Efficacy of tumor necrosis factor alpha and eicosanoid inhibitors in experimental models of neonatal sepsis.

The potential role of tumor necrosis factor alpha (TNF alpha) and eicosanoids in the pathogenesis of experimental neonatal sepsis models was investigated. Lethality was induced in neonatal rats by administration of heat killed group B streptococci (GBS, 7 mg kg-1 intracardially) or Salmonella enteritidis endotoxin (0.35 mg kg-1 intracardially). The relative efficacy of six compounds with putative TNF alpha and eicosanoid inhibitory actions were tested. These were: ibuprofen (3 and 20 mg kg-1), a cyclo-oxygenase inhibitor; CGS85515 (30 mg kg-1), a lipoxygenase inhibitor; LY203647 (30 mg kg-1), a leukotriene D4 receptor antagonist; pentoxifylline (10, 50 and 100 mg kg-1), a TNF inhibitor; cloricromene (2 and 10 mg kg-1), a thromboxane A2 synthetase inhibitor with TNF alpha inhibitory actions; and SKF86002 (2.5, 5, 10 and 20 mg kg-1), a dual cyclo-oxygenase/lipoxygenase inhibitor with TNF alpha inhibitory activity. Pentoxifylline, cloricromene and SKF86002, when given intraperitoneally 2 h before challenge, produced 45, 52 and 61% reductions, respectively, in plasma levels of TNF alpha at 2.5 h post-injection with killed GBS (P < 0.05). On the contrary, pretreatment with ibuprofen, CGS85515 or LY203647 did not significantly affect TNF alpha levels. All compounds significantly attenuated the lethality by killed GBS and S. enteritidis endotoxin. These data suggest that TNF alpha and eicosanoids contribute to the pathogenesis of shock induced by killed GBS and endotoxemia.