Heme oxygenase/carbon monoxide-biliverdin pathway down regulates neutrophil rolling, adhesion and migration in acute inflammation

Authors

  • A Freitas,

    1. Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
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    • 4

      These authors contributed equally to this work.

  • J C Alves-Filho,

    1. Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
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    • 4

      These authors contributed equally to this work.

  • D D Secco,

    1. Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
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    • 4

      These authors contributed equally to this work.

  • A F Neto,

    1. Department of Pharmaceutical Science, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
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  • S H Ferreira,

    1. Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
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  • C Barja-Fidalgo,

    1. Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
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  • F Q Cunha

    Corresponding author
    1. Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
      Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil. E-mail: fdqcunha@fmrp.usp.br
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Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil. E-mail: fdqcunha@fmrp.usp.br

Abstract

Background and purpose:

Heme oxygenase (HO) activity is known to down-regulate inflammatory events. Here, we address the role of HO and its metabolites, carbon monoxide (CO) and biliverdin (BVD), in leukocyte rolling, adhesion and neutrophil migration during inflammatory processes.

Experimental approach:

Intravital microscopy was used to evaluate leukocyte rolling and adhesion in the mesenteric microcirculation of mice. TNFα and IL-1β were determined by ELISA and HO-1 protein expression by Western blot.

Key results:

Intraperitoneal challenge with carrageenan enhanced HO-1 protein expression in mesentery and bilirubin concentration in peritoneal exudates. Pretreatment of mice with a non-specific inhibitor of HO (ZnDPBG) or with a HO-1 specific inhibitor (ZnPP IX) enhanced neutrophil migration, rolling and adhesion on endothelium induced by carrageenan. In contrast, HO substrate (hemin), CO donor (DMDC) or BVD reduced these parameters. The reduction of neutrophil recruitment promoted by HO metabolites was independent of the production of chemotactic cytokines. Inhibitory effects of CO, but not of BVD, were counteracted by treatment with a soluble guanylate cyclase (sGC) inhibitor, ODQ. Furthermore, inhibition of HO prevented the inhibitory effect of a nitric oxide (NO) donor (SNAP) upon neutrophil migration, while the blockade of NO synthase (NOS) activity by aminoguanidine did not affect the CO or BVD effects.

Conclusions and Implications:

Metabolites of HO decreased leukocyte rolling, adhesion and neutrophil migration to the inflammatory site by a mechanism partially dependent on sGC. Moreover, inhibition by NO of neutrophil migration was dependent on HO activity.

British Journal of Pharmacology (2006) 149, 345–354. doi:10.1038/sj.bjp.0706882

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