PREVENTION OF ELASTASE-INDUCED EXPERIMENTAL EMPHYSEMA BY ORAL-ADMINISTRATION OF A SYNTHETIC ELASTASE INHIBITOR

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Abstract
Whether oral administration of a synthetic elastase inhibitor would prevent or diminish the severity of emphysema induced by intrapulmonary instillation of elastase into mice was examined. Lightly anesthetized male Swiss-Webster mice were given a transoral dose of 6 units of porcine pancreatic elastase dissolved in 50 .mu.l of saline. These same animals also received 0.3 ml of water by stomach tube. Four weeks later, the average mean linear intercept in the lungs of these mice (94 .+-. 23 .mu.m) was more than twice the normal value (43 .+-. 1 .mu.m in untreated mice and 44 .+-. 5 .mu.m in mice given 50 .mu.l of saline transorally). Other mice simultaneously treated with porcine pancreatic elastase also received a single dose of 300-400 .mu.g of methoxysuccinyl-alanyl-alanyl-prolyl-valine-chlormethyl ketone (dissolved in 0.3 ml of water) by stomach tube, at times ranging from 2 h before instillation of the enzyme to 48 h after the enzyme. Mice that received chloromethyl ketone within 15 min before instillation of elastase were protected from development of emphysema, and their lungs were completely free of alveolar deformation. No significant protection was afforded by treatment chloromethyl ketone 1 h or more before challenge with the enzyme or at any time after challenge. Chloromethyl ketone alone did not affect the mean linear intercept. Although many questions remain concerning toxicity, immunogeneicity and carcinogenicity of chloromethyl ketones, oral treatment with these agents might prove useful in preventing emphysema in persons with .alpha.1-antitrypsin deficiency.

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