Ozone is one of the most ubiquitous and toxic urban air pollutants known. Exposure to toxic levels of ozone is associated with breakdown of interstitial collagen and the accumulation of macrophages and neutrophils (PMN) in the lungs. Although the function of these cells in normal host defense has been established, their potential role in oxidant induced lung injury, and their interaction with interstitial connective tissue has not been elucidated. It is the overall objective of this proposal to examine the role of interstitial and alveolar macrophages in this process. We hypothesize that ozone exposure damages lung connective tissue causing the release of chemotactic collagen fragments. These fragments attract macrophages and PMN to the lungs. Once localized, these cells become activated by collagen fragments and macrophage derived factors, and release mediators that augment the inflammatory response and contribute to toxicity. In preliminary studies we found that ozone causes breakdown of lung collagen in vitro. In addition, treatment of rats with ozone (3 ppm) for 3 hr caused a time dependent accumulation of macrophages in the lungs which produced elevated levels of hydrogen peroxide and Interleukin-1. Furthermore, both native and synthetic collagen peptides related to connective tissue breakdown products induced chemotaxis and stimulated the release of reactive oxygen mediators from alveolar macrophages. These results suggest that ozone injured lung interstitium release connective tissue fragments that attract and activate macrophages. To test our hypothesis we will analyze the effects of ozone exposure of rats on lung collagen and macrophage accumulation. We will then characterize the mechanism underlying the accumulation and activation of macrophages in the lungs and the potential contribution of these cells to ozone induced pulmonary injury.
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