GRAIN DUST, ENDOTOXIN, AND AIRFLOW OBSTRUCTION

这项建议的目标是减少急性呼吸道反应 应用呼吸道生物和生理标志物吸入颗粒尘 评估具体干预措施的效果。谷物粉尘 诱发呼吸道疾病是一种常见的职业和环境形式的 肺部疾病。仅在北美，就有500多万农业工人 每年暴露在谷物粉尘中，10%到20%的人会出现呼吸道 疾病。这项研究的总体假设是内毒素是 脑尘的主要成分对脑血管疾病的发展起作用 呼吸道炎症和气流阻塞。我们的初步结果 提示肺泡巨噬细胞和特定细胞因子似乎是 在最初的炎症反应中尤为重要。我们的特定 目的首先探讨吸入内毒素与内毒素的关系 下呼吸道炎症，将这些结果与什么进行比较 我们之前在吸入谷物粉尘后观察到过。接下来，我们 内毒素致下呼吸道感染的相关性研究 炎症与气流阻塞的发展，再比较 这些结果与我们之前观察到的谷物尘埃是一致的。基于 根据我们的初步观察，我们提出了四种截然不同的干预措施 (谷物粉尘的生物修饰，己酮可可碱的预给药， 吸入色甘酸前用药和诱导耐受性 内毒素)；每个干预针对的是 暴露-反应关系。一系列双盲、交叉 本次调查将采用干预试验。主题将是 吸入暴露于缓冲盐水、谷物粉尘提取物或 一种内毒素溶液。生理(肺功能)和生物(细胞) 以及外周血、支气管肺泡灌洗液中的细胞产物， 支气管腔内灌洗和活检，以及支气管镜刷检)标记 将测量对这些暴露的反应，以及每个 将对具体干预措施进行评估。虽然谷物的成分 粉尘，而不是内毒素，可能导致谷物粉尘的发展 诱导哮喘和支气管炎，重点研究其作用 内毒素在谷物粉尘所致呼吸道疾病中的发展 显著提高我们治疗谷物粉尘患者的能力 为控制和预防肺病提供科学依据 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.