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

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Objective. Heme oxygenase 1 (HO-1) can be induced by inflammatory mediators as an adaptive response. The objective of the present study was to determine the consequences of HO-1 modulation in the murine collagen-induced arthritis (CIA) model.Methods. DBA/1J mice were treated with an inhibitor of HO-1, tin protoporphyrin IX (SnPP), or with an inducer of HO-1, cobalt protoporphyrin IX (CoPP), from day 22 to day 29 after CIA induction. The clinical evolution of disease was monitored visually. At the end of the experiment, joints were examined for histopathologic changes. Cytokine levels in paws were measured by enzyme-linked immunosorbent assay. Levels of HO-1, cyclooxygenase 2 (COX-2), and prostaglandin E 2 (PGE 2 ) were determined. Effects of treatments on the early phase of disease and after prophylactic administration were also assessed.Results. CoPP strongly induced HO-1, resulting in the inhibition of cartilage erosion accompanied by extensive fibrosis in the joint. Levels of tumor necrosis factor ␣ (TNF␣), interleukin-2 (IL-2), and IL-10 were inhibited by CoPP, whereas levels of vascular endothelial growth factor were increased. Treatment with SnPP significantly reduced the severity of CIA, with inhibition of joint inflammation and cartilage destruction. The levels of PGE 2 , IL-1␤, and TNF␣ were also significantly reduced by SnPP treatment, which did not modify COX-2 protein expression. SnPP was more effective than CoPP in preventing the development of CIA (prophylactic administration).Conclusion. HO-1 is induced during CIA. Although overexpression of this protein causes some beneficial effects, strategies aimed at HO-1 overexpression cannot slow the progression of the chronic inflammatory disease, whereas treatment with SnPP, which inhibits HO-1, exerts prophylactic and therapeutic effects.

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 60%

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

Devesa¹,

Ferrándiz²,

Terencio³

et al. 2005

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“…In contrast, very little HO-1 was detected in noninflammatory synovial tissues. HO-1 expression was also up-regulated in joint lesions in a model of rat adjuvant arthritis (27).…”

Section: Discussionmentioning

confidence: 86%

“…Indeed, a recent study revealed a pathologic role of HO-1 in the progression of adjuvant arthritis in a rat model (27), in that HO-1 expression was up-regulated in the joint lesions and that treatment with an HO inhibitor, tin protoporphyrin IX, suppressed leukocyte infiltration, hyperplastic synovitis, erosion of articular cartilage and osteolysis, and the production of inflammatory mediators. In that experimental rat model, HO-1 induced vascular endothelial growth factor (VEGF), which is involved in angiogenesis in inflammatory lesions in the joint.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, of the disease-modifying antirheumatic drugs (DMARDs), gold agents induce Nrf2-dependent HO-1 transcription in vitro (26). In contrast, up-regulation of HO-1 expression is found in rat adjuvant arthritis (27). Furthermore, we recently found that the serum level of HO-1 is excessively increased in patients with some inflammatory disorders such as adult-onset Still's disease and hemophagocytic syndrome, suggesting that HO-1 is involved in the development of systemic inflammation (28).…”

mentioning

confidence: 98%

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Regulatory role of heme oxygenase 1 in inflammation of rheumatoid arthritis

Kobayashi

Takeno

Saito

et al. 2006

112

103

Objective. To examine the expression and pathogenetic roles of heme oxygenase 1 (HO-1), an inducible heme-degrading enzyme with antiinflammatory properties, in rheumatoid arthritis (RA).Methods. HO-1 expression in synovial tissue from patients with RA, patients with osteoarthritis, and patients with noninflammatory joint diseases was determined by immunoblotting and immunohistochemistry. Conclusion. Our data demonstrate that HO-1 is expressed in RA synovial tissues and plays a regulatory role in the development of inflammation. The pharmacologic effects of auranofin depend, in part, on the levels of HO-1, suggesting that HO-1 induction is a novel therapeutic strategy for RA.

Tumor necrosis factor α acceleration of inflammatory responses by down‐regulating heme oxygenase 1 in human peripheral monocytes

Kirino¹,

Takeno²,

Murakami³

et al. 2007

Objective. To examine the interaction between heme oxygenase 1 (HO-1), a stress-induced antiinflammatory protein, and tumor necrosis factor ␣ (TNF␣) in human peripheral blood monocytes. Heme oxygenase (HO) is an enzyme that converts heme into carbon monoxide, Fe 2ϩ , and biliverdin (1,2). HO-1, an inducible isozyme of HO, is a 32-kd heat-shock protein that is expressed in response to a variety of noxious stimuli, including heavy metals, hyperoxia, hypoxia, endotoxins, and hydrogen peroxide (1,2). Evidence suggests that increased expression of HO-1 is beneficial in a variety of pathologic conditions (1,2). For example, HO-1 gene therapy has been successfully used to treat various lung diseases in animals (3-7), and chemical induction of HO-1 expression has been shown to improve lupus nephritis in MRL/lpr mice (8). In contrast, a deficiency of HO-1 expression is associated with severe chronic inflammation, as shown in studies of HO-1-knockout mice (9) and in a patient with HO-1 deficiency (10). These findings are consistent with a physiologic role of HO-1 in protection against inflammation. Methods. Peripheral blood mononuclear cells (PBMCs