Deciphering Occupational Asthma Pathogenesis Caused by Isocyanate

 描述(申请人提供)：这项资助申请集中在由异氰酸酯化学品引起的职业性哮喘，异氰酸酯化学品是制造聚亚安酯所需的呼吸道毒素，通常用于制造、建筑和运输行业。异氰酸酯的健康危害被广泛认识，工作场所空气中的浓度受到当地政府监管机构的限制，然而，异氰酸酯仍然是世界各地职业性哮喘的主要原因。我们对异氰酸酯哮喘发病机制的认识存在很大差距，与其他类型的外源性哮喘相比可能存在差异，这些都有助于疾病的持久性。我们为异氰酸酯哮喘的发病机制提出了一个令人兴奋的新假说，并开始破译涉及多个宿主分子的动态生化途径。我们已经确定谷胱甘肽(GSH)是异氰酸酯的一个重要的“自身”反应靶标，并表明GSH-异氰酸酯反应产物可以将异氰酸酯转移到(转氨甲酰基)其他自身分子上，在此过程中产生抗原性变化。职业性接触者的血清抗体可与谷胱甘肽-异氰酸酯转氨甲酰化的白蛋白特异性结合。在动物研究中，GSH-异氰酸酯反应产物导致哮喘样呼吸道炎症，并在免疫致敏的宿主中产生显著的嗜酸性粒细胞和粘液。GSH-异氰酸酯引起的呼吸道炎症类似于对常见蛋白过敏原的典型TH2型反应，但发生时IL-4或IL-13没有明显增加。相反，在IL-12/IL-23的共有β亚基、几丁质酶(YM-1/YM-2)、RELmα/FIZZ-1以及其他选择性激活的巨噬细胞标志物中观察到选择性的增加。这些数据开始定义异氰酸酯哮喘发病机制的新范式，解释了令人费解的疾病特征，并为监测、预防和治疗提出了新的方法。我们建议阐明GSH介导异氰酸酯诱导的呼吸道炎症反应的不同途径，从而为开发新的干预策略提供必要的见解，并确定适用于暴露监测和疾病预防的生物标志物。具体地说，我们提出了以下三个目标：目的1.确定内源性GSH水平对异氰酸酯免疫增敏和暴露诱导的呼吸道炎症的影响。目的2.阐明异氰酸酯刺激的细胞类型、细胞因子和信号转导通路在免疫增敏和暴露诱导的呼吸道病理中的关键作用。目的3.确定异氰酸酯暴露和疾病的生物标志物。这些研究与Nora建筑和制造部门相关，并将为呼吸、免疫和皮肤病联合部门提供洞察。

 DESCRIPTION (provided by applicant): This grant application focuses on occupational asthma caused by isocyanate chemicals, which are respiratory toxins needed to make polyurethane and commonly used in the manufacturing, construction and transportation industry sectors. Isocyanates' health hazards are widely recognized and workplace airborne levels are restricted by local governmental regulatory agencies, however, isocyanates remain a leading cause of occupational asthma throughout the world. Substantial knowledge gaps in our understanding of the mechanisms underlying isocyanate asthma and potential differences compared with other types of extrinsic asthma contribute to disease persistence. We have developed an exciting new hypothesize for the pathogenesis of isocyanate asthma and begun to decipher a dynamic biochemical pathway involving multiple host molecules. We have identified glutathione (GSH) as an important primary "self" reaction target for isocyanate and shown that GSH-isocyanate reaction products can transfer isocyanate to (transcarbamoylate) other self molecules, creating antigenic changes in the process. Serum antibodies from occupationally exposed workers specifically bind albumin transcarbamoylated by GSH-isocyanate. In animal studies, GSH-isocyanate reaction products cause asthma-like airway inflammation with significant eosinophilia and mucus production in immune sensitized hosts. The airway inflammation elicited by GSH-isocyanate resembles the prototypical TH2-type response to common protein allergens, but occurs without measurable increases in IL-4 or IL-13. Instead selective increases are observed in the shared beta subunit of IL-12/IL-23, chitinases (YM-1/YM-2), RELMα/Fizz-1, and other markers of alternatively activated macrophages. The data begin to define a new paradigm for isocyanate asthma pathogenesis, which explain the diseases puzzling features and suggest novel approaches for surveillance, prevention, and treatment. We propose to elucidate the distinct pathways through which GSH mediates isocyanate-induced airway inflammatory responses, thus, providing insight necessary to develop new intervention strategies, and to identify biomarkers applicable to exposure surveillance and disease prevention. Specifically, we propose the following three aims: AIM 1. Determine the influence of endogenous GSH levels on isocyanate immune sensitization and exposure induced airway inflammation. AIM 2. Elucidate the isocyanate-stimulated cell types, cytokines, and signal transduction cascades critical to immune sensitization and exposure-induced airway pathology. AIM 3. Identify biomarkers of isocyanate exposure and disease. The studies are relevant to NORA Construction and Manufacturing Sectors, and will provide insight into the Respiratory, and Immune and Dermal Disease Co-Sectors.