The effect of a tyrosine kinase inhibitor on endotoxin mortality and splenocyte mediator production in the neonatal rat

Tyrosine kinases mediate cellular signal transduction to endotoxin. A class of tyrosine kinase inhibitors, the tyrphostins, have been shown to protect mice from endotoxin-induced lethality. Neonatal rats and mice have been sh own to be uniquely susceptible to lethal endotoxic shock. In our study, the effect of a lipophilic tyrphostin, AG 556, on endotoxin-induced neonatal a nd adult mortality and in vitro neonatal splenic cell thromboxane (TxB(2)), tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO) production were examined. Neonatal rats (<24 h old) were administered tyrphostin (100 mu g subcutaneous) 2 h before an approximate LD,, dose of Salmonella enteri tidis endotoxin (.024 mg/kg/intracardiac). There was a significant decrease in mortality in the animals pretreated with 100 mu g of tyrphostin (29% mo rtality in the treated group, n = 41 versus 53% in the vehicle control grou p, n = 40; p < .05). Also in adult rats tyrphostin (5 mg/kg intraperitoneal ) 2 h before endotoxin (10 mg/kg intravenous) significantly improved surviv al (50% drug treated versus 84% in control, n = 12/group; p < .05). Adheren t neonatal splenic cell mediator production of TxB(2), TNF-alpha, and NO (m easured by nitrite) in tyrphostin pretreated splenic cells were compared wi th endotoxin-stimulated splenic cells in vitro. The studies (n = 4) demonst rate an increase (p < .05) in the production of TxB(2), TNF-alpha, and NO i n the endotoxin- (10 mu g/mL) stimulated adherent splenic cells compared wi th basal. Tyrphostin pretreatment (10, 20, 50 mu M) produced a dose-depende nt decrease (p < .05) in endotoxin-stimulated TxB(2) and TNF-alpha producti on. NO production was not significantly reduced. in conclusion, tryphostin appears to have a protective effect on mortality in both adult and neonatal rat endotoxic shock. Tyrphostin decreased specific mediator production in stimulated neonatal cells. Thus, inhibition of signal transduction pathways of endotoxin activation by tyrosine kinase inhibition may provide an effec tive approach to treat endotoxic shock in the neonate.