Protective effect of tyrphostin AG-556 on shock induced by endotoxin or gram positive bacteria

The effects of tyrphostin AG-556 (TYR), a tyrosine kinase inhibitor, were e valuated on shock induced by lipopolysaccharide (LPS) or group B streptococ cus (GBS) in rats. Mortality and mean survival time were monitored. Plasma 6-keto prostaglandin F-1 alpha (6-keto PGF(1 alpha)) was also measured at f our hours after LPS injection. The effects of TYR on the production of 6-ke to PGF(1 alpha), thromboxane B-2 (TXB2) and nitrite (NO) from LPS or GBS st imulated in vitro peritoneal rat macrophage were also examined. Salmonella enteritidis LPS (12 mg/kg, i.v.) (n = 6) produced severe shock (100% mortal ity). Simultaneous treatment with TYR (n = 6 ) significantly (p < 0.01) ext ended mean survival time and 33% of rats survived. Plasma 6-keto PGF(1 alph a) concentrations were increased in LPS controls, whereas TYR (5 mg/kg) sig nificantly (p < 0.05) decreased the production. Animals treated with GBS/D- galactosamine (n = 9) also exhibited shock with 100% lethality and TYR agai n prolonged survival time (p < 0.05) with 55% of the animals surviving. To evaluate direct effects of TYR on mediator production induced by LPS or GBS , rat macrophages were stimulated with heat-killed GBS or LPS with or witho ut TYR. Supernatants were collected at 24 h for determination of TXB2, 6-ke to PGF(1 alpha) and NO. All mediators measured were significantly increased (p < 0.05) with LPS or GBS. TYR inhibited (p < 0.05) the production of all mediators from macrophages induced by LPS or GBS. The decrease in eicosano ids was associated with a reduction of the content of cyclooxygenase-2 (COX -2) as determined by western blotting. Collectively, these results suggest that TYR ameliorates toxic shock induced by LPS or gram positive bacteria. This protection is associated with suppression of macrophage mediator produ ction.