Deciphering Occupational Asthma Pathogenesis Caused by Isocyanate

 描述（由申请人提供）：本资助申请的重点是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氨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已被广泛认识，工作场所空气中的水平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。在我们对异氰酸酯哮喘的潜在机制的理解方面存在大量的知识缺口，与其他类型的外源性哮喘相比存在潜在的差异，这些都有助于疾病的持续存在。 对于异氰酸酯哮喘的发病机制，我们已经提出了一个令人兴奋的新假设，并开始破译一个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）作为一个重要的主要的异氰酸酯的“自我”反应目标，并表明GSH-异氰酸酯反应产物可以转移异氰酸酯（transcarbamoylate）其他自我分子，在这个过程中产生抗原性的变化。职业暴露工人的血清抗体特异性结合GSH-异氰酸酯转氨甲酰化的白蛋白。在动物研究中，GSH-异氰酸酯反应产物在免疫致敏宿主中引起哮喘样气道炎症，伴有显著的嗜酸性粒细胞增多和粘液产生。由GSH-异氰酸酯引起的气道炎症类似于对常见蛋白质过敏原的原型TH 2型反应，但发生时IL-4或IL-13没有可测量的增加。相反，在IL-12/IL-23的共有β亚基、几丁质酶（YM-1/YM-2）、RELMα/Fizz-1和其他交替活化巨噬细胞标志物中观察到选择性增加。这些数据开始定义异氰酸酯哮喘发病机制的新范例，解释了疾病令人困惑的特征，并提出了监测、预防和治疗的新方法。我们建议阐明GSH介导异氰酸酯诱导的气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。具体而言，我们提出了以下三个目标：目标1。测定内源性GSH水平对异氰酸酯免疫致敏和暴露诱导的气道炎症的影响。AIM 2.阐明异氰酸酯刺激的细胞类型，细胞因子和信号转导级联反应对免疫致敏和呼吸道感染诱导的气道病理学至关重要。AIM 3.识别异氰酸酯暴露和疾病的生物标志物。这些研究与诺拉建筑和制造业相关，并将深入了解呼吸系统、免疫和皮肤病共同部门。

 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.