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Infection and Immunity, July 2002, p. 3602-3610, Vol. 70, No. 7
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.7.3602-3610.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Inhibition of Leukocyte Rolling by Nitric Oxide during Sepsis Leads to Reduced Migration of Active Microbicidal Neutrophils

Claudia Farias Benjamim,1 João Santana Silva,2 Zuleica Bruno Fortes,3 Maria Aparecida Oliveira,3 Sérgio Henrique Ferreira,1 and Fernando Queiroz Cunha1*

Departments of Pharmacology,1 Biochemistry, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto SP,2 Department of Pharmacology, Instituto de Ciências Biomédicas, University of São Paulo, São Paulo SP, Brazil3

Received 16 November 2001/ Returned for modification 6 February 2002/ Accepted 25 March 2002

We developed two models of sepsis with different degrees of severity, sublethal and lethal sepsis, induced by cecal ligation and puncture. Lethal sepsis induced by cecal ligation and puncture (L-CLP) resulted in failure of neutrophil migration to the infection site and high mortality. Treatment of septic animals with aminoguanidine (AG), a nitric oxide (NO) synthase inhibitor, precluded the failure of neutrophil migration and protected the animals from death. However, cytokine-induced NO synthase (iNOS)-deficient (iNOS-/-) mice subjected to L-CLP did not present neutrophil migration failure, but 100% lethality occurred. iNOS-/- mice subjected to sublethal sepsis induced by cecal ligation and puncture (SL-CLP) also suffered high mortality despite the occurrence of neutrophil migration. This apparent paradox could be explained by the lack of microbicidal activity in neutrophils of iNOS-/- mice present at the infection site due to their inability to produce NO. Notably, SL- and L-CLP iNOS-/- mice showed high bacterial numbers in exudates. The inhibition of neutrophil migration by NO is due to inhibition of a neutrophil/endothelium adhesion mechanism, since a reduction in leukocyte rolling, adhesion, and emigration was observed in L-CLP wild-type mice. These responses were prevented by AG treatment and were not observed in the iNOS-/- L-CLP group. There was no significant change in L-selectin expression in neutrophils from L-CLP mice. Thus, it seems that the decrease in leukocyte rolling is due to a defect in the expression of adhesion molecules on endothelial surfaces mediated by iNOS-derived NO. In conclusion, the results indicate that despite the importance of NO in neutrophil microbicidal activity, its generation in severe sepsis reduces neutrophil migration by inhibiting leukocyte rolling and their firm adhesion to the endothelium, in effect impairing the migration of leukocytes and consequently their fundamental role in host cell defense mechanisms.

* Corresponding author. Mailing address: Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, 14049-900 Ribeirão Preto SP, Brazil. Phone: 55 16 602-3205. Fax: 55 16 633-2301. E-mail: fdqcunha{at}fmrp.usp.br.

Editor: B. B. Finlay

Infection and Immunity, July 2002, p. 3602-3610, Vol. 70, No. 7
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.7.3602-3610.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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