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

• Published in: British journal of pharmacology 2006-10, Vol.149 (4), p.345-354
• Main Authors: Freitas, A, Alves‐Filho, J C, Secco, D D, Neto, A F, Ferreira, S H, Barja‐Fidalgo, C, Cunha, F Q
• Format: Article
• Language: English
• Subjects: Animals; biliverdin; Biliverdine - pharmacology; Biological and medical sciences; carbon monoxide; Carbon Monoxide - pharmacology; Carrageenan; Cell Adhesion - drug effects; Cell Movement - drug effects; Deuteroporphyrins - pharmacology; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Guanylate Cyclase - metabolism; heme oxygenase; Heme Oxygenase (Decyclizing) - antagonists & inhibitors; Heme Oxygenase (Decyclizing) - metabolism; Hemin - pharmacology; Inflammation - blood; Inflammation - chemically induced; Inflammation - enzymology; Interleukin-1beta - blood; Leukocyte Rolling - drug effects; Medical sciences; Mesenteric Veins; Mice; Mice, Inbred BALB C; Microscopy, Video; neutrophil migration; Neutrophils - drug effects; Neutrophils - enzymology; nitric oxide; Nitric Oxide - metabolism; Pharmacology. Drug treatments; Protoporphyrins - pharmacology; Receptors, Cytoplasmic and Nuclear - metabolism; Research Papers; soluble guanylate cyclase; Soluble Guanylyl Cyclase; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0706882

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