Recombinant thrombomodulin prevents endotoxin-induced lung injury in rats by inhibiting leukocyte activation.
Acute respiratory distress syndrome (ARDS) is a serious complication of sepsis. Thrombomodulin, an important endothelial anticoagulant, binds thrombin to generate activated protein C (APC). We have previously demonstrated that APC prevents endotoxin (ET)-induced pulmonary vascular injury by inhibiting activated leukocytes. We therefore examined whether recombinant human soluble thrombomodulin (rhs-TM) prevents activated leukocyte-induced pulmonary vascular injury in rats receiving ET. Intravenous administration of rhs-TM prevented ET-induced pulmonary accumulation of leukocytes and increase in pulmonary vascular permeability, as well as ET-induced histological changes, such as leukocyte infiltration and pulmonary interstitial edema. Dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, did not prevent these effects of ET. rhs-TM did not prevent ET-induced pulmonary accumulation of leukocytes and pulmonary vascular injury in rats pretreated with DEGR-Xa. These results suggest that rhs-TM prevents ET-induced pulmonary vascular injury by inhibiting pulmonary accumulation of leukocytes and that this effect may be mediated primarily by APC generation.
Uchiba
M
M
Department of Medicine, Kumamoto University Medical School, Japan.
Okajima
K
K
Murakami
K
K
Johno
M
M
Okabe
H
H
Takatsuki
K
K
D000818:Animals; D004731:Endotoxins / Q000633:toxicity*; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D011652:Pulmonary Circulation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D018180:Thrombomodulin
D004731:Endotoxins; D011994:Recombinant Proteins; D018180:Thrombomodulin