChrna7attenuated lung arginase 1+Ly6C+cells, Masson's trichrome staining, hydroxyproline levels, and expression of α-SMA at protein levels in BLM-challenged mice. Mechanistically, activation of α7 nAChR in human fibroblasts increased TGF-β-induced phosphorylation of Smad2/3 and transcription of fibrogenic genes (Acta2,Col1a1). In isolated mouse lung fibroblasts, activation of α7 nAChR also enhanced TGF-β induced-transcription of fibrogenic genes; however, deletion ofChrna7diminished these effects. Taken together, deficiency of α7 nAChR could suppress the development of BLM-induced lung fibrosis. Thus, α7 nAChR might be a novel therapeutic target for treating lung fibrosis.
authors.affiliation: Life and Environment Science College, Shanghai Normal University, Shanghai, China.
authors.forename: Peiyu
authors.initials: P
authors.lastname: Sun
authors.affiliation: Unit of Respiratory Infection and Immunity, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Unit of Respiratory Infection and Immunity, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
authors.forename: Caiqi
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Unit of Respiratory Infection and Immunity, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
authors.forename: Mengyao
authors.initials: M
authors.lastname: Pan
authors.affiliation: Unit of Herpesvirus and Molecular Virology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zhikang
authors.initials: Z
authors.lastname: Qian
authors.affiliation: Unit of Respiratory Infection and Immunity, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Su
mesh_terms: D000818:Animals; D001761:Bleomycin; D002460:Cell Line; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000172:deficiency* / Q000235:genetics
chemical_list: C579166:Chrna7 protein, mouse; D016212:Transforming Growth Factor beta; D064569:alpha7 Nicotinic Acetylcholine Receptor; D001761:Bleomycin
keywords: Bleomycin; Lung fibrosis; PTP1B; TGF-β; α7 nAChR