Sepsis-induced respiratory failure remains a serious clinical problem with a mortality rate of 40-90% and a poorly understood etiology. The ovine lung lymph preparation given endotoxin is used as an animal model. This model allows assessment of the pulmonary microcirculation with measurement of pulmonary lymph flow and protein. It also enables measurements of hemodynamic variables in the awake state in an animal species that has cardiopulmonary anatomy and physiology that are similar to the human species. Preliminary data in this model given Ps. aeruginosa by central infusion, indicates that the sheep lung removes 65-95% of the bacteria from the blood which passes through it. High rates of pulmonary intravascular clearance of bacteria are found in other species that develop sepsis-induced respiratory failure. A study comparing two doses of bacteria will determine if this clearance is protective at lower doses by decreasing the number of bacteria exposed to the systemic circulation, and whether higher doses lead to a pulmonary permeability injury. In a porcine model give Ps. aeruginosa, electron microscopy showed that both polymorphonuclear and mononuclear cells phagocytized the bacteria. Preliminary studies show these cells are also present in sheep. Morphometric analysis will be used to study sequential changes in these cells and if they are phagocytizing bacteria. The role of the mononuclear cell in pulmonary intravascular clearance of bacteria and in the production of lung injury will be studied in sheep depleted of their neutrophils. Oxygen free radicals have chemotactic properties, may induce permeability changes, and are released during phagocytosis, so an oxygen free radical scavenger will be studied to see if it has protective properties. The complement system, which also stimulates release of oxygen free radicals, will be studied to see if decreased chemotactic stimuli and phagocytosis result in less pulmonary injury. It will be determined if the fat emulsions used for nutritional support decrease pulmonary intravascular clearance of bacteria resulting in more severe septicemia. These studies will examine the lung's function as a reticulo-endothelial organ and define the pulmonary mononuclear phagocyte. It is believed that the phagocytic stimulation presented to this cell by bacteria may result in different responses to treatments or manipulations of potential mediators than if endotoxin is used.
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