Characterization of the Innate Immune Response to Crystalline Silica

对结晶二氧化硅的先天免疫反应的表征

• 批准号: 7846828
• 负责人: CHRISTIAN W SCHINDLER
• 金额: $ 19.76万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846828
• 关键词: Accounting; Acute; Affinity; Alveolar Macrophages; Animal Model; Binding; Biological; Breathing; C Type Lectin Receptors; Calcium Pyrophosphate Dihydrate; Cell Death; Cells; Cessation of life; Charge; Chronic; Chronic Obstructive Airway Disease; Country; Developing Countries; Disease; Endosomes; Environment; Enzymes; Evaluation; Exhibits; Exposure to; Family; Functional disorder; Glass; Goals; Gout; Homeostasis; Human; Immune; Immune response; Immune system; Income; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-1; Knock-out; Laboratories; Ligands; Lung; Lung diseases; Mediating; Microbe; Minerals; Mining; Modeling; Modification; Molecular; Natural Immunity; Nature; Nucleotides; Occupations; Particulate; Pathogenesis; Pathway interactions; Pattern; Pattern recognition receptor; Peritoneal Macrophages; Play; Pneumonia; Process; Production; Quartz; Role; Sampling; Signal Pathway; Signal Transduction; Silicates; Silicon Dioxide; Silicosis; Site; Smoking; Specificity; Surface; System; TNF gene; Testing; Tissues; Toll-like receptors; Up-Regulation; Urate; Water; antimicrobial; base; chemokine; cytokine; in vivo; macrophage; member; occupational hazard; oxidant stress; pathogen; public health relevance; receptor; response; scavenger receptor; sensor; silanol; uptake

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.

描述（由申请人提供）：二氧化硅是地球地壳中最丰富的矿物质，即富裕和发展中国家在许多职业中普遍暴露于可呼吸的硅酸盐。除吸烟外，这是慢性阻塞性肺部疾病的主要可预防原因，二氧化硅引起了一组特别毁灭性的疾病，称为肺硅质硅。对人类样品和动物模型的仔细研究已经确定晶体形成二氧化硅（即SiO2）是肺部炎症的原因，最终导致COPD的表现。此外，这些研究暗示了先天免疫系统的激活，包括巨噬细胞依赖性TNF和IL-1的分泌？在肺硅化病的病理生理学中。但是，结晶二氧化硅刺激这些急性炎症反应的机制仍然有争议。几项研究已暗示了清道夫受体家族的成员促进了包括晶体二氧化硅在内的颗粒物的吸收。但是，这些受体似乎还促进了非晶硅酸盐的摄取和缺少信号的基序，这些基序是刺激与晶体硅胶暴露有关的细胞内炎症反应所必需的。其他研究将这种炎症活性归因于硅酸盐颗粒刺激氧化剂应激并促进细胞死亡的潜力。但是，这些模型无法说明那些刺激炎症的二氧化硅晶体的独特结构特征。氧化剂应激，巨噬细胞死亡与暴露于晶体二氧化硅的巨噬细胞表现出的炎症反应之间的不良相关性进一步破坏了它们。有趣的是，两种促炎性晶体单钠尿酸盐（MSU）和焦磷酸钙二氢酸钙（CPPD）最近已被证明可以通过Nalp3/CIAS（一种胞质模式识别受体（C-PRR）介导其有效的生物学活性。这增加了以下可能识别与微生物相关的重复分子模式的PRR的可能性，也可能识别出对环境中存在的重复模式生物活性晶体。具体来说，我们建议：1。清道夫受体是否有助于与晶体二氧化硅相关的炎症反应？ 2。来自TLR，NDB或C型凝集素受体家族的PRR会引导对晶体二氧化硅的独特且特异性的炎症反应吗？ 公共卫生相关性吸入结晶硅酸盐是一种常见的职业危害，代表了几种破坏性肺部炎症性疾病的重要原因。然而，二氧化硅晶体刺激这种有效的先天免疫反应的机制尚未阐明。基于有趣的初步研究，我们建议研究先天免疫系统在介导对晶体二氧化硅的特异性和破坏性炎症反应中发挥的作用。

项目成果

Brain interstitial fluid TNF-alpha after subarachnoid hemorrhage.

• DOI: 10.1016/j.jns.2009.12.023
• 发表时间: 2010-04-15
• 期刊: JOURNAL OF THE NEUROLOGICAL SCIENCES
• 影响因子: 4.4
• 作者: Hanafy, Khalid A.;Grobelny, Bartosz;Fernandez, Luis;Kurtz, Pedro;Connolly, E. S.;Mayer, Stephan A.;Schindler, Christian;Badjatia, Neeraj
• 通讯作者: Badjatia, Neeraj