Lung Polymers in Z α1-Antitrypsin Deficiency-related Emphysema
| ISSN: | 1535-4989 1044-1549 |
|---|---|
| Přístupová URL adresa: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e275f75c3c0c36d9cd5aa638578809fb https://doi.org/10.1165/ajrcmb.18.5.3065 |
| Přírůstkové číslo: | edsair.doi.dedup.....e275f75c3c0c36d9cd5aa638578809fb |
| Autor: | David A. Lomas, Diana Bilton, Peter R. Elliott |
| Rok vydání: | 1998 |
| Předmět: |
Electrophoresis
Pulmonary and Respiratory Medicine Pathology medicine.medical_specialty Cirrhosis Polymers Protein Conformation Clinical Biochemistry Biology Protein Structure Secondary Western blot alpha 1-Antitrypsin Deficiency medicine Humans Respiratory system Molecular Biology Reactive center Emphysema Lung Alpha 1-antitrypsin deficiency medicine.diagnostic_test Cell Biology respiratory system medicine.disease respiratory tract diseases Bronchoalveolar lavage medicine.anatomical_structure alpha 1-Antitrypsin Hepatocellular carcinoma Bronchoalveolar Lavage Fluid |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 18:670-674 |
| ISSN: | 1535-4989 1044-1549 |
| Popis: | Patients with alpha1-antitrypsin (alpha1-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 alpha1-AT is most commonly due to the Z mutation (342Glu--> Lys), which results in a block in alpha1-AT processing within the endoplasmic reticulum of hepatocytes. The retained alpha1-AT forms inclusions, which are associated with neonatal hepatitis, juvenile cirrhosis, and hepatocellular carcinoma. Our recent studies have shown that the accumulation of alpha1-AT is due to the Z mutation perturbing the structure of alpha1-AT to allow polymer formation, with a unique linkage between the reactive center loop of one alpha1-AT molecule and the A beta-pleated sheet of a second. The detection of loop-sheet polymers and other conformations of alpha1-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 alpha1-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 alpha1-AT-deficiency-related emphysema. Polymers were the predominant conformational form of alpha1-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 alpha1-AT controls. Because alpha1-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 alpha1-AT homozygote, and so exacerbate tissue damage. |
| Databáze: | OpenAIRE |
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