MODEL TO STUDY THE ORIGIN OF PERSISTENT ENVIRONMENTAL AIRWAY DISEASE

这个项目将解决儿童哮喘的一个基本问题：为什么 只有少数在幼年喘息的儿童会发展成顽固不化 终生持续的呼吸道疾病。虽然变稠了 和基底膜下上皮下区的纤维化 与哮喘直接相关的一致的组织学特征 这种疾病的临床严重性，导致 可逆性呼吸道炎症后的局部纤维化反应 没有很好地定义。谷物粉尘引起的呼吸道疾病是一种 研究可逆性骨肉瘤生物学特性的理想模型 呼吸道炎症是慢性支气管炎发展的基础 哮喘。在我们的人类和小鼠谷物粉尘诱导的呼吸道模型中 疾病方面，我们以前发现：1)内毒素是 颗粒粉尘中引起可逆性呼吸道炎症的主要因素 和气流阻塞；2)吸入后的急性生理反应 谷物粉尘与巨噬细胞、中性粒细胞和 谷物粉尘是自我限制的；4)拮抗内毒素或亲-内毒素的药物 炎性细胞因子可有效减轻急性炎症反应。 对吸入谷物粉尘的反应；以及5)慢性吸入谷物粉尘 导致持续的气道高反应性和气道重塑。 然而，人们对急性和非传染性疾病之间的关系知之甚少。 可逆性气道炎性反应与慢性阻塞性肺疾病的发展 谷物粉尘引起的呼吸道疾病。对此的总体假设是 调查表明，急性和非传染性支气管炎的许多生物学特征 可逆性呼吸道炎症是慢性支气管炎发生发展的基础 慢性谷物粉尘所致呼吸道疾病。这个项目的目标是 确定急性炎症反应的哪些特定元素 吸入谷物粉尘是慢性谷物粉尘发生发展的关键 诱发的呼吸道疾病，定义为持续性的呼吸道高反应性和 呼吸道重塑。我们提出了以下目标。 。确定最初的炎症反应是否是内毒素的一个关键 吸入颗粒粉尘中的生物成分，影响疾病的发展 慢性谷物粉尘所致呼吸道疾病。 。确定炎症性疾病的扩增和定位 气道腔内的反应对慢性支气管炎的发展至关重要。 谷物性呼吸道疾病。 。确定抗炎细胞因子(IL-1ra或IL-10)是否调节 慢性谷物粉尘所致呼吸道疾病的严重程度。

This project will address a fundamental issue in childhood asthma: why only a minority of children who wheeze at an early age develop persistent airway disease that continues throughout their life. Although thickening and fibrosis of the subepithelial region beneath the basement membrane are consistent histologic features of asthma that are directly related to the clinical severity of this disease, the biological factors that lead to a localized fibrotic response following reversible airway inflammation have not been well defined. Grain dust induced airway disease serve as an excellent model to investigate the biological features of reversible airway inflammation that are fundamental to the development of chronic asthma. In our human and murine models of grain dust induced airway disease, we have previously found that: 1) endotoxin is one of the principle agents in grain dust that causes reversible airway inflammation and airflow obstruction; 2) the acute physiologic response to inhaled grain dust is associated with activation of macrophages, neutrophils, and grain dust is self-limited; 4) agents that antagonize either LPS or pro- inflammatory cytokines are effective in decreasing the acute inflammatory response to inhaled grain dust; and 5) chronic inhalation of grain dust results in persistent airway hyperreactivity and airway remodeling. However, little is known about the relationship between the acute and reversible airway inflammatory response and the development of chronic grain dust induced airway disease. The overall hypothesis of this investigation is that many of the biologic features of acute and reversible airway inflammation are fundamental to the development of chronic grain dust induced airway disease. The goal of this project is to determine which specific elements of the acute inflammatory response to inhaled grain dust are essential to the develop of chronic grain dust induced airway disease, defined as persistent airway hyperreactivity and airway remodeling. We propose the following aims. . Determine whether the initial inflammatory response to endotoxin, a key biological component of inhaled grain dust, affects the development of chronic grain dust induced airway disease. . Determine whether amplification and localization of an inflammatory response in the airway lumen is essential to the development of chronic grain induced airway disease. . Determine whether anti-inflammatory cytokines (IL-1ra or IL-10) modulate the severity of chronic grain dust induced airway disease.