Nature  Medicine：石国平文章发现动脉硬化发病新机制

    生物谷综合：来自美国哈佛大学医学院，  布莱根妇女医院（Brigham  and  Women's  Hospital），加州大学旧金山分校，中国南方医科大学的研究人员为肥大细胞（mast  cell）参予动脉粥样硬化过程提出了直接证据，这是这一常见疾病的病理学机制的一个崭新的观点。这一研究成果公布在Nature  Medicine上。  

    肥大细胞（mast  cell）是免疫系统的重要构成部分，是过敏和哮喘等过敏反应中的响应成分。这种存在于气管支气管粘膜的细胞在速发型支气管哮喘中起着十分重要的作用，即I型变态反应，当受到抗原刺激后可释放活性介质而引起气管支气管痉挛。

    之前的研究发现在人类动脉粥样硬化（atherosclerotic  lesions）过程中有肥大细胞的积累，但未得到直接的证据。在这篇研究报告中，研究人员提出了低密度脂蛋白受体缺陷小鼠（low-density  lipoprotein  receptor–deficient  ，Ldlr-/-）中肥大细胞直接参与动脉粥样化形成的证据。

    Ldlr-/-KitW-sh/W-sh突变小鼠中atheromata表明小鼠受损大小，脂类沉积（lipid  deposition），T细胞和巨噬细胞数目，细胞增殖与细胞凋亡都会减少，而胶原质（collagen）的含量及纤维帽（fibrous  cap）相反则有所增加。同时研究人员也发现野生型或肿瘤坏死因子（tumor  necrosis  factor，TNF）-缺陷型肥大细胞过继转移（adoptive  transfer）能逆转Ldlr-/-KitW-sh/W-sh小鼠的动脉粥样化的形成。

    而且令人惊讶的是，白介素6（IL6）或干扰素（IFN）缺陷型肥大细胞都无法逆转，这说明Ldlr-/-KitW-sh/W-sh小鼠中动脉粥样化的抑制是来自于肥大细胞，以及IL-6  and  IFN-的缺失。除此之外，将野生型和TNF-缺陷型肥大细胞进行比较，研究人员发现缺乏IL-6或IFN-并不会诱导促动脉粥样硬化半胱氨酸蛋白酶的表达，以及动脉粥样硬化损伤中基质金属蛋白酶（matrix  metalloproteinase）的表达，这又说明了肥大细胞IL-6和IFN-可以通过增加基质降解蛋白酶的表达导致动脉粥样硬化的发生。因此研究人员认为他们的研究说明了小鼠肥大细胞和肥大细胞源IL-6  and  IFN-参予了动脉粥样硬化，为这一常见疾病的病理发生学的机制研究提出了新的观点。 

原始出处:

Nature Medicine 13, 719 - 724 (2007)
Published online: 3 June 2007 | doi:10.1038/nm1601

Mast cells promote atherosclerosis by releasing proinflammatory cytokines

Jiusong Sun1,4, Galina K Sukhova1,4, Paul J Wolters2,4, Min Yang1,3,4, Shiro Kitamoto1, Peter Libby1, Lindsey A MacFarlane1, Jon Mallen-St Clair2 & Guo-Ping Shi1

Mast cells contribute importantly to allergic and innate immune responses by releasing various preformed and newly synthesized mediators1, 2. Previous studies have shown mast cell accumulation in human atherosclerotic lesions3. This report establishes the direct participation of mast cells in atherogenesis in low-density lipoprotein receptor–deficient (Ldlr-/-) mice4. Atheromata from compound mutant Ldlr-/-KitW-sh/W-sh mice5 showed decreased lesion size, lipid deposition, T-cell and macrophage numbers, cell proliferation and apoptosis, but increased collagen content and fibrous cap development. In vivo, adoptive transfer of syngeneic wild-type or tumor necrosis factor (TNF)--deficient mast cells restored atherogenesis to Ldlr-/-KitW-sh/W-sh mice. Notably, neither interleukin (IL)-6- nor interferon (IFN)--deficient mast cells did so, indicating that the inhibition of atherogenesis in Ldlr-/-KitW-sh/W-sh mice resulted from the absence of mast cells and mast cell–derived IL-6 and IFN-. Compared with wild-type or TNF--deficient mast cells, those lacking IL-6 or IFN- did not induce expression of proatherogenic cysteine proteinase cathepsins from vascular cells in vitro or affect cathepsin and matrix metalloproteinase activities in atherosclerotic lesions, implying that mast cell–derived IL-6 and IFN- promote atherogenesis by augmenting the expression of matrix-degrading proteases. These observations establish direct participation of mast cells and mast cell–derived IL-6 and IFN- in mouse atherogenesis and provide new mechanistic insight into the pathogenesis of this common disease.

1. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cardiovascular Medicine NRB-7, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
2. Department of Medicine, University of California, HSE-201, 513 Parnassus Avenue, San Francisco, California 94143, USA.
3. Department of Rheumatology, Nanfang Hospital and Nanfang Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, China.
4. These authors contributed equally to this study.

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