DESCRIPTION: (Adapted from the applicant's abstract and Specific Aims.) Acute lung injury accounts for a significant percentage of patient mortality. The hypothesis is that damage to the airway triggers a neuroinflammatory response which induces pulmonary parenchymal injury and multiple organ failure. Specific Aim 1 is to demonstrate that damage to the airway by compounds in smoke results in the release of mediators into the bronchial venous drainage that directly (proteases, O2 free radicals, peptidoleukotrienes, thromboxane, substance P and calcitonin gene related peptide) or indirectly (tumor necrosis factor or leukotriene B4) damage lung parenchyma, resulting in an increase in transvascular fluid flux. This will be tested in a sheep chronically prepared for study in the unanesthetized state. They will have a lymph fistula involving the left lung only, pneumatic occluders on the left pulmonary artery and veins which, when occluded isolates the venous drainage from the airway (broncho-pulmonary portal system), occluders on the right pulmonary veins to raise pulmonary artery pressure for determination of reflection coefficient, thermal dilution catheters for cardiac output determination, left atrial and aortic catheters, and a flow probe on the bronchial artery. The parameters of the Starling- Landis equation which defines transvascular fluid flux will be determined. Changes in bronchial blood flow, pulmonary transvascular fluid flux, and its determinants and lung lymph and bronchial venous concentration of the above mediators will be measured after smoke inhalation.In one group animals handled in the same fashion the bronchial artery will be occluded by injection of ethanol and make the same determination. The source of the mediators will be determined from their temporal appearance and disappearance with bronchial artery occlusion. The changes in mediation will be correlated with observed pathophysiology. Experiments to validate the bronchial occlusion, its duration, and how it is affected by inhalation injury will be determined. The extent of hematogenous and chylogenous contribution to the injury will be determined by producing inhalation injury to the right lung and determining how this affects left lung physiology. Specific Aim 2 is to determine if neuropeptides, especially Substance P and calcitonin gene-related peptide, play a major role in the increases in airway blood flow, edema formation, and release of other mediators into the bronchial venous drainage and lymph which occurs with smoke inhalation. The above ovine model of acute lung injury will be used. Neuropeptide agonist and antagonist will be examined in the presence and absence of inhalation injury. Specific Aim 3 is to determine the role of airway injury in the changes in systemic vascular resistance and microvascular permeability and myocardial contractility noted with inhalation injury. Sheep will be instrumented as above and additionally with transducers on the heart for measurement of cardiac function. A systemic lymph fistula will be established. Organ blood flow will be determined with the microsphere technique. These will be evaluated in animals after inhalation injury and in animals with inhalation injury and bronchial artery occlusion.