Shimizu Shino, Gabazza Esteban C, Taguchi Osamu, Yasui Hiroki, Taguchi Yukiko, Hayashi Tatsuya, Ido Masaru, Shimizu Takeshi, Nakagaki Tomohiro, Kobayashi Hiroshi, Fukudome Kenji, Tsuneyoshi Naoko, D'Alessandro-Gabazza Corina N, Izumizaki Masahiko, Iwase Michiko, Homma Ikuo, Adachi Yukihiko, Suzuki Koji
Department of Molecular Pathobiology, Mie University School of Medicine, Tsu City, Japan.
Am J Respir Crit Care Med. 2003 May 15;167(10):1416-26. doi: 10.1164/rccm.200206-515OC.
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.
天然抗凝剂活化蛋白C可能抑制肺部炎症和纤维化。血小板衍生生长因子参与肺纤维化的发病机制。本研究评估了活化蛋白C对人细胞系以及肺纤维化体内模型中血小板衍生生长因子表达的影响。活化蛋白C显著抑制人肺细胞系、原代支气管上皮细胞和巨噬细胞中血小板衍生生长因子的分泌和表达。体外研究还表明，肺上皮细胞和巨噬细胞表达内皮活化蛋白C受体，且该受体以及活化蛋白的蛋白水解活性与血小板衍生生长因子表达的抑制有关。在肺纤维化体内模型中，气管内给予活化蛋白C可降低血小板衍生生长因子的表达并抑制肺纤维化的发展。同时气管内给予活化蛋白C与抗内皮活化蛋白C受体或抗血小板衍生生长因子可抑制活化蛋白C在体内的抑制活性。简而言之，本研究描述了活化蛋白C的一种新的生物学功能，这可能进一步解释其对肺部炎症和纤维化的抑制活性。
