The proposed research is designed to address five specific problems: (1) to characterize the relationship in the lung between the capillary filtration coefficient and the osmotic reflection coefficient, which describe the capillary permeability to fluid and proteins respectively, over a wide range of pulmonary microvascular permeabilities, to correlate these changes with the accumulation of alveolar fluid and protein and to assess the role of endothelial surface charge, the glycoprotein orosomucoid (a modulator of neutrophil radical production), and interstitial hydration in altering permeability, as all are potentially a result of lung trauma; (2) to determine the effect of high intravascular pressures on the reflection coefficient - the threshold for and reversibility of pressure-induced injury will be assessed, as well as the dependence of the injury on the duration of the pressure stress; (3) to determine whether prior injury to the lung induced by fatty acids or complement fragments predisposes the pulmonary microvasculature to pressure-induced permeability changes; (4) to determine whether pressure-induced injury is associated with redistribution of blood flow in the lung; and (5) to evaluate the gross anatomic sites of pressure-induced versus chemically-induced ling injury -are there gross leaks or tears in the alveolo-capillary barrier? Pulmonary microvascular permeability will be assessed by measuring the capillary filtration coefficient and the osmotic reflection coefficient, the latter using osmotic transients, protein vs. hematocrit fluid filtration volumes and lymphatic flux analysis. The ability of both the pulmonary capillary barrier and the combined alveolar epithelial- capillary endothelial barrier to sieve proteins will be determined. These parameters will be assessed in dog and sheep lungs, and in intact dog lungs (lymphatic flux analysis only). The effects of high intravascular pressures will be tested in normal lung lobes and in those with modest lung injury induced by oleic acid (canine lungs) or complement fragments (ovine lungs), also, the role of blood cells in complement injury will be evaluated in this isolated ovine lung model. Regional distributions of pulmonary blood flow before and after injury will be determined by the distributions of pulmonary blood flow before and after injury will be determined by the distribution of radiolabelled microspheres. Finally, acrylic corrosion casts will be made of the pulmonary vasculature to evaluate the gross anatomic locus of pressure- and permeability- induced injuries.
