GRAIN DUST, ENDOTOXIN, AND AIRFLOW OBSTRUCTION

该建议的目的是减少急性气道反应， 应用呼吸道生物学和生理学指标检测吸入颗粒粉尘 以评估具体干预措施的有效性。粮食粉尘 诱发性气道疾病是一种常见的职业和环境形式， 肺病。仅在北美，就有超过500万的农业工人 每年暴露在谷物粉尘中，10%到20%的人会患上呼吸道疾病。 疾病本研究的总体假设是内毒素是 脑尘的主要成分负责发展 气道炎症和气流阻塞。我们的初步结果 表明肺泡巨噬细胞和特定的细胞因子似乎是 在最初的炎症反应中尤其重要。我们的具体 目的探讨吸入性内毒素 和下呼吸道炎症，将这些结果与 我们以前观察到吸入谷物粉尘后。接下来我们 探讨内毒素与下呼吸道感染的关系 炎症和气流阻塞的发展，再次比较 这些结果与我们以前对谷物尘埃的观察结果一致。基于 根据我们的初步观察，我们提出了四种不同的干预措施， （谷物粉尘的生物改性，预先给药戊氨酰茶碱， 吸入性色甘酸盐的前驱用药，以及诱导对 内毒素）;每次干预针对的是 反应关系。一系列的双盲，交叉 本研究将采用干预试验。受试者将 吸入暴露于缓冲盐水、谷物粉尘提取物或 内毒素溶液。生理（肺功能）和生物（细胞 和外周血中的细胞产物，支气管肺泡灌洗液， 支气管内灌洗和活检，以及支气管内刷检）标记物 将测量对这些暴露的反应， 将评估具体干预措施。虽然谷物的成分 除内毒素外，粉尘也可能导致谷物粉尘的发生 诱发哮喘和支气管炎，重点调查的作用， 内毒素在谷物粉尘引起的气道疾病的发展中将 显着提高我们的能力，治疗个人与粮食粉尘引起的 肺疾病，建立科学的控制和预防的基础 这种常见的职业性和环境性肺部疾病。

The goal of this proposal is to decrease the acute airway response to inhaled grain dust by using biologic and physiologic markers of airway injury to assess the efficacy of specific interventions. Grain dust induced airway disease is a common occupational and environmental form of lung disease. In North America alone, over 5 million agricultural workers are exposed to grain dust each year and between 10 and 20% develop airway disease. The overall hypothesis of this investigation is that endotoxin is the principle component of brain dust responsible for the development of airway inflammation and airflow obstruction. Our preliminary results indicate that the alveolar macrophage and specific cytokines appear to be particularly important in the initial inflammatory response. Our specific aims first investigate the relationship between inhalation of endotoxin and lower respiratory tract inflammation, comparing these results to what we have previously observed following inhalation of grain dust. Next, we study the relationship between endotoxin induced lower respiratory tract inflammation and the development of airflow obstruction, again comparing these results to what we have previously observed for grain dust. Based on our preliminary observations, we have proposed four distinct interventions (biological modification of grain dust, premedication with pentoxifylline, premedication with inhaled cromoglycate, and induction of tolerance to endotoxin); each intervention directed at a specific aspect of the exposure-response relationship. A series of double blinded, crossover intervention trials will be used in this investigation. Subjects will be inhalationally exposed to either buffered saline, grain dust extract, or an endotoxin solution. The physiologic (lung function) and biologic (cell and cell products in the peripheral blood, bronchoalveolar lavage fluid, endobronchial lavage and biopsy, and endobronchial brush biopsy) markers of response to these exposures will be measured and the effect of each specific intervention will be evaluated. Although components of grain dust, other than endotoxin, may lead to the development of grain dust induced asthma and bronchitis, a focused investigation of the role of endotoxin in the development of grain dust induced airway disease will markedly enhance our ability to treat individuals with grain dust induced lung disease and establish the scientific basis for control and prevention of this common occupational and environmental lung disorder.