This grant 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 glactosamine, a general hepatic synthesis depressant, cycloheximide which depresses protein; colchicine which inhibits hepatic glycoprotein secretion and arabinofuranosyl-cytosine and puromycin, which inhibits 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 serine peptides, specific for elastase namely, acetylanyl-alanyl-prolyl-alanyl chloromethylketone comprise a new group of protease inhibitors. We will study the in vivo effects of AAPACMK on elastase induced emphysema and the effects of the pro-val (AAPVCK) form on leucocytic elastase induced emphysems. 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 role of PI in the genesis of experimental emphysema. In a like manner the effect of AAPACK on experimental emphysema will be studied.
| Bolmer, S D; Kleinerman, J (1987) Galactosamine-induced alpha 1-antitrypsin deficiency in rats. Alterations in plasma glycoproteins and alpha 1-antitrypsin carbohydrate composition. Am J Pathol 126:209-19 |
| Bolmer, S; Kleinerman, J (1986) Isolation and characterization of alpha 1-antitrypsin in PAS-positive hepatic granules from rats with experimental alpha 1-antitrypsin deficiency. Am J Pathol 123:377-89 |
| Bolmer, S D; Kleinerman, J (1985) Altered glycosidase activity in the liver of rats with galactosamine-induced alpha 1-antiprotease deficiency. Enzyme 34:144-51 |
