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American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 1416-1426, (2003)
© 2003 American Thoracic Society

Activated Protein C Inhibits the Expression of Platelet-derived Growth Factor in the Lung

Shino Shimizu, Esteban C. Gabazza, Osamu Taguchi, Hiroki Yasui, Yukiko Taguchi, Tatsuya Hayashi, Masaru Ido, Takeshi Shimizu, Tomohiro Nakagaki, Hiroshi Kobayashi, Kenji Fukudome, Naoko Tsuneyoshi, Corina N. D'Alessandro-Gabazza, Masahiko Izumizaki, Michiko Iwase, Ikuo Homma, Yukihiko Adachi and Koji Suzuki

Department of Molecular Pathobiology, Third Department of Internal Medicine, Department of Otorhinolaryngology, Mie University School of Medicine, Tsu City, Mie; Chemo-Sero-Therapeutic Research Institute, Kumamoto; Department of Gynecology and Obstetrics
Hamamatsu University School of Medicine, Hamamatsu, Shizuoka; Department of Immunology, Saga Medical School, Saga;
and Second Department of Physiology, Showa University School of Medicine, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Dr. Esteban Cesar Gabazza, Ph.D., M.D., Third Department of Internal Medicine, Mie University School of Medicine, Edobashi 2–174, Tsu City, Mie 514–8507, Japan. E-mail: gabazza{at}clin.medic.mie-u.ac.jp

The natural anticoagulant-activated protein C may inhibit inflammation and fibrosis in the lung. Platelet-derived growth factor is involved in the pathogenesis of lung fibrosis. This study assessed the effect of activated protein C on platelet-derived growth factor expression in human cell lines and in an in vivo model of lung fibrosis. Activated protein C significantly inhibited the secretion and expression of platelet-derived growth factor in human lung cell lines, primary bronchial epithelial cells, and macrophages. In vitro studies also showed that the endothelial activated protein C receptor is expressed by lung epithelial cells and macrophages, and that this receptor and the proteolytic activity of activated protein are implicated in the inhibition of platelet-derived growth factor expression. In the in vivo model of lung fibrosis, intratracheal administration of activated protein C decreased the expression of platelet-derived growth factor and suppressed the development of lung fibrosis. Concomitant intratracheal administration of activated protein C and anti-endothelial activated protein C receptor or anti-platelet-derived growth factor suppressed the inhibitory activity of activated protein C in vivo. In brief, this study describes a novel biological function of activated protein C that may further explain its inhibitory activity on lung inflammation and fibrosis.

Key Words: activated protein C receptor • coagulation • epithelial cells • growth factor • lung fibrosis




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