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* Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, and Health Services Center, Denver, CO 80262;
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; and
Pulmonary and Critical Care Division, Chang Gung Memorial Hospital–Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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-
cytokine levels. These proinflammatory effects of the uPA KD appeared to be mediated through activation of Akt and NF-
B. 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported, in part, by National Institutes of Health Grants HL76206 (to E.A.) and HL60169, HL66442, and HL67381 (to D.B.C.).
2 Address correspondence and reprint requests to Dr. Edward Abraham, Department of Medicine, University of Alabama at Birmingham, Boshell Diabetes Building 420, 1530 3rd Avenue South, Birmingham, AL 35294-0012. E-mail address: eabraham{at}UAB.edu
3 Abbreviations used in this paper: uPA, urokinase plasminogen activator; GFD, growth factor domain; KD, kringle domain; PD, proteolytic domain; scuPA, single-chain uPA; MPO, myeloperoxidase; PAI-1, plasminogen activator inhibitor 1.
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