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

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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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Acknowledgements

The authors wish to thank Yu Cao, Yvonne Fitz, and LaShon Middleton for their expert technical support. This research was supported by the Intramural Research Program of the NIH Clinical Center, National Institutes of Health. The authors have no conflict of interest to report.

Author information

Authors and Affiliations

  1. Critical Care Medicine Department, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD, USA

    Xizhong Cui & Peter Eichacker

  2. Department of Anesthesia and Surgical Services, National Institutes of Health Clinical Center, National Institutes of Health, 10 Center Drive, Building 10, Room 2C624, MSC-1512, 20892-1512, Bethesda, MD, USA

    Virginia Besch, Alfia Khaibullina, Adrienne Hergen & Zenaide M. N. Quezado

  3. Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Martha Quezado

Authors
  1. Xizhong Cui
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  2. Virginia Besch
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  3. Alfia Khaibullina
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  4. Adrienne Hergen
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  5. Martha Quezado
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  6. Peter Eichacker
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  7. Zenaide M. N. Quezado
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Corresponding author

Correspondence to Zenaide M. N. Quezado.

Additional information

Drs. Cui and Besch contributed equally to this work.

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Cui, X., Besch, V., Khaibullina, A. et al. Neuronal nitric oxide synthase deficiency decreases survival in bacterial peritonitis and sepsis. Intensive Care Med 33, 1993–2003 (2007). https://doi.org/10.1007/s00134-007-0814-9

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  • DOI: https://doi.org/10.1007/s00134-007-0814-9

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