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

Abstract

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 zymosaninjected 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 B 4 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.

Influence of heme oxygenase 1 modulation on the progression of murine collagen‐induced arthritis

“…HO-1 overexpression has shown antiinflammatory or immunomodulatory effects in models of acute disease (10,16,36,(45)(46)(47). Less is known about the possible role of this enzyme in chronic inflammatory diseases, which involve complex interactions between different cell populations and a wide range of mediators.…”

“…HO-1 induction has also been shown to down-regulate the inflammatory response in animal models of acute inflammation. For example, we have recently demonstrated the antiinflammatory effects of HO-1 in the zymosan-injected mouse air-pouch model (16). In addition, several studies have suggested that HO-1 expression in response to different inflammatory mediators may contribute to the resolution of inflammation (17).…”

Potential role of heme oxygenase-1 in the progression of rat adjuvant arthritis

“…11 It has been found that iNOS activity upregulates HO-1 in inflammatory models such as rat nephritis 31 or mouse air pouch. 25 In the chronic phase of rat adjuvant arthritis, we have shown that selective iNOS inhibition results in decreased HO-1 expression, suggesting that endogenously NO generated by this enzyme participates Heme oxygenase-1 in adjuvant arthritis I Devesa et al in HO-1 induction. In a number of in vitro and in vivo systems, there is a negative feedback interaction between iNOS and HO-1 and thus overexpression of HO-1 results in inhibition of iNOS expression or activity, which can be protective against NOmediated toxicity.…”

“…We have shown that iNOS participates in HO-1 modulation in RAW 264.7 macrophages 24 and in a model of acute inflammation. 25 However, the interaction between both pathways during chronic arthritis has not been examined previously.…”

Upregulation of heme oxygenase-1 gene by turpentine oil-induced localized inflammation: involvement of interleukin-6

“…48 Indeed, numerous recent observations point to a potential role of HO-1 in the downregulation of proinflammatory cytokine expression at the site of inflammation in various model systems. [49][50][51][52][53] It has also been shown that HO-1 might provide an anti-inflammatory action in vivo through the downmodulation of cell adhesion molecules accompanied by inhibition of leukocyte infiltration, [54][55][56] and via promotion of noninflammatory angiogenesis facilitating tissue repair. 56 Moreover, an increased leukocyte adhesion to the vascular wall and spontaneous perivascular infiltration of leukocytes in various tissues of HO-1-deficient mice has been reported before.…”