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Lung Polymers in Z α1-Antitrypsin Deficiency-related Emphysema
- Source :
- American Journal of Respiratory Cell and Molecular Biology. 18:670-674
- Publication Year :
- 1998
- Publisher :
- American Thoracic Society, 1998.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 15354989 and 10441549
- Volume :
- 18
- Database :
- OpenAIRE
- Journal :
- American Journal of Respiratory Cell and Molecular Biology
- Accession number :
- edsair.doi.dedup.....e275f75c3c0c36d9cd5aa638578809fb