title: Protein S is protective in pulmonary fibrosis.
abstract: Essentials Epithelial cell apoptosis is critical in the pathogenesis of idiopathic pulmonary fibrosis. Protein S, a circulating anticoagulant, inhibited apoptosis of lung epithelial cells. Overexpression of protein S in lung cells reduced bleomycin-induced pulmonary fibrosis. Intranasal therapy with exogenous protein S ameliorated bleomycin-induced pulmonary fibrosis.
  
  
  
  Background Pulmonary fibrosis is the terminal stage of interstitial lung diseases, some of them being incurable and of unknown etiology. Apoptosis plays a critical role in lung fibrogenesis. Protein S is a plasma anticoagulant with potent antiapoptotic activity. The role of protein S in pulmonary fibrosis is unknown. Objectives To evaluate the clinical relevance of protein S and its protective role in pulmonary fibrosis. Methods and Results The circulating level of protein S was measured in patients with pulmonary fibrosis and controls by the use of enzyme immunoassays. Pulmonary fibrosis was induced with bleomycin in transgenic mice overexpressing human protein S and wild-type mice, and exogenous protein S or vehicle was administered to wild-type mice; fibrosis was then compared in both models. Patients with pulmonary fibrosis had reduced circulating levels of protein S as compared with controls. Inflammatory changes, the levels of profibrotic cytokines, fibrosis score, hydroxyproline content in the lungs and oxygen desaturation were significantly reduced in protein S-transgenic mice as compared with wild-type mice. Wild-type mice treated with exogenous protein S showed significant decreases in the levels of inflammatory and profibrotic markers and fibrosis in the lungs as compared with untreated control mice. After bleomycin infusion, mice overexpressing human protein S showed significantly low caspase-3 activity, enhanced expression of antiapoptotic molecules and enhanced Akt and Axl kinase phosphorylation as compared with wild-type counterparts. Protein S also inhibited apoptosis of alveolar epithelial cells in vitro. Conclusions These observations suggest clinical relevance and a protective role of protein S in pulmonary fibrosis.
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Tsu, Mie, Japan.|Department of Immunology, Tsu, Mie, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Urawa
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Tsu, Mie, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Department of Immunology, Tsu, Mie, Japan.
authors.forename: C N
authors.initials: CN
authors.lastname: D'Alessandro-Gabazza
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Tsu, Mie, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Fujimoto
authors.affiliation: Department of Immunology, Tsu, Mie, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Toda
authors.affiliation: Department of Immunology, Tsu, Mie, Japan.
authors.forename: Z
authors.initials: Z
authors.lastname: Roeen
authors.affiliation: Department of Immunology, Tsu, Mie, Japan.
authors.forename: J A
authors.initials: JA
authors.lastname: Hinneh
authors.affiliation: Department of Immunology, Tsu, Mie, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yasuma
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Tsu, Mie, Japan.|Department of Gastroenterology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Takei
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Tsu, Mie, Japan.
authors.forename: O
authors.initials: O
authors.lastname: Taguchi
authors.affiliation: Department of Immunology, Tsu, Mie, Japan.
authors.forename: E C
authors.initials: EC
authors.lastname: Gabazza
mesh_terms: D000072283:A549 Cells; D000368:Aged; D000818:Animals; D017209:Apoptosis; D001761:Bleomycin; D001798:Blood Proteins / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid; D053148:Caspase 3 / Q000378:metabolism; D004847:Epithelial Cells / Q000473:pathology*; D005260:Female; D005355:Fibrosis / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000097:blood* / Q000139:chemically induced; D007124:Immunoenzyme Techniques; D007249:Inflammation; D008168:Lung / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D010766:Phosphorylation; D017293:Protein S / Q000378:metabolism*
chemical_list: D001798:Blood Proteins; C523390:PROS1 protein, human; D017293:Protein S; D001761:Bleomycin; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: anticoagulants; apoptosis; coagulation; lung fibrosis; protein S