title: Direct effects of protein S in ameliorating acute lung injury.
abstract: OBJECTIVE
  Protein S may exert an anticoagulant activity by enhancing the anticoagulant activity of activated protein C and/or by directly inhibiting the prothrombinase complex. Protein S itself may also directly regulate inflammatory responses and apoptosis. The role of protein S in acute lung injury (ALI) was unknown. This study evaluated the effect of protein S on ALI in the mouse.
  
  
  METHODS
  Animal ALI was induced in C57/BL6 mice by intratracheal instillation of lipopolysaccharide (LPS). Mice were treated with protein S or saline by intraperitoneal injection 1 h before LPS instillation.
  
  
  RESULTS
  Activated protein or protein S alone and combined activated protein C + protein S therapy decreased inflammatory markers and cytokines in mice with acute lung injury. In LPS-treated mice compared with controls ALI was induced as shown by significantly increased levels of total protein, tumor necrosis factor-alpha, interleukin-6 and monocyte chemoattractant protein-1 in the bronchoalveolar lavage fluid. Mice with ALI treated with protein S had significantly decreased concentrations of tumor necrosis factor-alpha and interleukin-6 in the lung compared with untreated animals. Thrombin-antithrombin III, a marker of the activity of the coagulation cascade, was unchanged. Protein S inhibited the expression of cytokines in vitro and increased activation of the Axl tyrosine kinase pathway in A549 epithelial cells.
  
  
  CONCLUSIONS
  Protein S protects against LPS-induced ALI, possibly by directly inhibiting the local expression of inflammatory cytokines without affecting coagulation.
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu City, Mie Prefecture, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Takagi
authors.forename: O
authors.initials: O
authors.lastname: Taguchi
authors.forename: S
authors.initials: S
authors.lastname: Aoki
authors.forename: M
authors.initials: M
authors.lastname: Toda
authors.forename: A
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: H
authors.initials: H
authors.lastname: Fujimoto
authors.forename: D
authors.initials: D
authors.lastname: Boveda-Ruiz
authors.forename: P
authors.initials: P
authors.lastname: Gil-Bernabe
authors.forename: A Y
authors.initials: AY
authors.lastname: Ramirez
authors.forename: M
authors.initials: M
authors.lastname: Naito
authors.forename: Y
authors.initials: Y
authors.lastname: Yano
authors.forename: C N
authors.initials: CN
authors.lastname: D'Alessandro-Gabazza
authors.forename: A
authors.initials: A
authors.lastname: Fujiwara
authors.forename: Y
authors.initials: Y
authors.lastname: Takei
authors.forename: J
authors.initials: J
authors.lastname: Morser
authors.forename: E C
authors.initials: EC
authors.lastname: Gabazza
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D004359:Drug Therapy, Combination; D007249:Inflammation; D015850:Interleukin-6 / Q000032:analysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011486:Protein C / Q000494:pharmacology / Q000627:therapeutic use; D017293:Protein S / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D015415:Biomarkers; D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011486:Protein C; D017293:Protein S; D014409:Tumor Necrosis Factor-alpha