Pharmacologic induction of heme oxygenase 1 reduces acute inflammatory arthritis in mice

被引:63
作者
Benallaoua, Mourad
Francois, Mathias
Batteux, Frederic
Thelier, Natacha
Shyy, John Y. -J.
Fitting, Catherine
Tsagris, Lydia
Boczkowski, Jorge
Savouret, Jean-Francois
Corvol, Marie-Therese
Poiraudeau, Serge
Rannou, Francois
机构
[1] Univ Paris, INSERM, UMR S 747, UFR Biomed, F-75006 Paris, France
[2] Univ Paris, CNRS, Hop Cochin, Assistance Publ Hop, Paris, France
[3] Univ Calif Riverside, Riverside, CA 92521 USA
[4] Inst Pasteur, Paris, France
[5] Univ Paris 07, INSERM, U 700, Paris, France
来源
ARTHRITIS AND RHEUMATISM | 2007年 / 56卷 / 08期
关键词
D O I
10.1002/art.22749
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective. To determine the consequences of pharmacologic up-regulation of heme oxygenase 1 (1101), and inhibition of HO-I by injection of an anti-HO-1 small interfering RNA (siRNA), in vivo in the acute phase of a mouse model of nonautoimmune arthritis. Methods. In the K/BxN mouse serum transfer model, which mimics human inflammatory arthritis without lymphocyte influence, HO-1 was up-regulated by intraperitoneal injection of cobalt protoporphyrin IX (CoPP), a potent pharmacologic inducer, and was inhibited using a specific siRNA. The clinical progress of arthritis was monitored by measurement of paw thickness. Interleukin-1 beta (IL-10), IL-6, tumor necrosis factor a (TNF alpha), serum antioxidant, and nitric oxide (NO) levels, prostaglandin E-2 (PGE(2)) production, and matrix metalloproteinase 9 (MMP-9) activity were measured in serum. At the end of the experiments, joints were examined for immunohistopathologic changes. Results. Intraperitoneal injection of CoPP alleviated disease symptoms, such as joint swelling, cartilage degradation, and proliferation of inflammatory tissue in joints, in the acute phase of inflammatory arthritis. The CoPP-induced expression of HO-1 in the joints and liver was associated with marked decreases in IL-10, IL-6, and TNFa levels, PGE, secretion, and MMP-9 activity in serum; and with a marked increase in systemic antioxidant activity. In contrast, NO production in serum and inducible NO synthase expression in chondrocytes were not affected by HO-I induction. Specific inhibition of HO-1 by in vivo delivery of anti-HO-1 ARNA repressed the protective effects. Conclusion. Our data provide the first evidence that pharmacologically induced up-regulation of HO-I triggers a robust protective antiinflammatory response in a model of nonautoimmune arthritis in mice. This suggests that exogenously induced HO-I may have potential as therapy in the acute phase of inflammatory arthritis in humans.
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收藏
页码:2585 / 2594
页数:10
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