Lung polymers in Z alpha1-antitrypsin deficiency-related emphysema.

Patients with α1-antitrypsin (α1-AT) deficiency are at risk of developing early-onset panlobular basal emphysema, which has been attributed to uncontrolled proteolytic activity within the lung. Severe genetic deficiency of α1-AT is most commonly due to the Z mutation (342Glu→ Lys), which results in a block in α1-AT processing within the endoplasmic reticulum of hepatocytes. The retained α1-AT forms inclusions, which are associated with neonatal hepatitis, juvenile cirrhosis, and hepatocellular carcinoma. Our recent studies have shown that the accumulation of α1-AT is due to the Z mutation perturbing the structure of α1-AT to allow polymer formation, with a unique linkage between the reactive center loop of one α1-AT molecule and the A β-pleated sheet of a second. The detection of loop-sheet polymers and other conformations of α1-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 us...