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-1 beta (IL-1 beta) and
tumor necrosis factor-alpha (
TNF-alpha) 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-1 beta and
TNF-alpha 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-1 beta and
TNF-alpha were qualitatively similar, some differences emerged. Most notably,
TNF-alpha led to a more sustained accumulation of
u-PA mRNA than did
IL-1 beta. In contrast to their effects on
u-PA expression,
IL-1 beta and
TNF-alpha had minimal effect on PA inhibitor-1 expression. These effects of
IL-1 beta and
TNF-alpha, 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.