PREVENTION OF LIPOPOLYSACCHARIDE-INDUCED LETHAL TOXICITY BY TYROSINE KINASE INHIBITORS

Septic shock results from excessive stimulation of the host immune sys tem, especially macrophages, by lipopolysaccharide (LPS), or endotoxin , which resides on the outer membrane of bacteria. Protein tyrosine ki nase inhibitors of the tyrphostin AG 126 family protect mice against L PS-induced lethal toxicity. The protection correlates with the ability of these agents to block LPS-induced production of tumor necrosis fac tor alpha (tNF-alpha) and nitric oxide in macrophages as well as LPS-i nduced production of TNF-alpha in vivo. Furthermore, this inhibitory e ffect correlated with the potency of AG 126 to block LPS-induced tyros ine phosphorylation of a p42(MAPK) protein substrate in the murine mac rophage.