Characterization of the Innate Immune Response to Crystalline Silica

描述(申请人提供)：二氧化硅是地壳中最丰富的矿物，是富裕国家和发展中国家许多职业普遍暴露于可呼吸硅酸盐的原因。除吸烟外，这是慢性阻塞性肺疾病的主要可预防原因，其中二氧化硅会导致一系列特别毁灭性的疾病，即肺矽肺。对人类样本和动物模型的仔细研究已经确定，结晶型二氧化硅(即二氧化硅)是肺部炎症的原因，最终导致COPD的表现。此外，这些研究还涉及到天然免疫系统的激活，包括巨噬细胞依赖的肿瘤坏死因子和白介素1的分泌。在肺矽肺的病理生理学方面。然而，结晶二氧化硅刺激这些急性炎症反应的机制仍然存在争议。几项研究表明，清道夫受体家族的成员可以促进包括结晶二氧化硅在内的颗粒物的摄取。然而，这些受体似乎也促进了非晶态硅酸盐的摄取，并缺失了刺激与晶态二氧化硅接触相关的细胞内炎症反应所必需的基序。其他研究将这种炎症活动归因于硅酸盐颗粒刺激氧化应激和促进细胞死亡的可能性。然而，这些模型未能解释那些刺激炎症的二氧化硅晶体的独特结构特征。氧化应激、巨噬细胞死亡和暴露在结晶性二氧化硅中的巨噬细胞所表现出的炎症反应之间的相关性很差，进一步削弱了它们的相关性。有趣的是，两种致炎晶体尿酸一钠(MSU)和二水焦磷酸钙(CPPD)最近被证明通过胞浆模式识别受体(c-PRR)NALP3/CIAS介导其强大的生物活性。这增加了一种可能性，即PRRs进化到识别与微生物相关的重复分子模式时，也可能识别环境中存在的生物活性晶体的重复模式。具体地说，我们建议：1.清道夫受体是否参与与结晶性二氧化硅相关的炎症反应？2.TLR、NDB或C型凝集素受体家族的PRR是否直接对结晶性二氧化硅产生独特和特异的炎症反应？ 公共卫生相关性吸入结晶硅酸盐是一种常见的职业危害，是几种破坏性肺部炎症性疾病的重要原因。然而，硅石晶体刺激这种强大的先天免疫反应的机制尚未阐明。在有趣的初步研究的基础上，我们建议调查来自天然免疫系统的受体在介导对结晶性二氧化硅的特异性和破坏性炎症反应中所起的作用。

DESCRIPTION (provided by applicant): Silica is the most abundant mineral in the earth's crust account for prevalent exposure to respirable silicates in many occupations in both affluent and developing nations. Besides smoking, this is the major preventable cause of chronic obstructive pulmonary disease, with silica the causing a particularly devastating set of diseases known as pulmonary silicoses. Careful studies in both human samples and animal models have determined that crystalline forms silica (i.e., SiO2) is the cause of pulmonary inflammation that culminates in the manifestations of COPD. Moreover, these studies have implicated activation of the innate immune system, including macrophage dependent secretion of TNF and IL-1? in the pathophysiology of pulmonary silicosis. The mechanism by which crystalline silica stimulates these acute inflammatory responses remains controversial, however. Several studies have implicated members of the scavenger receptor family in promoting uptake of particulates, including crystalline silica. However, these receptors also appear to promote the uptake of noncrystalline silicates and missing signaling the motifs that would be necessary to stimulate the intracellular inflammatory responses uniquely associated with exposure to crystalline silica. Other studies have ascribed this inflammatory activity to the potential for silicate particulates to stimulate oxidant stress and promote cell death. However, these models fail to account for the unique structural features of those silica crystals that stimulate inflammation. They are further undermined by the poor correlations between oxidant stress, macrophage death and the inflammatory response exhibited by macrophages exposed to crystalline silica. Intriguingly, two pro-inflammatory crystals monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD), have recently been shown to mediate their potent biological activity through Nalp3/CIAS, a cytosolic Pattern Recognition Receptors (c-PRR). This raises the possibility that PRRs, which evolved to recognize repeating molecular patterns associated with microbes, may also recognize the repetitive pattern biologically active crystals present to the environment. Specifically, we propose to: 1. Do scavenger receptors contribute to the inflammatory response associated with crystalline silica? 2. Do PRRs from the TLR, NDB or C-type lectin receptor families direct the unique and specific inflammatory response to crystalline silica? PUBLIC HEALTH RELEVANCE The inhalation of crystalline silicates is a common occupational hazard and represents an important cause of several destructive pulmonary inflammatory diseases. However, the mechanism by which silica crystals stimulate this potent innate immune response has not been elucidated. Based on intriguing preliminary studies, we propose to investigate the role receptors from the innate immune system play in mediating the specific and destructive inflammatory response to crystalline silica.