title: The roles of urokinase-type plasminogen activator in leukocyte infiltration and inflammatory responses in mice corneas treated with lipopolysaccharide.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Ophthalmology, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors: Koji
authors: K
authors: Sugioka
authors: Department of Ophthalmology, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors: Aya
authors: A
authors: Kodama
authors: Department of Biochemistry, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors: Koji
authors: K
authors: Yoshida
authors: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors: Kiyotaka
authors: K
authors: Okada
authors: Department of Ophthalmology, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors: Hiroshi
authors: H
authors: Mishima
authors: Department of Ophthalmology, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors: Keiichi
authors: K
authors: Aomatsu
authors: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors: Osamu
authors: O
authors: Matsuo
authors: Department of Ophthalmology, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors: Yoshikazu
authors: Y
authors: Shimomura
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D003315:Cornea / Q000187:drug effects*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007634:Keratitis / Q000473:pathology / Q000503:physiopathology*; D007962:Leukocytes / Q000166:cytology* / Q000276:immunology; D008070:Lipopolysaccharides; D008264:Macrophages / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*
chemical_list: D018932:Chemokine CCL2; D054426:Chemokine CXCL2; D008070:Lipopolysaccharides; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: LPS; cornea; leukocyte; u-PA; wound healing