In vivo isolated lung perfusion is a method for targeting chemotherapy, serotherapy, and other therapeutic modalities to the lungs. Hemibody irradiation is also a method of targeting the lungs. The synergistic effects of combining modalities can also be exploited using these targeting approaches. With systemic toxicity removed as the factor limiting the severity of the cytotoxic conditions which are of practical therapeutic value, toxicity to normal lung tissue becomes the limiting factor. The contribution of this laboratory program to this project will be to evaluate the injury to the normal (nontumorous) lung caused by exposing the lungs to the combinations of potentially therapeutic procedures to be used and/or developed in laboratory programs 1, 2 and 4. Lung injury will be evaluated by following pulmonary hemodynamics, mechanics, and gas exchange functions, but particular attention will be given to the metabolic and barrier functions of the pulmonary endothelium. These endothelial functions will be studied using indicator dilution methods in the intact perfused lung. The metabolic functions to be studied include endothelial serotonin uptake and endothelial angiotensin converting enzyme activity. Barrier functions include extravascular lung water and urea permeability surface area product. Studies will be carried out on ex vivo isolated perfused dogs lungs to determine the acute effects of perfusate composition, hyperthermia, chemotherapeutic drugs, etc. on the normal lung tissue within the intact perfused lung. Once conditions (perfusate composition, temperature, etc.) are established which can be tolerated during the two hour perfusion period in acute studies the long term effects of using these conditions during in vivo perfusion will be determined in normal dogs and in dogs with lung tumors. In addition, the long term effects of hemibody irradiation with and without hyperthermia will be evaluated in a similar manner.
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