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 只有少数儿童在幼年时发生喘息， 呼吸道疾病会持续一生。虽然增厚 基底膜下的上皮下区域的纤维化是 哮喘的一致组织学特征与 这种疾病的临床严重程度、导致疾病的生物学因素 可逆性气道炎症后的局部纤维化反应 没有被很好地定义。谷物粉尘引起的呼吸道疾病是 一个很好的模型来研究可逆性 气道炎症是慢性炎症发展的基础， 哮喘在我们的人类和小鼠模型的粮食粉尘诱导的气道 疾病，我们以前已经发现：1）内毒素是其中之一， 谷物粉尘中引起可逆性气道炎症的主要物质 和气流阻塞; 2）吸入的急性生理反应 谷物粉尘与巨噬细胞、中性粒细胞和 谷物粉尘是自限性的; 4）拮抗LPS或促 炎性细胞因子可有效降低急性炎症反应， 对吸入谷物粉尘的反应; 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，人们对急性和慢性炎症之间的关系知之甚少。 可逆性气道炎症反应和慢性 谷物粉尘引起的呼吸道疾病。这个问题的总体假设 研究表明，急性和 可逆的气道炎症是发展的基础， 慢性谷物粉尘引起的呼吸道疾病。该项目的目标是 确定急性炎症反应的哪些特定元素， 吸入粮尘是慢性粮尘形成的必要条件 诱发的气道疾病，定义为持续气道高反应性， 气道重塑我们提出以下目标。 .确定是否初始炎症反应的内毒素，一个关键 吸入谷物粉尘的生物成分，影响 慢性谷物粉尘引起的呼吸道疾病。 .确定是否扩增和定位的炎症 气道腔内的反应对于慢性炎症的发展至关重要。 谷物引起的呼吸道疾病。 .确定抗炎细胞因子（IL-1 ra或IL-10）是否调节 慢性谷物粉尘所致气道疾病的严重程度。

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.