rhs-TM prevents ET-induced increase in pulmonary vascular permeability through protein C activation

• Published in: American journal of physiology. Lung cellular and molecular physiology 1997-10, Vol.273 (4), p.889-L894
• Main Authors: Uchiba, Mitsuhiro, Okajima, Kenji, Murakami, Kazunori, Johno, Masayoshi, Mohri, Mitsunobu, Okabe, Hiroaki, Takatsuki, Kiyoshi
• Format: Article
• Language: English
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.1997.273.4.l889

M. Uchiba, K. Okajima, K. Murakami, M. Johno, M. Mohri, H. Okabe and K. Takatsuki Department of Medicine, Kumamoto University School of Medicine, Japan. 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.