MODEL TO STUDY THE ORIGIN OF PERSISTENT ENVIRONMENTAL AIRWAY DISEASE

研究持续性环境气道疾病起源的模型

• 批准号: 6564454
• 负责人: David A Schwartz
• 金额: $ 15.22万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-11-01 至 2002-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564454
• 关键词: asthma; chronic disease /disorder; cytokine; dust; environmental toxicology; grain; inflammation; laboratory mouse; pathologic process; respiratory disorder; respiratory disorder epidemiology; respiratory function; respiratory hypersensitivity

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.

该项目将解决儿童哮喘中的一个基本问题：为什么 只有少数在幼年时喘气的孩子持续持久 气道疾病一生都在继续。虽然增厚 和地下膜下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，导致的生物学因素 可逆气道炎症后的局部纤维化反应具有 没有很好地定义。谷物尘埃引起的气道疾病作为 出色的模型来研究可逆的生物学特征 气道炎症是慢性发展的基础 哮喘。在我们的人类和鼠类谷物灰尘诱发气道的模型中 疾病，我们以前发现：1）内毒素是其中之一 谷物灰尘中的主要代理，导致可逆气道炎症 和气流阻塞； 2）对吸入的急性生理反应 谷物灰尘与巨噬细胞，中性粒细胞的激活有关 谷物灰尘是自限的； 4）拮抗LP或Pro-的药物 炎性细胞因子可有效减少急性炎症 对吸入谷物灰尘的反应； 5）长期吸入谷物灰尘 导致持续的气道高反应性和气道重塑。 但是，对急性和急性之间的关系知之甚少 可逆气道炎症反应和慢性的发展 谷物粉尘引起的气道疾病。总体假设 调查是急性和 可逆气道炎症是发展的基础 慢性谷物灰尘诱导气道疾病。这个项目的目标是 确定急性炎症反应的哪些特定元素 吸入谷物灰尘对于发展慢性谷物灰尘至关重要 诱导气道疾病，定义为持续的气道高反应性和 气道重塑。我们提出以下目标。 。确定最初对内毒素的炎症反应是钥匙 吸入谷物灰尘的生物成分会影响 慢性谷物灰尘诱导气道疾病。 。确定炎症的放大和定位 气道管腔中的反应对于慢性发展至关重要 谷物诱导的气道疾病。 。确定抗炎细胞因子（IL-1RA或IL-10）是否调节 慢性谷物灰尘的严重程度引起的气道疾病。