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01.11.2007 | Experimental

Neuronal nitric oxide synthase deficiency decreases survival in bacterial peritonitis and sepsis

verfasst von: Xizhong Cui, Virginia Besch, Alfia Khaibullina, Adrienne Hergen, Martha Quezado, Peter Eichacker, Zenaide M. N. Quezado

Erschienen in: Intensive Care Medicine | Ausgabe 11/2007

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Abstract

Objective

To investigate the role of neuronal nitric oxide synthase (NOS1) in murine polymicrobial peritonitis and sepsis.

Design

Randomized experimental trial.

Setting

Animal research facility.

Subjects

B6129S NOS1^+/+ and B6;129S4 NOS^−/− mice.

Interventions

NOS1^+/+ and NOS1^−/− animals underwent cecal ligation and puncture (CLP) or sham surgery and received the NOS1 inhibitor 7-nitroindazole (7-NI) or vehicle.

Measurements and main results

After CLP, genetic deficiency and pharmacologic inhibition of NOS1 significantly increased risk of mortality [8.69 (3.27, 23.1), p < 0.0001 and 1.71 (1.00, 2.92) p = 0.05, hazard ratio of death (95% confidence interval) for NOS1^−/− and 7-NI-treated NOS1^+/+ respectively] compared with NOS1^+/+ animals. In 7-NI-treated NOS1^+/+ animals, there were increases (6 h) and then decreases (24 h), whereas in NOS^−/− animals persistent increases in blood bacteria counts ( p = 0.04 for differing effects of 7-NI and NOS1^−/−) were seen compared with NOS1^+/+ animals. After CLP, NOS1^−/− had upregulation of inducible NOS and proinflammatory cytokines and greater increases in serum tumor necrosis factor-α and interleukin-6 levels compared with NOS1^+/+ mice (all p < 0.05). Following CLP, there were similar significant decreases in circulating leukocytes and lung lavage cells ( p ≤ 0.0008) and significant increases in peritoneal lavage cells ( p = 0.0045) in all groups. Over 6 h and 24 h following CLP, compared with NOS1^+/+, NOS^−/− mice had significantly higher peritoneal cell concentrations {respectively 0.40 ± 0.09 vs 0.79 ± 0.15 [log(× 10⁴cells/ml)] averaged over both times p = 0.038}.

Conclusions

Deficiency and inhibition of NOS1 increases mortality, possibly by increasing proinflammatory cytokine response and impairing bacterial clearance after CLP. These data suggest that NOS1 is important for survival, bacterial clearance, and regulation of cytokine response during infection and sepsis.

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Titel: Neuronal nitric oxide synthase deficiency decreases survival in bacterial peritonitis and sepsis
verfasst von: Xizhong Cui
Virginia Besch
Alfia Khaibullina
Adrienne Hergen
Martha Quezado
Peter Eichacker
Zenaide M. N. Quezado
Publikationsdatum: 01.11.2007
Verlag: Springer-Verlag
Erschienen in: Intensive Care Medicine / Ausgabe 11/2007
Print ISSN: 0342-4642
Elektronische ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-007-0814-9

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Neuronal nitric oxide synthase deficiency decreases survival in bacterial peritonitis and sepsis

Abstract

Objective

Design

Setting

Subjects

Interventions

Measurements and main results

Conclusions

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Springer Medizin

Abstract

Objective

Design

Setting

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Measurements and main results

Conclusions

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