rhs-TM prevents ET-induced increase in pulmonary vascular permeability through protein C activation.
We have previously demonstrated that recombinant human soluble (rhs) thrombomodulin (TM) inhibits the endotoxin (ET)-induced increase in pulmonary vascular permeability by inhibiting leukocyte activation. In the present study, we examined whether rhs-TM could inhibit the ET-induced increase in pulmonary vascular permeability in rats by activating protein C. rhs-TM did not inhibit ET-induced increases in pulmonary vascular permeability when its protein C activation ability was selectively inhibited by a monoclonal antibody (MAb) against rhs-TM (MAb R5G12). Histological examination revealed that neutrophil infiltration in lung tissues after ET administration was significantly reduced by rhs-TM, but infiltration was not reduced by MAb R5G12-pretreated rhs-TM. ET-induced intravascular coagulation was prevented by rhs-TM and by MAb R5G12-pretreated rhs-TM. However, ET-induced coagulation was not prevented by rhs-TM that had been treated with MAb F2H5, which cannot bind thrombin or activate protein C. These observations strongly suggest that rhs-TM prevents ET-induced pulmonary vascular injury by inhibiting pulmonary accumulation of leukocytes through thrombin binding and the subsequent protein C activation and may prevent ET-induced intravascular coagulation through thrombin binding.
Uchiba
M
M
Department of Medicine, Kumamoto University School of Medicine, Japan.
Okajima
K
K
Murakami
K
K
Johno
M
M
Mohri
M
M
Okabe
H
H
Takatsuki
K
K
D000818:Animals; D000911:Antibodies, Monoclonal; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D004731:Endotoxins / Q000633:toxicity*; D004789:Enzyme Activation; D004926:Escherichia coli; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000473:pathology / Q000502:physiology; D009195:Peroxidase / Q000032:analysis; D011486:Protein C / Q000378:metabolism*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology*; D013917:Thrombin / Q000378:metabolism; D018180:Thrombomodulin / Q000502:physiology*
D000911:Antibodies, Monoclonal; D004731:Endotoxins; D008070:Lipopolysaccharides; D011486:Protein C; D011994:Recombinant Proteins; D018180:Thrombomodulin; C088784:ZK 157138; D009195:Peroxidase; D013917:Thrombin