title: Neutrophil migration in inflammation: nitric oxide inhibits rolling, adhesion and induces apoptosis.
abstract: There is controversy in the literature over whether nitric oxide (NO) released during the inflammatory process has a pro- or inhibitory effect on neutrophil migration. The aim of the present investigation was to clarify this situation. Treatment of rats with non-selective, NG-nitro-L-arginine (nitro), or selective inducible NO synthase (iNOS), aminoguanidine (amino) inhibitors enhanced neutrophil migration 6h after the administration of low, but not high, doses of carrageenan (Cg) or Escherichia coli endotoxin (LPS). The neutrophil migration induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) was also enhanced by nitro or amino treatments. The enhancement of Cg-induced neutrophil migration by NOS inhibitor treatments was reversed by co-treatment with L-arginine, suggesting an involvement of the L-arginine/NOS pathway in the process. The administration of Cg in iNOS deficient (iNOS(-/-)) mice also enhanced the neutrophil migration compared with wild type mice. This enhancement was markedly potentiated by treatment of iNOS(-/-) mice with nitro. Investigating the mechanisms by which NOS inhibitors enhanced the neutrophil migration, it was observed that they promoted an increase in Cg-induced rolling and adhesion of leukocytes to endothelium and blocked the apoptosis of emigrated neutrophils. Similar results were observed in iNOS(-/-) mice, in which these mechanisms were potentiated and reverted by nitro and L-arginine treatments, respectively. In conclusion, these results suggest that during inflammation, NO released by either constitutive NOS (cNOS) or iNOS down-modulates the neutrophil migration. This NO effect seems to be a consequence of decreased rolling and adhesion of the neutrophils on endothelium and also the induction of apoptosis in migrated neutrophils.
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900-Ribeirão Preto, São Paulo, Brazil.
authors.forename: Daniela
authors.initials: D
authors.lastname: Dal Secco
authors.forename: Juliane Alves
authors.initials: JA
authors.lastname: Paron
authors.forename: Sandra H P
authors.initials: SH
authors.lastname: de Oliveira
authors.forename: Sérgio Henrique
authors.initials: SH
authors.lastname: Ferreira
authors.forename: João Santana
authors.initials: JS
authors.lastname: Silva
authors.forename: Fernando de Queiroz
authors.initials: Fde Q
authors.lastname: Cunha
mesh_terms: D000818:Animals; D017209:Apoptosis; D002351:Carrageenan / Q000494:pharmacology; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D036904:Leukocyte Rolling; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D019335:Nitroarginine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D008070:Lipopolysaccharides; D019335:Nitroarginine; D009569:Nitric Oxide; D009240:N-Formylmethionine Leucyl-Phenylalanine; D002351:Carrageenan; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; C004479:pimagedine