The goal of this proposal is to use a well developed-animal model to investigate the early inflammatory events in the lower respiratory tract which are responsible for the development of environmentally induced airway injury. Current evidence indicates that environmentally induced airway injury is primarily mediated by acute and chronic inflammation in the lower respiratory tract. However, the mechanisms responsible for the development of environmentally induced airway injury and inflammation are poorly understood. Organic dust serves as an excellent model to investigate the early inflammatory events associated with inhalation of environmental particles. The overall hypothesis of this investigation is that acute injury to the airway epithelia induced by organic dusts is mediated by proinflammatory cytokines which are produced and released from alveolar and airway macrophage and airway epithelial cells. We further hypothesize that if alveolar and airway macrophage are prevented from binding endotoxin or releasing specific proinflammatory cytokines following an organic dust challenge. the physiologic response and biological activity of the airway epithelia will be substantially reduced. Our preliminary results indicate that grain dust induced lung disease is primarily caused by endotoxin, and that the alveolar macrophage, airway epithelia, and specific proinflammatory cytokines appear to be particularly important in the initial inflammatory response. Our specific hypotheses for this investigation will determine whether the inflammatory response to inhaled organic dusts is compartmentalized, and will systematically evaluate the relative importance of alveolar and airway macrophage, specific proinflammatory cytokines, and airway epithelia in amplifying components of the inflammatory response. This project is designed as a series of exposure- response studies where mice will be exposed to sufficient doses of grain dust to elicit an objective physiologic response. This approach will allow us to focus our attention on the early inflammatory changes in the lower respiratory tract. Initial studies will be directed toward identifying whether the inflammatory response to inhaled grain dust is compartmentalized while later studies will determine whether the inflammatory and physiologic response to this environmental toxin is affected by acquired or inherited tolerance to endotoxin, blocking the primary endotoxin receptor on macrophage, minimizing the production or function of specific proinflammatory cytokines, or modifying the capacity of cells to recognize TNF-alpha. Investigation of the biological determinants of organic dust induced inflammation in the lower respiratory tract of mice will provide novel approaches to the early detection of airway injury, enhance our ability to treat environmental airway disease, and provide information concerning the pathogenesis of environmentally induced airway disease in humans.
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