Studies will test a controversial hypothesis linking pulmonary edema (PE) to hypertensive PA wall damage, leakage and mural thromboembolism in PE at altitude, in heroin overdose, brain traumatic asphyxia, and perhaps shock lung, pulmonary embolism and neonatal RDS. Using our rat model of hypoxic pulmonary edema (HPE), we will test the time course and relationship to arterial diameter of the developing peri-arterial interstitial cuffs to learn which size artery is most susceptible. Arterial walls will be examined by scanning EM for holes, microaneurysms and platelet accumulation. Possible heparin therapy will be first evaluated in several species and then in patients. Experiments to directly test arterial wall permeability after HPE in rats and autopsy lungs are proposed. In high and low altitude dogs, and in pigs, asymmetric PA flow will be induced by asymmetric hypoxia and by oil emboli to separate arterial from capillary sites of edema formation, test the role of vasoreactivity and of hyperventilation, determine whether high flow or high arterial pressure underlies the pathogenesis of HPE. Two non-invasive methods of measuring lung water, developed and modified by us to overcome problems of sensitivity and accuracy, will be further modified and used in both animals and patients to explore the hypotheses, test therapeutic implications, determine clinical and pathological limitations of the methods, assess their value in optimizing therapy, and to compare with clinical, radiologic and pathologic evidence of PE. These methods are 1) a focused electrical lung impedance bridge, and 2) a single breath test of soluble gas uptake using a computerized mass spectrometer. Studies will assess the effect on lung water of a) renal dialysis, b) post-cardiac surgery manipulation of left atrial pressure, c) ventilatory pressure variations in acute respiratory failure, d) pulmonary vasodilator therapy and PEEP and CPAP in neonatal respiratory distress syndrome, and e) acute ascent to high altitude in association with tests of Diamox plus slat and water prophylaxis of mountain sickness.
