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Thromb Haemost 1995; 74(05): 1265-1270
DOI: 10.1055/s-0038-1649924
Original Article
Coagulation
Schattauer GmbH Stuttgart

Recombinant Human Soluble Thrombomodulin Reduces Endotoxin-Induced Pulmonary Vascular Injury Via Protein C Activation in Rats

Mitsuhiro Uchiba
1   The Department of Medicine, Kumamoto University Medical School, Kumamoto, Japan
,
Kenji Okajima
2   The Laboratory Medicine, Kumamoto University Medical School, Kumamoto, Japan
,
Kazunori Murakami
1   The Department of Medicine, Kumamoto University Medical School, Kumamoto, Japan
,
Katsuhico Nawa
3   The Research Institute, daiichi Pharmaceutical Co. Ltd., Edogawa, Tokyo, Japan
,
Hiroaki Okabe
2   The Laboratory Medicine, Kumamoto University Medical School, Kumamoto, Japan
,
Kiyoshi Takatsuki
1   The Department of Medicine, Kumamoto University Medical School, Kumamoto, Japan
› Author Affiliations
Further Information

Publication History

Received 28 February 1995

Accepted after revision 08 August 1995

Publication Date:
10 July 2018 (online)

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Summary

Adult respiratory distress syndrome (ARDS) is a serious complication of disseminated intravascular coagulation (DIC) or multiple organ failure. To determine whether recombinant soluble human thrombomodulin (rsTM) may be useful in treating ARDS due to sepsis, we investigated the effect of rsTM on lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats. The intravenous administration of rsTM prevented the increase in pulmonary vascular permeability induced by LPS. Neither heparin plus antithrombin III (AT III) nor dan- syl Glu Gly Arg chloromcthyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, prevented LPS-induced vascular injury. The agents rsTM, heparin plus AT III, and DEGR-Xa all significantly inhibited the LPS-induced intravascular coagulation. Recombinant soluble TM pretreated with a monoclonal antibody (moAb) that inhibits protein C activation by rsTM did not prevent the LPS-induced vascular injury; in contrast, rsTM pretreated with a moAb that does not affect thrombin binding or protein C activation by rsTM prevented vascular injury. Administration of activated protein C (APC) also prevented vascular injury. LPS-induced pulmonary vascular injury was significantly reduced in rats with leukopenia induced by nitrogen mustard and by ONO-5046, a potent inhibitor of granulocyte elastase.

Results suggest that rsTM prevents LPS-induced pulmonary vascular injury via protein C activation and that the APC-induced prevention of vascular injury is independent of its anticoagulant activity, but dependent on its ability to inhibit leukocyte activation.

 

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