Tumor necrosis factor-α-induced inhibition of phosphatidylcholine synthesis by human type II pneumocytes is partially mediated by prostaglandins

Abstract

TNFα seems to play an important role in the pathogenesis of adult respiratory distress syndrome. We studied the effect of TNFα on phospholipid synthesis by isolated type II pneumocytes and attempted to characterize the role of arachidonate metabolites and the influence of pentoxifylline on such an effect. Lung tissue obtained from both multiple organ donors (n = 14) and lung cancer patients (n = 11) was used for cell isolation. Surfactant synthesis was measured by the incorporation of D-[U-14C]glucose into phosphatidylcholine (PC). The basal PC synthesis was higher in the donor group than in the malignant group (3.44±0.19 vs 2.15±0.15 pmol/μg protein x 120 min, P < 0.01), and, in the presence of 100 ng/ml of TNFα, the incorporation of labeled glucose into PC was reduced significantly in both donor (1.13±0.11 vs 3.44±0.19 pmol/μg protein x 120 min, P < 0.01) and cancer (0.99±0.11 vs 2.15±0.15 pmol/μg protein x 120 min, P < 0.01) groups. Indomethacin was able to completely block the cytokine-induced decrease in PC synthesis by pneumocytes from the malignant group and to attenuate the inhibitory effect of TNFα in those from donors, nordihydroguaiaretic acid having a similar effect. The TNFα effect can be blocked by pentoxifylline (100 μg/ml), a substance which can even succeed in reverting the basal secretory inhibition of cancer patients' pneumocytes to levels similar to those of the donor group. TNFα may contribute to the pathophysiology of adult respiratory distress syndrome by inhibiting the synthesis of surfactant. TNFα might be produced in lung tumors, resulting in chronic paracrine or systemic exposure of pneumocytes to low concentrations of the cytokine. The TNFα effect was not prevented completely by the blockage of the arachidonic acid metabolism, hence other mediators should also be implicated.