Am. J. Respir. Cell Mol. Biol., Volume 18, Number 5, May, 1998 670-674

Lung Polymers in Z ₁-Antitrypsin Deficiency-related Emphysema

Peter R. Elliott, Diana Bilton, and David A. Lomas

Departments of Medicine and Haematology, University of Cambridge, and Chest Medical Unit, Papworth Hospital, Cambridge, United Kingdom

Patients with ₁-antitrypsin (₁-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 ₁-AT is most commonly due to the Z mutation (342Glu Lys), which results in a block in ₁-AT processing within the endoplasmic reticulum of hepatocytes. The retained ₁-AT forms inclusions, which are associated with neonatal hepatitis, juvenile cirrhosis, and hepatocellular carcinoma. Our recent studies have shown that the accumulation of ₁-AT is due to the Z mutation perturbing the structure of ₁-AT to allow polymer formation, with a unique linkage between the reactive center loop of one ₁-AT molecule and the A -pleated sheet of a second. The detection of loop-sheet polymers and other conformations of 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 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 ₁-AT-deficiency-related emphysema. Polymers were the predominant conformational form of 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 ₁-AT controls. Because 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 ₁-AT homozygote, and so exacerbate tissue damage.

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