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Koji Sugioka, Aya Kodama, Koji Yoshida, Kiyotaka Okada, Hiroshi Mishima, Keiichi Aomatsu, Osamu Matsuo, Yoshikazu Shimomura; The Roles of Urokinase-Type Plasminogen Activator in Leukocyte Infiltration and Inflammatory Responses in Mice Corneas Treated With Lipopolysaccharide. Invest. Ophthalmol. Vis. Sci. 2014;55(8):5338-5350. doi: https://doi.org/10.1167/iovs.14-14867.
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© ARVO (1962-2015); The Authors (2016-present)
Urokinase-type plasminogen activator (u-PA) plays an important role in corneal wound healing, yet its role in corneal inflammation remains poorly understood. We investigated the role of u-PA in a murine model of lipopolysaccharide (LPS)–induced corneal inflammation.
The corneal epithelium was scraped and LPS was applied to u-PA wild-type (u-PA+/+) and u-PA–deficient (u-PA−/−) mice. Corneal re-epithelialization and opacity were measured by stereomicroscopy. Fibrin zymography was performed to detect plasminogen activators in corneas from u-PA+/+ and u-PA−/− mice. Neutrophil, macrophage, and u-PA receptor (u-PAR) expression were determined by immunohistochemistry. Gene expression of corneal macrophage chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-2 was assessed with reverse transcription–polymerase chain reaction. The in vitro effects of endogenous u-PA on MCP-1, MIP-2, matrix metalloproteinase (MMP)-2, and MMP-9 expression, and macrophage migration activity in mouse ocular fibroblasts stimulated by LPS, were examined.
The u-PA+/+ mice showed enhanced corneal inflammation as compared with u-PA−/− mice. The u-PA expression was increased by LPS stimulation. Immunohistochemical analyses indicated that more neutrophils and macrophages were present in corneas from u-PA+/+ mice than u-PA−/− mice. The u-PAR expression was detected in inflammatory cells and in the leading edges of the epithelial migrating cells. Enhanced mRNA expression of MCP-1 and MIP-2 was observed in corneas from u-PA+/+ mice compared to u-PA−/− mice. Macrophage chemoattractant protein-1, MIP-2, and MMP-9, but not MMP-2, significantly increased in corneal fibroblasts from u-PA+/+ mice compared with u-PA−/− mice.
These data indicate that u-PA promotes LPS-induced leukocyte infiltration in cornea and that u-PA is an important component in LPS-induced corneal inflammatory responses.
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