The overall objectives of the proposed studies are to define the extent to which neutrophils contribute to acute lung injury resulting from ozone exposure and to explore the mechanisms involved. There are five specific aims. Our first specific aim is to determine the extent to which neutrophils contribute to acute lung injury resulting from ozone exposure. Our second specific aim is to determine how neutrophil are recruited into the pulmonary centriacinar region by ozone-induced epithelial injury at that site. The role of neutrophils will be investigated using three-dimensional morphometry and selected biochemical measurements in bronchoalveolar lavage (BAL) of rat lungs. To explore mechanisms, we will use neutrophil depletion, repletion an inhibition to define the role of the neutrophil in ozone induced lung injury in vivo A unique approach using direct ozone exposure of the isolated perfused lung will enable the role of neutrophils in ozone-induced lung injury to be explored by modifying the perfusate or by intratracheal instillation of the cells. A cell culture system will be used to characterize the nature of the interaction among neutrophils, epithelial an endothelial cells in the presence and absence of ozone. Our third specific aim is to determine the relative roles of oxygen metabolites and elastase in causing neutrophil dependent acute lung injury associated with ozone-exposure. To evaluate how neutrophils injure centriacinar epithelium in vivo, we will expose neutrophil-depleted rats to ozone, treat them with oxidant scavengers and replete them with neutrophils a critical times. In the isolated lung we will add neutrophil cytoplasts and exogenous elastase to the perfusate to examine the role of neutrophil-derived oxygen metabolite and elastase, respectively. Neutrophil cytoplasts and exogenous elastase will also be examined in our cell culture system. Our fourth specific aim is to investigate the role of prostaglandins in mediating neutrophil-dependent lung injury associated with ozone exposure. By the use of specific inhibitors of arachidonic acid metabolism, we will assess their potential inhibition on neutrophil emigration, neutrophil-dependent lung injury and neutrophil activation. In cell culture we will examine the potential for epithelial cells to produce arachidonic acid metabolites that influence neutrophil dependent epithelial injury. Our fifth specific aim is to investigate epithelia necrosis, neutrophil influx and accumulation that results from short-term ozone exposure in the ozone-adapted lung.
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