Structural Studies of Elastase-Inhibitor Complexes with ß-Lactams

Abstract

Emphysema is a chronic disease of the lower respiratory tract, characterized by the destruction of the alveolar walls of the lung (Robbins, et. al., 1984). It is a progressively degenerative disease for which there is no effective therapy at present. Human neutrophil elastase (HNE) is a serine protease which is stored in the azurophilic granules of neutrophils, and which has broad specificity for small aliphatic groups at the P1 position of substrates (Powers et. al., 1986). HNE digestion of elastin, the principal structural protein in the alveoli, is believed to be the molecular event that underlies the clinical manifestation of emphysema (Janoff, 1985). HNE is a single chain glycoprotein of 27,000 daltons molecular weight (Sinha et. al., 1987) which is synthesized during the development of the mature neutrophil (Clark et. al., 1984). Normally, proteolytic activity is released intracellularly within the neutrophil after the azurophilic granules entraining the enzyme are discharged into phagosomes containing engulfed debris (Parmley et. al., 1986). Tissue damage results when enzyme inevitably leaks out of the neutrophil (and into the extracellular space) by regurgitation during phagocytosis or by cell death, for example. To counter this dangerous condition, proteinaceous inhibitors have evolved that can rapidly inactivate HNE and arrest the process of tissue destruction. Some idea of the importance of these inhibitors is given by their concentration in serum, which is normally around 1.3 grams per liter for the alphas proteinase inhibitor (Carrell et. al.,1982). Health problems are noted when these concentrations drop below about 35% of normal (Carrell, 1986). Because alphal proteinase inhibitor is sensitive to oxidation, it has been suggested that the correlation between smoking and emphysema might be the result of an imbalance between free HNE and its inhibitors in the lung (Carp et. al., 1982).