Pentoxifylline Prevents Tumor Necrosis Factor-induced Lung Injury

Abstract

Human tumor necrosis factor-alpha (TNF) is a monokine produced by mononuclear cells after many stimuli, including bacterial endotoxin. Full exploration of its antineoplastic effects has been limited by side effects. We have previously shown that the administration of TNF to guinea pigs is associated with a syndrome similar to gram-negative septic shock, which includes capillary permeability lung injury. In this study, we measured the effects of pentoxifylline (PTX) on parameters of TNF-induced lung injury including: lung wet-to-dry weight ratio, the ratio of lung-to-plasma 125I-labeled albumin (albumin index), bronchoalveolar lavage (BAL) and peripheral leukocyte counts, and serial measurements of mean arterial pressure (MAP). Four groups of animals were studied: a TNF group received 3.75 .times. 106 U/kg TNF; a PTX group received a 20-mg/kg bolus of PTX followed by an infusion of 6 mg/kg/h; the PTX-TNF group received both; and the final group was a saline control. ANOVA analysis revealed significant elevations of lung wet-to-dry ratio only in the TNF group (5.9 [5.6 to 6.3], p < 0.001), expressed as the mean followed by 95% confidence intervals. Lung albumin index was elevated only in the TNF group (0.24 [0.19 to 0.29], p < 0.01). BAL lekocytes (9.7 [7.8 to 11.6] .times. 106/ml, p < 0.0001) and polymorphonuclear leukocytes (3.3 [2.5 to 4.1] .times. 106/ml, p < 0.001) were elevated only in the TNF group. A marked fall in MAP at 6 h (-19 [-12 to -26] mm Hg, p < 0.0005) and 8 h (-21 [-16 to -26] mm Hg, p < 0.0001) was noted only in the TNF group. Furthermore, the PTX and PTX-TNF groups were not significantly different from the saline control group in any of these parameters. Thus, these results demonstrate a protective effect of PTX on TNF-induced lung injury. In order to determine whether PTX directly inhibited TNF, an in vitro cytotoxicity assay was performed. Results indicated that PTX did not have an inhibitory effect on TNF.