MODEL TO STUDY THE ORIGIN OF PERSISTENT ENVIRONMENTAL AIRWAY DISEASE

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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.