Involvement of the urokinase kringle domain in lipopolysaccharide-induced acute lung injury.
Urokinase plasminogen activator (uPA) plays a major role in fibrinolytic processes and also can potentiate LPS-induced neutrophil activation through interactions with its kringle domain (KD). To investigate the role of the uPA KD in modulating acute inflammatory processes in vivo, we cloned and then developed Abs to the murine uPA KD. Increased pulmonary expression of uPA and the uPA KD was present in the lungs after LPS exposure. Administration of anti-kringle Abs diminished LPS-induced up-regulation of uPA and uPA KD in the lungs, and also decreased the severity of LPS-induced acute lung injury, as determined by development of lung edema, pulmonary neutrophil accumulation, histology, and lung IL-6, MIP-2, and TNF-alpha cytokine levels. These proinflammatory effects of the uPA KD appeared to be mediated through activation of Akt and NF-kappaB. The present studies indicate that the uPA KD plays a major role in the development of TLR4-mediated acute inflammatory processes, including lung injury. Blockade of the uPA KD may prevent the development or ameliorate the severity of acute lung injury induced through TLR4-dependent mechanisms, such as would occur in the setting of Gram-negative pulmonary or systemic infection.
Wang
Xue-Qing
XQ
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, and Health Services Center, Denver, CO 80262, USA.
Bdeir
Khalil
K
Yarovoi
Sergei
S
Cines
Douglas B
DB
Fang
Wenfeng
W
Abraham
Edward
E
D000818:Animals; D000906:Antibodies / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation; D018082:Kringles / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000201:enzymology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012128:Respiratory Distress Syndrome / Q000188:drug therapy*; D051197:Toll-Like Receptor 4 / Q000276:immunology; D014568:Urokinase-Type Plasminogen Activator / Q000737:chemistry / Q000276:immunology*
D000906:Antibodies; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014568:Urokinase-Type Plasminogen Activator