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Molecular Medicine

, Volume 23, Issue 1, pp 34–49 | Cite as

Deficiency of α7 Nicotinic Acetylcholine Receptor Attenuates Bleomycin-Induced Lung Fibrosis in Mice

  • Peiyu Sun
  • Ling Li
  • Caiqi Zhao
  • Mengyao Pan
  • Zhikang Qian
  • Xiao Su
Research Article

Abstract

α7 nicotinic acetylcholine receptor (α7 nAChR, coded by Chrna7) is indispensable in dampening proinflammatory responses. However, whether α7 nAChR plays a role in regulating bleomycin (BLM)-induced lung fibrosis is less investigated. Here, we challenged wild-type and Chrna7−/− mice with BLM intratracheally to elicit lung fibrosis. Taking advantage of this model, we measured body weight loss, lung fibrogenic genes (Acta2, Col1a1, Fsp1 and Fstl1), histology, Masson’s trichrome staining, hydroxyproline levels and expression of α-SMA at protein levels in the BLM-challenged lung to evaluate the 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 lung Chrna7 expression and CD4+CHAT+ cells (choline acetyltransferase, an enzyme for local acetylcholine synthesis) were elevated 12-fold and 4.5-fold, respectively, in the early stage of lung fibrosis. Deletion of Chrna7 prevented body-weight loss and reduced lung fibrogenic genes (Acta2, Colla1, Fsp1 and Fstl1) and Arg 1 (coding arginase 1). Deletion of Chrna7 attenuated 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, Colla1). In isolated mouse lung fibroblasts, activation of α7 nAChR also enhanced TGF-β-induced transcription of fibrogenic genes; however, deletion of Chrna7 diminished 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.

Notes

Acknowledgments

The authors appreciate Yiyi Jiang for breeding and genotyping animals and Bangguo Qian for technical assistance in histological staining.

Our research is supported by the Major Research plan of NSFC 91542105, NSFC 81270139 and 81470269; the 100 Talents Project of the CAS 2A2013311211004; the Knowledge Innovation Program of CAS 24P201200201; the STS Plan of CAS KFJ-EW-STS-098); and Shanghai Key Grant 12JC1408900.

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Authors and Affiliations

  • Peiyu Sun
    • 1
  • Ling Li
    • 2
  • Caiqi Zhao
    • 2
  • Mengyao Pan
    • 2
  • Zhikang Qian
    • 3
  • Xiao Su
    • 2
  1. 1.Life and Environment Science CollegeShanghai Normal UniversityShanghaiChina
  2. 2.Unit of Respiratory Infection and Immunity, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of ShanghaiChinese Academy of SciencesShanghaiChina
  3. 3.Unit of Herpesvirus and Molecular VirologyInstitut Pasteur of ShanghaiShanghaiChina

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