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). This study was designed to determine the effect of TNF-alpha and pentoxifylline (PTXF) on surfactant synthesis by isolated human type II pneumocytes. In order to isolate the pneumocytes, lungs obtained from both previously healthy multiple organ donors (n = 11) and patients who underwent surgical excision for lung cancer (n = 8) were used. Surfactant synthesis was measured by the incorporation of labeled glucose into the two most important phospholipid components of surfactant: phosphatidylcholine (PC) and phosphatidylglycerol (PGL). The pneumocytes of the 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 cancer (0.99 +/- 0.11 versus 2.15 +/- 0.15 pmol/mu g protein, p < 0.01) groups was decreased by TNF-alpha (100 ng/ml). This effect was blocked by PTXF (100 mu g/ml), a substance that also increased PC production in the control-group pneumocytes from cancer patients, the final PC levels being similar to those of the donors in the absence of TNF-alpha. These results suggest that one of the mechanisms of TNF-alpha participation in the pathophysiology of ARDS is inhibition of surfactant synthesis, and support the hypothesis of in vivo production of TNF-alpha in lung-cancer patients, with subsequent chronic exposure of the rung epithelial cells to this cytokine. Our results also suggest that PTXF could have a therapeutic role in ARDS and sepsis, since it antagonizes the acute effects of TNF-alpha on type II pneumocytes, and apparently also the chronic effects as well.