and Specific Aims.) The objective of this application is to define the expression, regulation and role of the epithelial cell plasminogen activator (PA)/plasmin system in the adult respiratory distress syndrome (ARDS). The central hypothesis is that tightly regulated proteolysis is pivotal in the repair of acute lung injury and that alveolar epithelial cells play a critical and direct role in this process. The following observations provide a background for the proposed studies: 1) ARDS remains a major public health problem, 2) pathological and biochemical evidence suggests that there is a disturbance in the normal fibrinolytic balance of ARDS, 3) the PA/plasmin cascade plays a key role in a number of physiologic and pathophysiologic processes which are relevant to acute lung injury, 4) alveolar epithelial cells have the capacity to directly participate in the fibrinolysis which accompanies repair of acute lung injury, 5) regulation of alveolar epithelial cell PA in ARDS is likely influenced by products of inflammation and tissue destruction.
The Specific Aims are: 1) to define urokinase-type plasminogen activator (u-PA) receptor expression by alveolar epithelial cells, and identify key physiological modulators and their mechanisms of action; 2) to further define the regulation of alveolar epithelial cell u-PA, PAI-I, and u-PAR by inflammatory mediators. This work will extend previous observations concerning the effects of cytokines, to include an analysis of the effects of reactive oxidant species and proteinases; and 3) to define the role of the PA/plasmin system in the reparative phase of an oxidant- induced model of acute lung injury. This work will include a descriptive analysis of the parenchymal expression of u-PA, PAI-I and u-PAR and will serve as a prelude to mechanistic studies testing the role of PA/plasmin in lung repair. The methodologic approaches range from in vitro and in vivo to in situ, tapping disciplines of molecular and cellular biology, oxidant biochemistry, and animal models of lung injury and repair. The proposed research may provide a better understanding of the mechanisms of lung repair in ARDS, which could potentially be exploited to help develop new therapeutic approaches.
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| Hasegawa, T; Sorensen, L; Ooi, H et al. (1999) Decreased intracellular iron availability suppresses epithelial cell surface plasmin generation. Transcriptional and post-transcriptional effects on u-PA and PAI-1 expression. Am J Respir Cell Mol Biol 21:275-82 |
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