The major aim of this proposal is to evaluate the changes which occur in lung endothelial and epithelial permeability and vascular resistances as related to capillary pressures, following neutrophil activation, complement activation (ZAP), and platelet activating factor and paraquat challenges via the circulation. Pulmonary edema can result because capillaries are abnormally leaky to plasma proteins and/or capillary pressure is elevated. We selected these challenges because they produce intense vasoconstriction,, with the exception of platelet activating factor which relaxes rat pulmonary circulation, pulmonary edema, and in some cases damaged endothelium. We will evaluate the effects of antioxidants (e.g., superoxide dismutase, catalase, promethazine, and DPPD), alpha and beta adrenergenic compounds (e.g., norepinephrine, isoproterenol), acetylcholine, arachidonic acid system (thromboxane synthetase inhibitor), histamine blockers (benadryl and cimetidine) in isolated rat, dog and guinea pig lungs subjected to these challenges. We will measure the large and small arterial and, venous resistances and compliances, along with capillary pressures in normal and damaged lungs to determine how the various components of the alpha, beta H1, H2, and AA systems alter resistances and compliances in each compartment. In addition, we will also evaluate an important permeability parameter, the permeability surface area product using prenodal lymph draining an open-chested dog preparation to determine this membrane-solute parameter for 6 endogenous plasma proteins. Also, we will measure unidirectional albumin fluxes across the endothelial barrier in isolated lungs to determine if the flux is the same in both directions, and whether or not these fluxes are altered in hypoxia and different forms lung damage. Finally, we will evaluate the permeability properties of the alveolar membrane in lungs challenged with PMA, ZAP, platelet activating factor or paraquat to determine the role this important membrane plays in the development of pulmonary edema.
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