Open AccessEfficacy of tumor necrosis factor α and eicosanoid inhibitors in experimental models of neonatal sepsis
Author(s) -
Mancuso Giuseppe,
Cusumano Vitaliano,
Cook James A.,
Smith Edward,
Squadrito Francesco,
Blandino Giovanna,
Teti Giuseppe
Publication year - 1994
Publication title -
fems immunology & medical microbiology
Language(s) - English
Resource type - Journals
eISSN - 1574-695X
pISSN - 0928-8244
DOI - 10.1111/j.1574-695x.1994.tb00473.x
Subject(s) - tumor necrosis factor alpha , neonatal sepsis , biology , sepsis , eicosanoid , tumor necrosis factor α , immunology , necrosis , microbiology and biotechnology , pharmacology , enzyme , biochemistry , arachidonic acid , genetics
The potential role of tumor necrosis factor α (TNFα) 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 TNFα 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 D 4 receptor antagonist; pentoxifylline (10, 50 and 100 mg kg −1 ), a TNF inhibitor; cloricromene (2 and 10 mg kg −1 ), a thromboxane A 2 synthetase inhibitor with TNFα inhibitory actions; and SKF86002 (2.5, 5, 10 and 20 mg kg −1 ), a dual cyclo‐oxygenase/lipoxygenase inhibitor with TNFα inhibitory activity. Pentoxifylline, cloricromene and SKF86002, when given intraperitoneally 2 h before challenge, produced 45, 52 and 61% reductions, respectively, in plasma levels of TNFα 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 TNFα levels. All compounds significantly attenuated the lethality by killed GBS and S. enteritidis endotoxin. These data suggest that TNFα and eicoisanoids contribute to the pathogenesis of shock induced by killed GBS and endotoxemia.