A family suffering a hereditary form of severe emphysema, with some family members also showing hepatic disease. Liver biopsy in one of the family members demonstrates increased reactivity with antibodies directed against a-1-antitrypsin. Serum levels of the enzyme are low, leading to increased activity of a number of serine proteases. Increased activity of which of the following serine proteases has been most closely tied to the emphysema that develops in these patients?
The autosomal recessive disease is a-1-antitrypsin deficiency, in which an abnormal form of a-1-antitrypsin can be produced by, but not released from, liver cells. This enzyme was named when it was found in vivo to function as a good inhibitor of the pancreatic protease trypsin. However, it actually inactivates a wide variety of enzymes with protease activity that have an essential serine residue in the catalytic centers. Examples of these serine proteases include all of the question choices, and additionally, cathepsin G and plasminogen. Surprisingly, a-1-antitrypsin disease specifically targets only the liver and the lungs. The liver disease, which can be mild to life-threatening (either due to cirrhosis or, rarely, massive acute hepatic failure), is related to retained a-1-antitrypsin with residual enzymatic activity. The lung disease seems to be the specific result of an inability to turn off elastase produced by neutrophils during lung infections. Neutrophil elastase is one of the few enzymes that can successfully destroy the heavily cross-linked, insoluble, elastin that is presented in the lung interstitium and contributes to its elasticity. With destruction of this lattice-like elastic tissue suppo structure, emphysema can develop in the lungs. Chymotrypsin is a pancreatic enzyme formed in the intestinal lumen that cleaves aromatic aminoacyl bonds. Plasmin is an enzyme in the blood-clotting cascade. Thrombin is an enzyme in the blood-clotting cascade.
Chymotrypsin
Elastase
Plasmin
Thrombin