GRAIN DUST, ENDOTOXIN, AND AIRFLOW OBSTRUCTION

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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.