Diffuse alveolar damage, presenting clinically as adult respiratory distress syndrome, is characterized initially by widespread intra-alveolar fibrin deposition. Alveolar epithelial cells play a central role in the subsequent repair process. We have recently shown that alveolar epithelial cells have the capacity to promote fibrinolysis (Marshall, B. C., Sageser, D. S., Rao, N. V., Emi, M., and Hoidal, J. R. (1990) J. Biol. Chem. 265, 8198- 8204) and may therefore directly participate in the extensive remodeling that follows acute lung injury. Because the tissue repair process occurs in an acute inflammatory setting, we investigated the effects of inflammatory mediators on urokinase-type plasminogen activator (u-PA) expression by pulmonary epithelial cells. We found that interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) upregulated PA activity in A549 human pulmonary epithelial cells. Biosynthetic labeling and immunoprecipitation showed that both cytokines caused marked accumulation of newly synthesized u-PA. Northern blot analyses demonstrated that both IL-1β and TNF-α induced relatively rapid accumulation of u-PA mRNA which did not require de novo protein synthesis and was substantially inhibited by glucocorticoids. Nuclear run-off transcription studies showed that both cytokines caused rapid transcriptional activation of the u-PA gene. While the effects of IL-1β and TNF-α were qualitatively similar, some differences emerged. Most notably, TNF-α led to a more sustained accumulation of u-PA mRNA than did IL-1β. In contrast to their effects on u-PA expression, IL-1β and TNF-α had minimal effect on PA inhibitor-1 expression. These effects of IL-1β and TNF-α, mediators known to play a key role in acute lung injury and inflammation, may promote lysis of alveolar fibrin by alveolar epithelium, thereby aiding in restoration of normal lung architecture.
|Original language||English (US)|
|Number of pages||8|
|Journal||Journal of Biological Chemistry|
|State||Published - 1992|
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology