Neutrophil migration in inflammation: nitric oxide inhibits rolling, adhesion and induces apoptosis

doi:10.1016/j.niox.2003.11.001

Nitric Oxide

Volume 9, Issue 3, November 2003, Pages 153-164

https://doi.org/10.1016/j.niox.2003.11.001 Get rights and content

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, N^G-nitro-l-arginine (nitro), or selective inducible NO synthase (iNOS), aminoguanidine (amino) inhibitors enhanced neutrophil migration 6 h 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.

Section snippets

Animals

Adult male Wistar rats weighing 180–200 g and adult male C57BL-6 (wild type) or iNOS deficient (iNOS^−/−) mice weighing 18–20 g were used in this study. The animals were housed in temperature-controlled rooms (22–25 °C), with access to water and food ad libitum, until use in the Departments of Pharmacology and Immunology of the School of Medicine of Ribeirão Preto, University of São Paulo. The wild type and iNOS^−/− mice were housed in a sterile laminar flow cabinet. Breeding pairs of mice with

Effect of nitro and amino on the neutrophil migration induced by Cg, LPS or fMLP

The i.p. injection of a low dose of Cg (30 μg/1.0 mL) induced a significant neutrophil migration in rats, determined 6 h after. The pretreatment of the animals with nitro (Fig. 1A) or amino (Fig. 1B) enhanced the observed neutrophil migration in a dose-dependent manner. Moreover, treatment with nitro or amino (50 mg/kg) significantly enhanced the neutrophil migration triggered i.p. injection of Cg (30 μg/1.0 mL) or LPS (20 ng/1.0 mL) and determined either 6 or 48 h later Fig. 2, Fig. 3, respectively. By

Discussion

In the present study, we demonstrated that the pretreatment of rats with nitro, an inhibitor of cNOS and iNOS [22], [56], [57], or with amino, a selective iNOS inhibitor [22], [57] promoted a dose-dependent (25–100 mg/kg) enhancement in the number of neutrophils that emigrated to the peritoneal cavity 6 h after i.p. administration of a low dose of Cg (30 μg/cavity). Furthermore, the nitro or amino pretreatment also enhanced the neutrophil migration in response to i.p. injection of low doses of Cg,

Acknowledgements

This work was supported by CAPES (Fundação Coordenação de Aperfeiçoamento de Pessoal de Nı́vel Superior), FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo), and PRONEX (Programa de Núcleos de Excelência). We thank Alexandra Rosa Vieira Dias for FACS analysis and Ana Kátia dos Santos, Fabı́ola Leslie Mestriner, Giuliana Bertozi Francisco, Diva Amabile Montanha de Sousa, Sérgio Roberto Rosa, and Ieda Regina dos Santos Schivo for technical assistance. We would also like to thank Prof.

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Neutrophil migration in inflammation: nitric oxide inhibits rolling, adhesion and induces apoptosis

Abstract

Section snippets

Animals

Effect of nitro and amino on the neutrophil migration induced by Cg, LPS or fMLP

Discussion

Acknowledgements

Kidney Int.

Semin. Immunol.

Eur. J. Pharmacol.

General Pharmacol.

Toxicon

Exp. Cell Res.

Free Radic. Biol. Med.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Trends Pharmacol. Sci.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Biochem. Pharmacol.

Biochem. Biophys. Res. Commun.

Gastroenterology

Nitric Oxide: Biol. Chem.

Neutrophils in human diseases

N. Engl. J. Med.

Rheumatoid arthritis: the role of neutrophil activation

Inflammation

Function of exudative neutrophilic granulocytes in patients with Crohn’s disease or ulcerative colitis

Scand. J. Gastroenterol.

Vasculits: phatogenic mechanisms of vessel damage

Tumor necrosis factor-alpha-induced ICAM-1 expression in human vascular endothelial and lung epithelial cells: modulation by tyrosine kinase inhibitors

Br. J. Pharmacol.

CXC chemokines, MIP-2 and KC, induce P-selectin-dependent neutrophil rolling and extravascular migration in vivo

Br. J. Pharmacol.

Migratory responses of ovine neutrophils to inflammatory mediators in vitro and in vivo

J. Leukoc. Biol.

Modulation of C5a-mediated effector functions of human polymorphonuclear leukocytes by tumor necrosis factor alpha and granulocyte macrophage colony-stimulating factor

Exp. Clin. Immunogenet.

Potential role of IL-8, platelet-activating factor and TNF-α in the sequestration of neutrophils in the lung: effects on neutrophil deformability, adhesion receptor expression, and chemotaxis

Eur. J. Immunol.

Lipoxin A4 and B4 inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells

J. Immunol.

Lipoxin A4 and aspirin-triggered 15-epi-LXA4 inhibit tumor necrosis factor-alpha-initiated neutrophil responses and trafficking: novel regulators of a cytokine-chemokine axis relevant to periodontal diseases

Periodontal Res.

Anti-inflammatory effects of IL-4 and IL-10 on human polymorphonuclear leukocytes

J. Korean Med. Sci.

Nitric oxide as a factor in inflammation

Nitric oxide. I. Physiological chemistry of nitric oxide and its metabolites: implications in inflammation

Am. J. Physiol.

Nitric oxide inhibits leukocyte migration in carrageenan-induced rat pleurisy

Inflamm. Res.

Nitric oxide synthase inhibitors have opposite effects on acute inflammation depending on their route of administration

J. Immunol.

Selective inhibition of inducible nitric oxide synthase exacerbates erosive joint disease

J. Immunol.

Nitric oxide: physiology, pathophysiology, and pharmacology

Pharmacol. Rev.

Nitric oxide synthases in mammals

Biochem. J.

Nitric oxide synthases: structure, function and inhibition

Biochem. J.

Nitric oxide: an endogenous modulator of leukocyte adhesion

Proc. Natl. Acad. Sci. USA