晚期糖基化终末产物受体是哮喘致病的重要介质
2012/10/11
摘要
晚期糖基化终末产物受体（RAGE）是一种多配体受体。研究发现，RAGE 参与了糖尿病、动脉硬化和神经变性等疾病的致病。然而，RAGE在哮喘和过敏性气道疾病中的作用尚不清楚。研究中，将屋尘螨（HDM）诱导的小鼠哮喘/过敏性气道疾病作为动物模型。评价呼吸道的机械力学，并比较野生型小鼠和RAGE基因敲除小鼠。采用定量评分评价支气管血管结构，采用标准蛋白检测法和/或定量RT-PCR评价RAGE、免疫球蛋白和相关细胞因子的表达。RAGE缺失能显著缓解大部分的病理表现，包括气道高反应性（呼吸阻力、组织阻尼和顺应性），抑制嗜酸性粒细胞性炎症和气道重构。RAGE缺失时，IL-4的分泌、同型转换和抗原识别未受影响。相反，正常增加的IL-5、IL-13、eotaxin和eotaxin-2在RAGE基因敲除小鼠显著下降。IL-17显示出复杂的调节，在RAGE基因敲除小鼠，IL-17基础表达升高，但抗原刺激不会诱导其表达。野生型小鼠给予RAGE抑制剂处理，能显著抑制HDM模型的炎症，表明RAGE抑制有望成为一种治疗策略。最后，HDM模型结果在卵清蛋白诱导的哮喘模型中进行验证。结果表明，RAGE在哮喘致病中起到重要作用。
（刘国梁 审校）
Am J Pathol. 2012 Aug 10. [Epub ahead of print]
Am J Pathol. 2012 Aug 10. [Epub ahead of print]
Source
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Abstract
The receptor for advanced glycation end-products (RAGE) is a multiligand receptor that has been shown to contribute to the pathogenesis of diabetes, atherosclerosis, and neurodegeneration. However, its role in asthma and allergic airway disease is largely unknown. These studies use a house dust mite (HDM) mouse model of asthma/allergic airway disease. Respiratory mechanics were assessed and compared between wild-type and RAGE knockout mice. Bronchovascular architecture was assessed with quantitative scoring, and expression of RAGE, immunoglobulins, and relevant cytokines was assessed by standard protein detection methods and/or quantitative RT-PCR. The absence of RAGE abolishes most assessed measures of pathology, including airway hypersensitivity (resistance, tissue dampening, and elastance), eosinophilic inflammation, and airway remodeling. IL-4 secretion, isotype class switching, and antigen recognition are intact in the absence of RAGE. In contrast, normal increases in IL-5, IL-13, eotaxin, and eotaxin-2 production are abrogated in the RAGE knockouts. IL-17 indicates complex regulation, with elevated baseline expression in RAGE knockouts, but no induction in response to allergen. Treatment of WT mice with an inhibitor of RAGE markedly reduces inflammation in the HDM model, suggesting that RAGE inhibition may serve as a promising therapeutic strategy. Finally, the results in the HDM model are recapitulated in an ovalbumin model of asthma, suggesting that RAGE plays a role in asthma irrespective of the identity of the allergens involved.
Am J Pathol. 2012 Aug 10. [Epub ahead of print]
上一篇：
膳食大豆染料木黄酮与肺功能和哮喘控制的关系：对前瞻性多中心临床试验患者的事后分析
下一篇：
农场效应，或者农场环境对哮喘和过敏性疾病的保护作用
