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 produce tumor necrosis factor (TNF)-alpha and interleukin (IL)-1. The cellular effects of LPS, TNF-alpha, and IL-1 are mediated via tyrosine phosphorylation pathways. A recent report indicated that selective inhibitors of tyrosine kinases, tyrphostins of the AG126 family, protect mice against LPS-induced lethal toxicity in mice. Protection was most effective when the tyrphostin was injected before the LPS. In the present 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 Escherichia coli-induced lethal toxicity when given 2 h before and, to a lesser extent, 2 h after the bacterial inoculation. AG556 may block a critical step downstream of the signaling pathway induced by LPS after TNF-alpha production.
Vanichkin
A
A
Felsenstein Medical Research Center, Petah-Tikva, Israel.
Patya
M
M
Gazit
A
A
Levitzki
A
A
Novogrodsky
A
A
D000818:Animals; D002478:Cells, Cultured; D004334:Drug Administration Schedule; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000737:chemistry; D004926:Escherichia coli / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051572:Proto-Oncogene Proteins c-hck; D012995:Solubility; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D020032:Tyrphostins
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009570:Nitriles; D010636:Phenols; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; C098981:AG 556; D011505:Protein-Tyrosine Kinases; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck