Rosiglitazone Abrogates Bleomycin-Induced Scleroderma and Blocks Profibrotic Responses Through Peroxisome Proliferator-Activated Receptor-γ
Rosiglitazone Abrogates Bleomycin-Induced Scleroderma and Blocks Profibrotic Responses Through Peroxisome Proliferator-Activated Receptor-γ
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DOI：
10.2353/ajpath.2009.080574
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发表时间：
2009-02-01
影响因子：
6
通讯作者：
Varga, John
中科院分区：
文献类型：
--
作者：
Wu, Minghua;Melichian, Denisa S.;Varga, John
核激素受体，过氧化物酶体增殖物激活受体（PPAR）-γ，最初被认为是脂肪生成的关键介质，广泛表达并参与多种生物反应。 PPAR-γ 的天然和合成激动剂均消除了体外转化生长因子 (TGF)-β 诱导的胶原合成和肌成纤维细胞分化的刺激。为了表征 PPAR-γ 在体内纤维化过程中的作用，在硬皮病小鼠模型中使用了合成激动剂罗格列酮。罗格列酮减轻了博莱霉素引起的皮肤炎症和真皮纤维化以及皮下脂肪萎缩，并抵消了病变皮肤中胶原蛋白基因表达的上调和肌成纤维细胞的积累。罗格列酮治疗原位减少了早期即刻转录因子 Egr-1 的诱导，但也没有阻断 Smad2/3 的激活。在外植的成纤维细胞和皮肤器官培养物中，罗格列酮阻止了 TGF-β 引起的胶原蛋白基因转录和细胞迁移的刺激。在 TGF-β 存在的情况下，罗格列酮驱动的成纤维细胞和前脂肪细胞的脂肪形成分化被消除；这种效应伴随着细胞 PPAR-γ mRNA 表达的下调。总的来说，这些结果表明，在硬皮病小鼠模型中，罗格列酮治疗可通过 PPAR-γ 减轻炎症、真皮纤维化和皮下脂肪萎缩，并表明广泛用作治疗 2 型糖尿病的胰岛素增敏剂的药理学 PPAR-γ 配体可能是硬皮病的潜在疗法。 (Am J Pathol 2009, 174:519-533; DOI: 10.2353/ajpath.2009.080574)
The nuclear hormone receptor, peroxisome proliferator-activated receptor (PPAR)-gamma, originally identified as a key mediator of adipogenesis, is expressed widely and implicated in diverse biological responses. Both natural and synthetic agonists of PPAR-gamma abrogated the stimulation of collagen synthesis and myofibroblast differentiation induced by transforming growth factor (TGF)-beta in vitro. To characterize the role of PPAR-gamma in the fibrotic process in vivo, the synthetic agonist rosiglitazone was used in a mouse model of scleroderma. Rosiglitazone attenuated bleomycin-induced skin inflammation and dermal fibrosis as well as subcutaneous lipoatrophy and counteracted the up-regulation of collagen gene expression and myofibroblast accumulation in the lesioned skin. Rosiglitazone treatment reduced the induction of the early-immediate transcription factor Egr-1 in situ without also blocking the activation of Smad2/3. In both explanted fibroblasts and skin organ cultures, rosiglitazone prevented the stimulation of collagen gene transcription and cell migration elicited by TGF-beta. Rosiglitazone-driven adipogenic differentiation of both fibroblasts and preadipocytes was abrogated in the presence of TGF-beta; this effect was accompanied by the concomitant down-regulation of cellular PPAR-gamma mRNA expression. Collectively, these results indicate that rosiglitazone treatment attenuates inflammation, dermal fibrosis, and subcutaneous lipoatrophy via PPAR-gamma in a mouse model of scleroderma and suggest that phamacological PPAR-gamma ligands, widely used as insulin sensitizers in the treatment of type-2 diabetes mellitus, may be potential therapies for scleroderma. (Am J Pathol 2009, 174:519-533; DOI: 10.2353/ajpath.2009.080574)