The objective of this project is to study mechanisms of injury and the consequences to lungs of prolonged breathing of 100% oxygen. At high partial pressures oxygen causes noncardiac, increased permeability pulmonary edema resulting in fatal respiratory failure. The clinical relevance of oxygen toxicity stems from the therapeutic use of high concentrations of oxygen in patients with hypoxemic respiratory failure. There are currently no good chemical or physiological markers of progressing oxygen toxicity, no predictive tests for susceptibility and there is no available clinical therapy once toxicity occurs. In this project, a large animal model of oxygen toxicity will be utilized to attempt to study these poorly understood areas. This model allows the measurement of multiple variables of lung vascular and airway function as well as sampling of blood, lung lymph, bronchoalveolar lavage fluid and lung biopsy tissue for biochemical markers of toxicity. Postmortem lung water and morphology will be studied and related to the normal baseline state. The general hypotheses of this proposal are, that the development of respiratory failure in oxygen toxicity is amplified and accelerated by the activation of leukocytes in the lung, that the protective effects of endotoxemia on oxygen toxicity are related to the acute inflammatory reaction to endotoxin in addition to induction of antioxidant enzymes, that the mechanical cause of respiratory failure in oxygen toxicity may be partly due to increased airway reactivity and reversible changes in dynamic compliance of the lung, that the potent chemotaxin released in lung lymph is a lipid mediator, and that potentially useful insights into oxygen tolerance can be gained through study of the effects of the instillation of erythrocytes into the lungs of oxygen exposed animals. A fuller description of whole lung dysfunction during oxygen toxicity should emerge from these studies as a step towards linking basic information about oxygen toxicity to a model which studies clinical outcome.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Pulmonary Research A Study Section (CVA)
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Vanderbilt University Medical Center
Schools of Medicine
United States
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