TOXICOLOGY OF PULMONARY OXIDANT INJURY IN AGING

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Progressive deterioration of pulmonary mechanics during aging has been documented repeatedly. Biochemical aspects of aging in the lung have received much less attention, and in particular, pulmonary bioenergetics have not been investigated at all. Bioenergetics in the aging lung are of immense importance to cellular viability and longevity, and hence, to maintenance of proper organ function and resistance to disease and injury. This project will examine the hypothesis that the aged lung has a decreased capacity for bioenergetic metabolism compared to the adult organ. Specifically, the pulmonary epithelium will be the focus of investigation. This lung surface is the site of gas exchange and as such, is the initial site for many types of pulmonary injury. The hypothesis predicts that the epithelial cells in aged lungs will respond less efficiently to injury. To investigate this, a reproducible model of oxidant lung injury has been developed using acute exposure (8 hours) to three concentrations of ozone. In this model, specific and separate phases of epithelial injury, cellular proliferation and recovery have been defined. Each of these phases may be ovserved during graded levels of injury defined as mild, moderate and severe by the extent of epithelial damage. To fully evaluate the bioenergetic consequences of this typical oxidant injury, both mitochondrial and cytoplasmic bioenergetic metabolism will be investigated. Also, the cellular consequences of this injury, both in adult and aged animals, will be quantitated in terms of lipid and protein damage and defensive responses. All biochemical studies will be correlated with the morphoetric alterations appearing both in the whole organ and in isolated Type II pulmonary epithelium. These combined studies will provide the first information on the effects of aging on pulmonary bioenergetics in the noral, healthy mammal and during the situation of lung injury from a chemical that is typical of numerous common pulmonary toxins.