Nitric oxide inhibits neutrophil migration by a mechanism dependent on ICAM-1: Role of soluble guanylate cyclase

In the present study, we addressed the role of intercellular adhesion molecule type I (ICAM-1/CD54) in neutrophil migration to inflammatory site and whether the inhibitory effect of nitric oxide (NO) upon the neutrophil rolling. adhesion and migration involves down-modulation of ICAM-1 expression through a cyclic GMP (cGMP) dependent mechanism. It was observed that neutrophil migration induced by intraperitoneal administration of endotoxin (LPS). carrageenan (Cg) or N-formyl peptide (fMLP) in ICAM-I deficient (ICAM-1(-/-)) is similar to that observed in wild type (WT) mice. The treatment of mice with NO synthase (NOS) inhibitors, N-G-nitro-L-arginine, aminoguanidine or with a soluble guanylate cyclase (sGC) inhibitor, ODQ enhanced LPS- or Cg-induced neutrophil migration, rolling and adhesion on venular endothelium. These parameters induced by LPS were also enhanced by 1400W, a specific iNOS inhibitor, treatment. On the other hand. the treatment of the mice with S-nitroso-N-acetylpenicillamine (SNAP), ail NO donor. reduced these parameters induced by LPS or Cg by a mechanism sensitive to ODQ pretreatment. The NOS inhibitors did not enhance LPS-, Cg- or fMLP-induced migration and adhesion in ICAM-1(-/-) mice. Moreover. genetic (iNOS(-/-) mice) or pharmacological inhibition of NOS or of sGC enhanced LPS-induced ICAM-1 expression on mesenteric microcirculation vessels of WT mice. By contrast, SNAP reduced the ICAM-1 expression by a mechanism dependent on cGMP. In conclusion. the results suggest that although during inflammation. ICAM-1 does not contribute to neutrophil migration. it is necessary for the down-modulatory effect of inflammation-released NO oil the adhesion and transmigration of neutrophils. Moreover. these NO effects are mediated via cGMP. (c) 2006 Elsevier Inc. All rights reserved.