Lung polymers in Z α1-antitrypsin deficiency-related emphysema

Patients with alpha(1)-antitrypsin (alpha(1)-AT) deficiency are at risk of developing early-onset panlobular basal emphysema. which has been attributed to uncontrolled proteolytic activity within the lung. Seven genetic deficiency of alpha(1)-AT is most commonly due to the Z mutation (342Glu-->Lys), which results in a block in alpha(1)-AT processing 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 have shown that the accumulation of alpha(1)-AT is due to the Z mutation 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 of loop-sheet polymers and other conformations of alpha(1)-AT in the lungs of patients with emphysema has been technically difficult. We show here that transverse urea-gradient-gel (TUG) electrophoresis and Western blot analysis may be used to characterize conformations of alpha(1)-AT in dilute samples of bronchoalveolar lavage fluid (BALF), This technique was used to demonstrate loop-sheet polymers in the lungs of patients with Z alpha(1)-AT-deficiency-related emphysema. Polymers were the predominant conformational form of alpha(1)-AT in BALF from the lungs of two of five Z homozygotes with emphysema, but were not detectable in any of 13 MM, MS, or MZ alpha(1)-AT controls. Because alpha(1)-AT loop-sheet polymers are inactive as proteinase inhibitors, this novel conformational transition will further reduce the levels of functional proteinase inhibitor in the lungs of the Z alpha(1)-AT homozygote, and so exacerbate tissue damage.