Characterization of the Innate Immune Response to Crystalline Silica

描述（由申请人提供）：二氧化硅是地壳中最丰富的矿物，在富裕国家和发展中国家的许多职业中都普遍暴露于可吸入硅酸盐。除了吸烟，这是慢性阻塞性肺病的主要可预防原因，二氧化硅会导致一系列特别具有破坏性的疾病，即肺矽肺病。在人类样本和动物模型中进行的仔细研究已经确定，结晶形式的二氧化硅（即SiO2）是导致肺部炎症的原因，最终导致COPD的表现。此外，这些研究还涉及先天免疫系统的激活，包括巨噬细胞依赖性分泌TNF和IL-1？肺矽肺的病理生理。然而，晶体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，清除受体家族的成员在促进颗粒的吸收，包括结晶二氧化硅。然而，这些受体似乎也促进了非晶体硅酸盐的摄取，并缺失了刺激细胞内炎症反应所必需的信号，而这些炎症反应与暴露于晶体二氧化硅有关。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潜力。然而，这些模型无法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于结晶二氧化硅的巨噬细胞所表现出的炎症反应之间的不相关性进一步破坏了它们。有趣的是，两种促炎晶体尿酸钠（MSU）和焦磷酸钙二水合物（CPPD）最近被证明通过细胞质模式识别受体（c-PRR） Nalp3/CIAS介导其强大的生物活性。这提出了一种可能性，即PRRs进化为识别与微生物相关的重复分子模式，也可能识别存在于环境中的重复模式生物活性晶体。具体而言，我们建议：1。清道夫受体是否与结晶二氧化硅相关的炎症反应有关？2. 来自TLR， NDB或c型凝集素受体家族的PRRs是否指导对结晶二氧化硅的独特和特异性炎症反应？

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.