オクニシ　カツヒデ   Okunishi Katsuhide   奥西　勝秀    所属   東邦大学  医学部 医学科    職種   教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice.
掲載誌名	正式名：The Journal of clinical investigation ISSNコード：0021-9738/1558-8238
掲載区分	国外
出版社	AMER SOC CLINICAL INVESTIGATION INC
巻・号・頁	120(6),pp.1950-60
著者・共著者	Kristy A Bauman,Scott H Wettlaufer,Katsuhide Okunishi,Kevin M Vannella,Joshua S Stoolman,Steven K Huang,Anthony J Courey,Eric S White,Cory M Hogaboam,Richard H Simon,Galen B Toews,Thomas H Sisson,Bethany B Moore,Marc Peters-Golden
発行年月	2010/06
概要	Plasminogen activation to plasmin protects from lung fibrosis, but the mechanism underlying this antifibrotic effect remains unclear. We found that mice lacking plasminogen activation inhibitor-1 (PAI-1), which are protected from bleomycin-induced pulmonary fibrosis, exhibit lung overproduction of the antifibrotic lipid mediator prostaglandin E2 (PGE2). Plasminogen activation upregulated PGE2 synthesis in alveolar epithelial cells, lung fibroblasts, and lung fibrocytes from saline- and bleomycin-treated mice, as well as in normal fetal and adult primary human lung fibroblasts. This response was exaggerated in cells from Pai1-/- mice. Although enhanced PGE2 formation required the generation of plasmin, it was independent of proteinase-activated receptor 1 (PAR-1) and instead reflected proteolytic activation and release of HGF with subsequent induction of COX-2. That the HGF/COX-2/PGE2 axis mediates in vivo protection from fibrosis in Pai1-/- mice was demonstrated by experiments showing that a selective inhibitor of the HGF receptor c-Met increased lung collagen to WT levels while reducing COX-2 protein and PGE2 levels. Of clinical interest, fibroblasts from patients with idiopathic pulmonary fibrosis were found to be defective in their ability to induce COX-2 and, therefore, unable to upregulate PGE2 synthesis in response to plasmin or HGF. These studies demonstrate crosstalk between plasminogen activation and PGE2 generation in the lung and provide a mechanism for the well-known antifibrotic actions of the fibrinolytic pathway.
DOI	10.1172/JCI38369
PMID	20501949