Tissue plasminogen activator (tPA) inhibits interleukin-1 induced acute lung leak

Because plasminogen activators (PA) may participate in the inflammatory process associated with the acute respiratory distress syndrome (ARDS), we measured the effect of tissue plasminogen activator (tPA) on inflammation and acute lung leak caused by intratracheal instillation of IL-1alpha (50 ng) into male (300-400 g) Sprague-Dawley rats. Lung leak, lung myeloperoxidase (MPO) activity, and lung lavage neutrophil counts were increased in rats given IL-1 intratracheally compared to control rats that were given saline intratracheally. Giving tPA (12 mg/kg) intraperitoneally increased lung tPA concentration and reduced acute lung leak in rats given IL-1 intratracheally (p < .01; lung leak index for sham-treated rats: 0.040 + 0.001, n=6; IL-1: 0.10 + 0.01, n=10; tPA + IL-1: 0.050 + 0.002, n=6). In contrast, administering tPA did not change IL-1-induced increases in lung lavage neutrophils or lung MPO activity (sham: 0.003 x 106 + 0.001 x 10(6) cells; IL-1: 2.9 x 10(6) + 0.4 x 10(6) cells; tPA + IL-1: 2.7 x 10(6) + 0.4 x 10(6) cells; and sham: 0.6 + 0.2 U/g lung; IL-1: 11.2 + 2.9 U/g lung, tPA + IL-1: 11.1 + 1.6 U/g lung, respectively). Our results suggest that intraperitoneal tPA administration increases lung tissue tPA levels and decreases acute lung leak without reducing lung neutrophil infiltration in rats given IL-1alpha intratracheally. This work suggests that tPA may suppress neutrophil activation in vivo and accordingly have anti-inflammatory effects.