This program proposes to stdy the pathogenesis of acute respiratory failure following pulmonary vascular injury. We hypothesize that acute respiratory failure due to vascular injury (ARDS; non-cardiac pulmonary edema) occurs because of lung edema, loss of hypoxic pulmonary vasoconstriction and abnormal airway function. We hyupothesize that all of those changes, regardless of the etiology, are mediated by metabolites of archidonic acid (and perhaps other related fatty acids) and granulocytes. We propose to test these hypotheses by 1) detailed stdies of effects of arachidonic acid (and related fatty acids) and their metabolites on lung function, 2) detailed studies of the interaction of granulocytes with the lung circulation, the pathophysiological effects of pulmonary leukostasis and themechanisms of those effects, 3) theoretical and experimental studies of transvascular transport which will define the contributions of pressures, flows, exchanging vessel surface area and vascular permeability to lung fluid balance, 4) studies of the pathogenesis of lung abnormalities in four animal models of human disease-gram negative endotoxemia, pulmonary oxygen toxicity, neurogenic pulmonary edema, and acute myocardial infarction, and 5) studies of the pathogenesis of lung abnormalities in humans with cardiogenic and noncardiogenic pulmonary edema and the therapeutic effects of high dose methylprednisolone in patients with the adult respiratory distress syndrome. Most of the animal studies will be done in chronically instrumented unanesthetized sheep prepared for collection of lung lymph; multiple indicator dilution measurements of lung water and permeability will be used in humans and animals. Measurements of prostaglandins, thromboxanes, arachidonate lipoxygenase products and in vitro chemotaxis assays as well as body plethysmographic measurements of lung mechanics, will also be important to the studies. Investigators in Medicine, Bioengineering, Pharmacology, Surgery and Pediatrics will participate in the program. The studies will help to define the pathogenesis of lung failure following vascular injury, enhance our understanding of physical factors affecting lung fluid following vascular injury, enhance our understanding of physical factors affecting lung fluid balance, provide a rational basis for designing therapies for patients with pulmonary edema (cardiogenic or ARDS) and critically evaluate the effects of methylprednisolone in humans with ARDS.
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