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Effect of nitric oxide on beta-glucan/indomethacin-induced septic shock

Sachiko Nameda1, Maki Saito, Noriko N Miura

  • 1Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Japan.

Biological & Pharmaceutical Bulletin
|July 6, 2005
PubMed

Insights

Nitric oxide (NO) plays a protective role in sepsis. Inhibiting NO synthesis in mice treated with beta-glucan and indomethacin increased mortality and bacterial translocation, indicating NO's crucial role in combating sepsis.

Area of Science:

  • Immunology
  • Pharmacology
  • Microbiology

Background:

  • Repeated nonsteroidal anti-inflammatory drug (NSAID) administration with beta-glucan in mice caused severe lethality.
  • This lethality is linked to enterobacterial translocation and cytokine network disruption.
  • Nitric oxide (NO) has a complex role in septic shock, potentially being effective or detrimental.

Purpose of the Study:

  • To investigate the role of NO in beta-glucan/indomethacin (IND)-induced septic shock.
  • To determine if inhibiting NO synthesis affects mortality and bacterial translocation in this model.
  • To elucidate the impact of NO on macrophage bactericidal activity during sepsis.

Main Methods:

  • Mice were treated with beta-glucan and indomethacin (IND).
  • N(G)-nitro-L-arginine methyl ester (L-NAME), a nonselective NO synthase (NOS) inhibitor, was administered to inhibit NO synthesis.
  • Nitrite concentration was measured as an indicator of NO generation.
  • Bacterial counts in organs and cytokine concentrations (TNF-alpha, IL-1beta, IL-6) in peritoneal exudate cells were assessed.

Main Results:

  • L-NAME administration increased mortality in beta-glucan/IND-treated mice.
  • Significant increases in bacterial numbers were observed in various organs after L-NAME administration.
  • Concentrations of TNF-alpha, IL-1beta, and IL-6 were enhanced in peritoneal exudate cells.
  • These findings suggest impaired macrophage bactericidal activity and increased enterobacterial invasion.

Conclusions:

  • NO production confers a protective effect in beta-glucan/IND-induced sepsis.
  • Inhibition of NO synthesis exacerbates sepsis by reducing macrophage bactericidal activity and promoting bacterial translocation.
  • NO is essential for maintaining the integrity of the peritoneal cavity and preventing systemic inflammatory response syndrome in this model.

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