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.