The hypothesis to be investigated is that low levels of A-1-AT render mice more susceptible to elastase induced emphysema. The hypothesis will be tested by instilling elastase induced emphysema. The hypothesis will be tested by instilling elastase intratracheally into mice with different A- 1-AT serum concentrations. Different serum concentrations of A-1-AT and a sexual dimorphism have been established in several strains of mice. We will use C57 BL/6J and RP1 (own laboratory strain) females (low levels of A-1-AT) and ICR and CBA 2/J males (high A-1-AT). The following sequences of experiments will be performed: 1. The maximal quantity of elastase will be established that produces no or minimal emphysema in animals with high A-1-AT concentrations. The same amount of elastase will be instilled into animals with low A-1-AT levels. Preliminary experiments indicate that a substantial proportion of animals in this group develops emphysema. 2. The A-1-AT level of males with high concentrations will be lowered by castration and the susceptibility to elastase induced emphysema will be tested. 3. Human A-1-AT will be supplemented to achieve a concentration of 1-2 mg/ml in plasma of low A-1-AT mice. The human A-1-AT will be prepared in our laboratory but A-1-AT from commercial and non-commercial sources, including preparations made by recombinant DNA technology will be tested. The protective effect against elastase-induced emphysema will be tested. These experiments are designed to: 1. Establish different strains of mice as models for elastase-induced emphysema. 2. Demonstrate the importance of low A-1-AT levels as predisposing factors to emphysema. 3. Demonstrate the therapeutic efficacy of human A-1-AT. If these experiments support our hypothesis, other elastase and protease inhibitors, some existing now, and others to be developed, may be tested in our mouse system.
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