Recombinant thrombomodulin prevents endotoxin-induced lung injury in rats by inhibiting leukocyte activation. Uchiba, Mitsuhiro, Kenji Okajima, Kazunori Murakami, Masayoshi Johno, Hiroaki Okabe, and Kiyoshi Takatsuki. Departments of Medicine, 2Laboratory Medicine, and 3Dermatology, Kumamoto University Medical School, Honjo 1-1-1, Kumamoto 860, Japan
APStracts 3:0084L, 1996.
Adult 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. 

Received 14 December 1995; accepted in final form 8 May 1996.
APS Manuscript Number L367-5.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 5 June 96