title: RhoA/Rho-kinase activation promotes lung fibrosis in an animal model of systemic sclerosis.
abstract: BACKGROUND
  Systemic sclerosis (SSc) is a connective-tissue disease characterized by vascular injury, immune-system disorders, and excessive fibrosis of the skin and multiple internal organs. Recent reports found that RhoA/Rho-kinase (ROCK) pathway is implicated in various fibrogenic diseases. Intradermal injection of hypochlorous acid (HOCl)-generating solution induced inflammation, autoimmune activation, and fibrosis, mimicking the cutaneous diffuse form of SSc in humans. Our study aimed firstly to describe pulmonary inflammation and fibrosis induced by HOCl in mice, and secondly to determine whether fasudil, a selective inhibitor of ROCK, could prevent lung and skin fibroses in HOCl-injected mice.
  
  
  METHODS
  Female C57BL/6 mice received daily intradermal injection of hypochlorous acid (HOCl) for 6 weeks to induce SSc, with and without daily treatment with fasudil (30 mg·kg(-1)·day(-1)) by oral gavage.
  
  
  RESULTS
  HOCl intoxication induced significant lung inflammation (macrophages and neutrophils infiltration), and fibrosis. These modifications were prevented by fasudil treatment. Simultaneously, HOCl enhanced ROCK activity in lung and skin tissues. Inhibition of ROCK reduced skin fibrosis, expression of α-smooth-muscle actin and 3-nitrotyrosine, as well as the activity of ROCK in the fibrotic skin of HOCl-treated mice, through inhibition of phosphorylation of Smad2/3 and ERK1/2. Fasudil significantly decreased the serum levels of anti-DNA-topoisomerase-1 antibodies in mice with HOCl-induced SSc.
  
  
  CONCLUSIONS
  Our findings confirm HOCl-induced pulmonary inflammation and fibrosis in mice, and provide further evidence for a key role of RhoA/ROCK pathway in several pathological processes of experimental SSc. Fasudil could be a promising therapeutic approach for the treatment of SSc.
authors.affiliation: a Laboratoire de Physiologie Respiratoire, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP) , Paris , France.|b Regeneration Lab and Experimental Center of Life Sciences, School of Life Science, Shanghai University , Shanghai , China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Bei
authors.affiliation: a Laboratoire de Physiologie Respiratoire, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP) , Paris , France.
authors.forename: Thong
authors.initials: T
authors.lastname: Hua-Huy
authors.affiliation: c Laboratoire d'Immunologie Clinique, Universite Paris Descartes, Sorbonne Paris Cite, Equipe Batteux, Institut Cochin, Hopital Cochin, Assistance Publique-Hopitaux de Paris (AP-HP) , Paris , France.
authors.forename: Carole
authors.initials: C
authors.lastname: Nicco
authors.affiliation: a Laboratoire de Physiologie Respiratoire, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP) , Paris , France.
authors.forename: Sy
authors.initials: S
authors.lastname: Duong-Quy
authors.affiliation: a Laboratoire de Physiologie Respiratoire, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP) , Paris , France.|d Department of Pneumology, St. Elisabeth Hospital , Namur , Belgium.
authors.forename: Nhat-Nam
authors.initials: NN
authors.lastname: Le-Dong
authors.affiliation: a Laboratoire de Physiologie Respiratoire, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP) , Paris , France.|e Department of Internal Medicine, Hospital of Vitry sur Seine , Site Pasteur , Vitry sur Seine , France.
authors.forename: Kiet-Phong
authors.initials: KP
authors.lastname: Tiev
authors.affiliation: b Regeneration Lab and Experimental Center of Life Sciences, School of Life Science, Shanghai University , Shanghai , China.
authors.forename: Christiane
authors.initials: C
authors.lastname: Chéreau
authors.affiliation: b Regeneration Lab and Experimental Center of Life Sciences, School of Life Science, Shanghai University , Shanghai , China.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
authors.affiliation: a Laboratoire de Physiologie Respiratoire, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP) , Paris , France.
authors.forename: Anh Tuan
authors.initials: AT
authors.lastname: Dinh-Xuan
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000199:Actins / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006997:Hypochlorous Acid / Q000494:pharmacology; D008168:Lung / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology*; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D012867:Skin / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D000199:Actins; D051899:Smad2 Protein; D051900:Smad3 Protein; C544013:alpha-smooth muscle actin, mouse; C002744:3-nitrotyrosine; D014443:Tyrosine; D006997:Hypochlorous Acid; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil
keywords: Rho-kinase; fasudil; pulmonary fibrosis; pulmonary inflammation; systemic sclerosis