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 evaluated on shock induced by lipopolysaccharide (LPS) or group B streptococcus (GBS) in rats. Mortality and mean survival time were monitored. Plasma 6-keto prostaglandin F1alpha (6-keto PGF1alpha) was also measured at four hours after LPS injection. The effects of TYR on the production of 6-keto PGF1alpha thromboxane B2(TXB2) and nitrite (NO) from LPS or GBS stimulated in vitro peritoneal rat macrophage were also examined. Salmonella enteritidis LPS (12 mg/kg, i.v. ) (n=6) produced severe shock (100% mortality). Simultaneous treatment with TYR (n=6) significantly (p < 0.01) extended mean survival time and 33% of rats survived. Plasma 6-keto PGF1alpha concentrations were increased in LPS controls, whereas TYR (5 mg/kg) significantly (p < 0.05) decreased the production. Animals treated with GBS/D-galactosamine (n=9) also exhibited shock with 100% lethality and TYR again 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 without TYR. Supernatants were collected at 24 h for determination of TXB2, 6-keto PGF1alpha 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 eicosanoids 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 production.
Ogura
S
S
Dept. of Anesthesiology and Emergency Medicine, Kagawa Medical University, Kita, Japan.
Umegaki
O
O
Genovese
F
F
Fernando
L P
LP
Cochran
J B
JB
Romeo
C M
CM
Cook
J A
JA
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D051546:Cyclooxygenase 2; D004731:Endotoxins; D006094:Gram-Positive Bacteria / Q000472:pathogenicity; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009573:Nitrites / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012772:Shock, Septic / Q000097:blood / Q000382:microbiology / Q000517:prevention & control*; D013291:Streptococcus / Q000472:pathogenicity; D013929:Thromboxane B2 / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology*
D004731:Endotoxins; D007527:Isoenzymes; D008070:Lipopolysaccharides; D009573:Nitrites; D020032:Tyrphostins; C098981:AG 556; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases