Involvement of NO in the failure of neutrophil migration in sepsis induced by Staphylococcus aureus

doi:10.1038/sj.bjp.0704734

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Wiley InterScience

British Journal of Pharmacology

Volume 136 Issue 5, Pages 645 - 658

Published Online: 2 Feb 2009

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Involvement of NO in the failure of neutrophil migration in sepsis induced by Staphylococcus aureus

D P Crosara-Alberto¹⁵, A L C Darini², R Y Inoue³, J S Silva⁴, S H Ferreira¹ & F Q Cunha¹

¹Department of Pharmacology, Faculty of Medicine Ribeirão Preto, University of São Paulo, São Paulo, Brazil ²Department of Clinical Analysis, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, São Paulo, Brazil ³Department of Internal Medicine, School of Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil ⁴Department of Biochemistry and Immunology, Faculty of Medicine Ribeirão Preto, University of São Paulo, São Paulo, Brazil

Correspondence to Department of Pharmacology, Faculty of Medicine Ribeirão Preto, University of São Paulo, São Paulo, Brazil. E-mail: fdqcunha@fmrp.usp.br

⁵Current address: Department of Clinical Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, São Paulo, Brazil

KEYWORDS

Nitric oxide • failure of neutrophil migration • S. aureus • sepsis

ABSTRACT

Sepsis induced by S. aureus was used to investigate whether neutrophil migration failure to infectious focus correlates with lethality in Gram-positive bacteria-induced sepsis in mice.
By contrast with the sub-lethal (SL-group), the lethal (L-group) intraperitoneal inoculum of S. aureus caused failure of neutrophil migration (92% reduction), high CFU in the exudate, bacteremia and impairment of in vitro neutrophil chemotactic activity.
Pre-treatments of L-group with adequate doses of aminoguanidine prevented the neutrophil migration failure and improved the survival of the animals (pre-treated: 43%; untreated: 0% survival). Thus, the impairment of neutrophil migration in the L-group appears to be mediated by nitric oxide (NO).
The injection of S. aureus SL-inoculum in iNOS deficient (−/−) or aminoguanidine-treated wild-type mice (pre- and post-treatment), which did not present neutrophil migration failure, paradoxically caused severe peritonitis and high mortality. This fact is explainable by the lack of NO dependent microbicidal activity in migrated neutrophils.
In conclusion, although the NO microbicidal mechanism is active in neutrophils, the failure of their migration to the infectious focus may be responsible for the severity and outcome of sepsis.

British Journal of Pharmacology (2002) 136, 645–658; doi:[DOI link]

(Received November 22, 2001, Revised February 12, 2002, Accepted March 25, 2002)

DIGITAL OBJECT IDENTIFIER (DOI)

10.1038/sj.bjp.0704734 About DOI