This proposal is a continuation of investigations concerning an experimental model of protease inhibitor (PI) deficiency. In man the importance of heterozygous (intermediate) levels of PI deficiency in the pathogenesis of emphysema is uncertain. Our studies will utilize specific metabolic inhibitors which perturb hepatic glycoprotein synthesis and secretion to alter plasma PI. These drugs will include galactosamine, a general hepatic synthesis depressant, cycloheximide which depresses protein; colchicine which inhibits hepatic glycoprotein secretion and arabinofuranosyl-cytosine and puromycin, which inhibit glycosylation of the newly synthesized potential glycoproteins. These agents will be analyzed in vitro in a liver perfusion system and after chronic in vivo administration. The effects of these agents on hepatic glycoprotein synthesis on hepatic and circulating protease inhibitors, and/or selected hepatic enzymes will be evaluated and correlated with light and transmission electron microscopy of the hepatic parenchymal cells. Low molecular weight peptide-chloramethyl ketones comprise a new group of synthetic elastase inhibitors. We will study the in vivo effects of ac -ala-ala-pro-ala chloromethyl ketone (AAPACK) or ac-ala-ala-pro-val (AAPVCK) to evaluate tissue distribution ability to penetrate leucocytes and effects on leucocyte and macrophage elastases. The effect of depression of the native hepatically generated PI on the course of a standardized lung injury induced by elastase will be evaluated to determine the rate of PI in the genesis of experimental emphysema. In a like manner, the effect of AAPACK on experimental emphysema will be studied. These studies of the effects of native and synthetic Pi on the course and extent of experimental emphysema will contribute to the understanding of the role of these substances in the pathogenesis of human emphysema.