RHS-TM PREVENTS ET-INDUCED INCREASE IN PULMONARY VASCULAR-PERMEABILITY THROUGH PROTEIN-C ACTIVATION

We have previously demonstrated that recombinant human soluble (rhs) t hrombomodulin (TM) inhibits the endotoxin (ET)-induced increase in pul monary vascular permeability by inhibiting leukocyte activation. In th e present study, we examined whether rhs-TM could inhibit the ET-induc ed increase in pulmonary vascular permeability in rats by activating p rotein C. rhs-TM did not inhibit ET-induced increases in pulmonary vas cular permeability when its protein C activation ability was selective ly inhibited by a monoclonal antibody (MAb) against rhs-TM (MAb R5G12) . Histological examination revealed that neutrophil infiltration in lu ng tissues after ET administration was significantly reduced by rhs-TM , but infiltration was not reduced by MAb R5G1B-pretreated rhs-TM. ET- induced intravascular coagulation was prevented by rhs-TM and by MAb R 5G12-pretreated rhs-TM. However, ET-induced coagulation was not preven ted by rhs-TM that had been treated with MAb F2H5, which cannot bind t hrombin or activate protein C. These observations strongly suggest tha t rhs-TM prevents ET-induced pulmonary vascular injury by inhibiting p ulmonary accumulation of leukocytes through thrombin binding and the s ubsequent protein C activation and may prevent ET-induced intravascula r coagulation through thrombin binding.