LATE ADMINISTRATION OF A LIPOPHILIC TYROSINE KINASE INHIBITOR PREVENTS LIPOPOLYSACCHARIDE AND ESCHERICHIA COLI-INDUCED LETHAL TOXICITY

Septic shock induced by gram-negative bacteria results primarily from excessive stimulation by lipopolysaccharide (LPS) of macrophages to pr oduce tumor necrosis factor (TNF)-alpha and interleukin (IL)-1. The ce llular effects of LPS, TNF-alpha, and IL-1 are mediated via tyrosine p hosphorylation pathways. A recent report indicated that selective inhi bitors of tyrosine kinases, tyrphostins of the AG126 family, protect m ice against LPS-induced lethal toxicity in mice. Protection was most e ffective when the tyrphostin was injected before the LPS. In the prese nt study, tyrphostin AG556, which is more lipophilic than those of the AG126 family, was effective in preventing LPS-induced lethal toxicity when administered 2 h after LPS. AG556 also prevented viable Escheric hia coli-induced lethal toxicity when given 2 h before and, to a lesse r extent, 2 h after the bacterial inoculation. AG556 may block a criti cal step downstream of the signaling pathway induced by LPS after TNF- alpha production.