EFFECT OF PENTOXIFYLLINE AND SOMATOSTATIN ON TUMOR-NECROSIS-FACTOR PRODUCTION BY HUMAN PULMONARY MACROPHAGES

Cytokines seem to act predominantly in a paracrine manner when produci ng their deleterious effects during sepsis. Therefore, local TNF alpha release by pulmonary macrophages would have a central role in the pat hogenesis of the adult respiratory distress syndrome (ARDS). By contra st, pentoxiphylline (PTXF) can reduce lung damage in septic animal mod els, and somatostatin (SS-14) has been shown to down-regulate TNF alph a-receptor expression in monocytes, suggesting an immunomodulatory act ion for this hormone. The aim of this work was to study the effect of PTXF and SS-14 on lipopolysaccharide (LPS)-induced TNF alpha release b y human pulmonary macrophages. Macrophages were obtained from multiple organ donor lungs. Donors with either a recent history of tobacco smo king, more than 72 hr of mechanical ventilation, or any radiological p ulmonary infiltrate were not included in this study. After 1 hr of cul ture, LPS stimulated TNF alpha release in a dose-dependent manner (2.3 4 +/- 0.20 and 11.32 +/- 1.38 pg/mu g protein, P < 0.01, in response t o 2.5 and 10 mu g/ml LPS, respectively). This response was significant ly inhibited by both PTXF, 100 mu g/ml (0.24 +/- 0.07 vs. 2.43 +/- 0.2 0, P < 0.01, and 1.30 +/- 0.08 vs. 11.32 +/- 1.38, P < 0.01, pg/mu g p rotein, 2.5 and 10 mu g/ml LPS, respectively) and SS-14, 0.4 ng/ml (0. 26 +/- 0.07 vs. 2.43 +/- 0.20, P < 0.01, and 0.60 +/- 0.19 vs. 11.32 /- 1.38, P < 0.01, pg/mu g protein, 2.5 and 10 mu g/ml LPS, respective ly). When macrophages were exposed to persistent stimulation (20 hr), SS-14 maintained its inhibitory action at both LPS concentrations, whi le PTXF lost its effect in the presence of 2.5 mu g/ml LPS and showed significantly less effect in the presence of 2.5 mu g/ml LPS. Our resu lts indicate that although both PTXF and SS-14 inhibited LPS-induced T NF alpha release by human pulmonary macrophages, SS-14 may be more eff ective if used for this purpose, suggesting a possible protective acti on for SS-14 on ARDS. (C) 1994 Wiley-Liss, Inc.