Prevention of lipopolysaccharide-induced lethal toxicity by tyrosine kinase inhibitors.
Septic shock results from excessive stimulation of the host immune system, especially macrophages, by lipopolysaccharide (LPS), or endotoxin, which resides on the outer membrane of bacteria. Protein tyrosine kinase inhibitors of the tyrphostin AG 126 family protect mice against LPS-induced lethal toxicity. The protection correlates with the ability of these agents to block LPS-induced production of tumor necrosis factor alpha (TNF-alpha) and nitric oxide in macrophages as well as LPS-induced production of TNF-alpha in vivo. Furthermore, this inhibitory effect correlated with the potency of AG 126 to block LPS-induced tyrosine phosphorylation of a p42MAPK protein substrate in the murine macrophage.
Novogrodsky
A
A
Felsenstein Medical Research Center, Petach Tikva, Israel.
Vanichkin
A
A
Patya
M
M
Gazit
A
A
Osherov
N
N
Levitzki
A
A
D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology*; D001681:Biological Assay; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D008070:Lipopolysaccharides / Q000633:toxicity*; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1; D009569:Nitric Oxide / Q000096:biosynthesis*; D009570:Nitriles / Q000494:pharmacology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis* / Q000633:toxicity; D020032:Tyrphostins
D001597:Benzylidene Compounds; D008070:Lipopolysaccharides; D009570:Nitriles; D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; C069028:AG 127; D009569:Nitric Oxide; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1