title: Relaxin regulates myofibroblast contractility and protects against lung fibrosis.
abstract: Myofibroblasts are specialized contractile cells that participate in tissue fibrosis and remodeling, including idiopathic pulmonary fibrosis (IPF). Mechanotransduction, a process by which mechanical stimuli are converted into biochemical signals, regulates myofibroblast differentiation. Relaxin is a peptide hormone that mediates antifibrotic effects through regulation of collagen synthesis and turnover. In this study, we demonstrate enhanced myofibroblast contraction in bleomycin-induced lung fibrosis in mice and in fibroblastic foci of human subjects with IPF, using phosphorylation of the regulatory myosin light chain (MLC(20)) as a biomarker of in vivo cellular contractility. Compared with wild-type mice, relaxin knockout mice express higher lung levels of phospho-MLC(20) and develop more severe bleomycin-induced lung fibrosis. Exogenous relaxin inhibits MLC(20) phosphorylation and bleomycin-induced lung fibrosis in both relaxin knockout and wild-type mice. Ex vivo studies of IPF lung myofibroblasts demonstrate decreases in MLC(20) phosphorylation and reduced contractility in response to relaxin. Characterization of the signaling pathway reveals that relaxin regulates MLC(20) dephosphorylation and lung myofibroblast contraction by inactivating RhoA/Rho-associated protein kinase through a nitric oxide/cGMP/protein kinase G-dependent mechanism. These studies identify a novel antifibrotic role of relaxin involving the inhibition of the contractile phenotype of lung myofibroblasts and suggest that targeting myofibroblast contractility with relaxin-like peptides may be of therapeutic benefit in the treatment of fibrotic lung disease.
authors: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Xiangwei
authors: X
authors: Huang
authors: Ying
authors: Y
authors: Gai
authors: Naiheng
authors: N
authors: Yang
authors: Baogen
authors: B
authors: Lu
authors: Chrishan S
authors: CS
authors: Samuel
authors: Victor J
authors: VJ
authors: Thannickal
authors: Yong
authors: Y
authors: Zhou
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D002478:Cells, Cultured; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000503:physiopathology / Q000517:prevention & control*; D040542:Mechanotransduction, Cellular; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D058628:Myofibroblasts / Q000187:drug effects*; D018994:Myosin Light Chains / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000139:chemically induced; D011994:Recombinant Proteins; D012065:Relaxin / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D018994:Myosin Light Chains; D011994:Recombinant Proteins; C485184:enhanced green fluorescent protein; D001761:Bleomycin; D049452:Green Fluorescent Proteins; D012065:Relaxin