The purpose of this study is to characterize the fundamental mechanisms of oxygen injury to the mammalian lung. Our specific goals are (1) to define the role of superoxide, hydrogen peroxide, hydroxyl and lipid peroxide radicals in development of lethal and sublethal injury to the alveolar epithelium, pulmonary surfactant system, pulmonary interstitial space, capillary endothelium and type II alveolar pneumocytes; (2) to assess to what extent the physiological manifestations of the hyperoxic injury to the mammalian blood-gas barrier (i.e. increased permeability, decreased total lung capacity, appearance of atelectasis) are due to direct damage by oxygen to the pulmonary surfactant system and (3) to identify the possible mechanisms that may account for the deactivation of the pulmonary surfactant system in hyperoxia. These goals will achieved be augmenting the lung defenses to radicals by (a) the intratracheal and intravenous injection of liposome-encapsulated antioxidant enzymes and free radical scavengers and (b) the intratracheal administration of exogenous lung surfactant and assessing the efficiency of these interventions in preventing the onset and limiting the progression of specific indices of hyperoxic lung injury. In contrast to previous studies, we will use novel and sensitive physiological, biochemical biophysical and ultrastructural techniques to document the appearance, progression and possible modification of hyperoxic injury in the lungs of conscious animals and isolated type II cells. The following variables will be measured: Arterial blood gases; (b) alveolar permeability to solute; (c) lung pressure- volume relationships; (d) minimum surface tension, phospholipid and protein content in the bronchoalveolar lavage; (e) albumin and IgG pulmonary extravascular spaces; (f) filtration coefficient of the pulmonary microvasculature; (g) biosynthetic abilities of type II cells; (h) length of survival to hyperoxia and (e) histological changes in lung tissues with light microscopy. We hope that this multidisciplinary approach will offer novel and important insights to the mechanisms of hyperoxic lung injury in mammalian lungs and help us to devise strategies by which oxygen toxicity could be limited thus expanding its potential therapeutic uses.
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