Effect of nitric oxide on beta-glucan/indomethacin-induced septic shock.
We have previously shown that repeated administration of nonsteroidal anti-inflammatory drugs (NSAIDs) to mice treated with beta-glucan, a biological response modifier, induced severe lethality. The lethality would be strongly related to the translocation of enterobacterial flora to the peritoneal cavity and disruption of the cytokine network. Reports suggest that nitric oxide (NO) can have an effective or detrimental role in septic shock. In the present study, we examined the effect of NO, an inflammatory mediator, on beta-glucan/indomethacin (IND)- induced septic shock by inhibiting its synthesis with N(G)-nitro-L-arginine methyl ester (L-NAME), a nonselective NO synthase (NOS) inhibitor. Nitrite concentration was used as an indicator of NO generation. Mortality in beta-glucan/IND-treated mice was increased by administering L-NAME. Numbers of bacteria in various organs of mice treated with beta-glucan/IND rose significantly within a couple of days of the administration of L-NAME. Additionally, TNF-alpha, IL-1beta, and IL-6 concentrations were enhanced in peritoneal exuded cells in culture. These results suggest a significant loss of the bactericidal activity of macrophages on the administration of a NOS inhibitor which enhanced the rate of enterobacterial invasion to the peritoneal cavity, resulting in systemic inflammatory response syndrome. The production of NO, therefore, provides a protective effect in beta-glucan/IND-induced sepsis.
Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Japan.
Sachiko
S
Nameda
Maki
M
Saito
Noriko N
NN
Miura
Yoshiyuki
Y
Adachi
Naohito
N
Ohno
D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D007213:Indomethacin / Q000633:toxicity*; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D012772:Shock, Septic / Q000503:physiopathology*; D012566:Sizofiran / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D047071:beta-Glucans / Q000633:toxicity*
D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D047071:beta-Glucans; D009569:Nitric Oxide; D012566:Sizofiran; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin