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INFLAMMATION AND IMMUNOPHARMACOLOGY

Beneficial Effects of Heme Oxygenase-1 Up-Regulation in the Development of Experimental Inflammation Induced by Zymosan

Department of Pharmacology (A.M.V., M.I.G., M.J.A.), University of Valencia, Valencia, Spain; and Departments of Biochemistry and Internal Medicine (A.H.), American University of Beirut, Beirut, Lebanon

Heme oxygenase-1 (HO-1) is part of the integrated response to oxidative stress. This enzyme may exert anti-inflammatory effects in some animal models, although the precise mechanisms are not fully understood. We have examined the role of HO-1 in the inflammatory response induced by zymosan in the mouse air pouch. Zymosan administration induced HO-1 protein expression in leukocytes migrating to exudates, with maximal levels in the late phase of this response (24–48 h). This was accompanied by ferritin induction and bilirubin accumulation, indicating that this enzyme is active in our model. HO-1 expression by zymosan treatment was partly reduced by aminoguanidine, suggesting the participation of endogenous nitric oxide in the mechanisms leading to HO-1 synthesis in the zymosan-injected mouse air pouch. Up-regulation of HO-1 by hemin administration resulted in inhibition of nitric-oxide synthase-2 activity, cellular infiltration into the air pouch exudate, and plasmatic exudation. Leukotriene B₄ levels in exudates were significantly decreased in the early phase of this response (4 h), whereas interleukin-1 and tumor necrosis factor- were inhibited at all time points. Inhibition of HO-1 activity by zinc protoporphyrin IX prevented most of the effects caused by hemin administration. Our results indicate that HO-1 exerts anti-inflammatory effects on the response to zymosan in the mouse air pouch and support a role for this enzyme in the modulation of inflammatory processes.

Address correspondence to: Prof. María José Alcaraz, Department of Pharmacology, University of Valencia, Av. Vicent Andres Estelles s/n, 46100 Burjasot, Valencia, Spain. E-mail: maria.j.alcaraz{at}uv.es

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