EFFECT OF PENTOXIFYLLINE ON THE INHIBITION OF SURFACTANT SYNTHESIS INDUCED BY TNF-ALPHA IN HUMAN TYPE-II PNEUMOCYTES

Tumor necrosis factor a (TNF-alpha) seems to play an important role in the pathogenesis of the adult respiratory distress syndrome (ARDS). T his study was designed to determine the effect of TNF-alpha and pentox ifylline (PTXF) on surfactant synthesis by isolated human type II pneu mocytes. In order to isolate the pneumocytes, lungs obtained from both previously healthy multiple organ donors (n = 11) and patients who un derwent surgical excision for lung cancer (n = 8) were used. Surfactan t synthesis was measured by the incorporation of labeled glucose into the two most important phospholipid components of surfactant: phosphat idylcholine (PC) and phosphatidylglycerol (PGL). The pneumocytes of th e donor group showed a greater degree of PC synthesis than those from the cancer group (3.44 +/- 0.19 versus 2.15 +/- 01.5 pmol/mu g protein , p < 0.001). The synthesis of PC by pneumocytes in both the donor (1. 13 +/- 0.19 versus 3.44 +/- 0.19 pmol/mu g protein, p < 0.01) and canc er (0.99 +/- 0.11 versus 2.15 +/- 0.15 pmol/mu g protein, p < 0.01) gr oups was decreased by TNF-alpha (100 ng/ml). This effect was blocked b y PTXF (100 mu g/ml), a substance that also increased PC production in the control-group pneumocytes from cancer patients, the final PC leve ls being similar to those of the donors in the absence of TNF-alpha. T hese results suggest that one of the mechanisms of TNF-alpha participa tion in the pathophysiology of ARDS is inhibition of surfactant synthe sis, and support the hypothesis of in vivo production of TNF-alpha in lung-cancer patients, with subsequent chronic exposure of the rung epi thelial cells to this cytokine. Our results also suggest that PTXF cou ld have a therapeutic role in ARDS and sepsis, since it antagonizes th e acute effects of TNF-alpha on type II pneumocytes, and apparently al so the chronic effects as well.