Direct effects of protein S in ameliorating acute lung injury

J Thromb Haemost. 2009 Dec;7(12):2053-63. doi: 10.1111/j.1538-7836.2009.03642.x. Epub 2009 Oct 8.


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.

Conclusion: Protein S protects against LPS-induced ALI, possibly by directly inhibiting the local expression of inflammatory cytokines without affecting coagulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / drug therapy*
  • Animals
  • Biomarkers / analysis
  • Cytokines / analysis
  • Drug Therapy, Combination
  • Inflammation
  • Interleukin-6 / analysis
  • Lipopolysaccharides / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein C / pharmacology
  • Protein C / therapeutic use
  • Protein S / pharmacology*
  • Protein S / therapeutic use
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / analysis


  • Biomarkers
  • Cytokines
  • Interleukin-6
  • Lipopolysaccharides
  • Protein C
  • Protein S
  • Tumor Necrosis Factor-alpha