LUNG POLYMERS IN Z-ALPHA(1)-ANTITRYPSIN DEFICIENCY-RELATED EMPHYSEMA

Patients with alpha(1)-antitrypsin (alpha(1)-AT) deficiency are at ris k of developing early-onset panlobular basal emphysema. which has been attributed to uncontrolled proteolytic activity within the lung. Seve n genetic deficiency of alpha(1)-AT is most commonly due to the Z muta tion (342Glu-->Lys), which results in a block in alpha(1)-AT processin g within the endoplasmic reticulum of hepatocytes. The retained alpha( 1)-AT forms inclusions, which are associated with neonatal hepatitis, juvenile cirrhosis, and hepatocellular carcinoma. Our recent studies h ave shown that the accumulation of alpha(1)-AT is due to the Z mutatio n perturbing the structure of alpha(1)-AT to allow polymer formation, with a unique linkage between the reactive center loop of one alpha(1) -AT molecule and the A beta-pleated sheet of a second. The detection o f loop-sheet polymers and other conformations of alpha(1)-AT in the lu ngs of patients with emphysema has been technically difficult. We show here that transverse urea-gradient-gel (TUG) electrophoresis and West ern blot analysis may be used to characterize conformations of alpha(1 )-AT in dilute samples of bronchoalveolar lavage fluid (BALF), This te chnique was used to demonstrate loop-sheet polymers in the lungs of pa tients with Z alpha(1)-AT-deficiency-related emphysema. Polymers were the predominant conformational form of alpha(1)-AT in BALF from the lu ngs of two of five Z homozygotes with emphysema, but were not detectab le in any of 13 MM, MS, or MZ alpha(1)-AT controls. Because alpha(1)-A T loop-sheet polymers are inactive as proteinase inhibitors, this nove l conformational transition will further reduce the levels of function al proteinase inhibitor in the lungs of the Z alpha(1)-AT homozygote, and so exacerbate tissue damage.