Published ahead of print on November 30, 2006, doi:10.1164/rccm.200601-103OC Am. J. Respir. Crit. Care Med., Volume 175, Number 5, March 2007, 490-497 A more recent version of this article appeared on March 1, 2007
Submitted on January 24, 2006 Down-Regulation of CXCR2 on Neutrophils in Severe Sepsis is Mediated by iNOS-Derived Nitric OxideFabricio Rios-Santos1,1 Department of Pharmacology, University of Sao Paulo, Faculty of Medicine of Ribeirao Preto, Sao Paulo, Brazil; Department of Health, University of Santa Cruz, Bahia, Brazil, 2 Department of Pharmacology, University of Sao Paulo, Faculty of Medicine of Ribeirao Preto, Sao Paulo, Brazil, 3 Department of Health, University of Santa Cruz, Bahia, Brazil, 4 Laboratory of Tissue Engineering and Immunopharmacology, Goncalo Moniz Research Center/FIOCRUZ, Bahia, Brazil, 5 Laboratory of Immunopharmacology, Department of Biochemistry and Immunlogy, Federal University of Minas Gerais, Institute of Biological Science, Belo Horizonte, MG, Brazil * To whom correspondence should be addressed. E-mail: fdqcunha{at}fmrp.usp.br.
Rationale: The failure of neutrophils to migrate to an infection focus during severe sepsis is an important determinant of the inability of a host to deal with an infectious insult. Our laboratory has shown that iNOS induction and NO production contribute to the failure of neutrophils to migrate in the context of sepsis. Objectives and methods: Here, we investigated whether CXCR2 expression contributed to the failure of neutrophils to migrate during severe sepsis and the role of NO in modulating CXCR2 expression on neutrophils in mice submitted to non-severe (NS-) or severe (S-) CLP. Results: Neutrophil migration to the infection focus was deficient in S-CLP mice, a phenomenon prevented by pharmacological (aminoguanidine, L-canavanine) or genetic (iNOS gene deletion) inhibition of iNOS. The expression of CXCR2 on neutrophils from S-CLP mice was significantly reduced when compared to neutrophils from NSCLP or sham-operated mice. CXCR2 expression was reestablished by pharmacological and genetic inhibition of iNOS. Immunofluorescence and confocal analysis revealed that iNOS blockade reduced neutrophil CXCR2 internalization. The adhesion and emigration of neutrophils in MIP-2-stimulated mesentery microcirculation were reduced in S-CLP as compared with NS-CLP mice and reestablished by pre-treatment with aminoguanidine or L-canavanine. The NO donor, SNAP, inhibited CXCL8-induced human neutrophil chemotaxis and CXCR2 expression on human and murine neutrophils. Conclusion: These results highlight evidences that the failure of neutrophils to migrate to an infection focus during severe sepsis is associated with excessive NO production and NO-dependent regulation of the expression of CXCR2 on the neutrophil surface. Key words: Sepsis, Neutrophil Migration, CXCR2, Nitric Oxide
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