Direct effects of protein S in ameliorating acute lung injury.
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.
Takagi
T
T
Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu City, Mie Prefecture, Japan.
Taguchi
O
O
Aoki
S
S
Toda
M
M
Yamaguchi
A
A
Fujimoto
H
H
Boveda-Ruiz
D
D
Gil-Bernabe
P
P
Ramirez
A Y
AY
Naito
M
M
Yano
Y
Y
D'Alessandro-Gabazza
C N
CN
Fujiwara
A
A
Takei
Y
Y
Morser
J
J
Gabazza
E C
EC
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
D015415:Biomarkers; D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011486:Protein C; D017293:Protein S; D014409:Tumor Necrosis Factor-alpha