Gooptu, Bibek and Ekeowa, U.I. and Lomas, D.A. (2009) Mechanisms of emphysema in 1-antitrypsin deficiency: molecular and cellular insights. European Respiratory Journal 34 (2), pp. 475-488. ISSN 0903-1936.
Abstract
The severe, early onset emphysema that occurs in patients with circulating deficiency of α1-antitrypsin (α1-AT) attests to the importance of this protease inhibitor in maintaining lung parenchymal integrity. It has led to the powerful concept of protease:antiprotease balance being crucial to alveolar homeostasis. Pathogenic mutations cause α1-AT to self-associate into polymer chains that accumulate intracellularly rather than proceeding along the secretory pathway. Polymerisation of α1-AT abolishes antiprotease activity and confers toxic gain-of-function effects. Since α1-AT is predominantly synthesised in the liver, where it does not play a major homeostatic role, the directly toxic effects of polymerisation are clearest here. However, data from molecular, cellular, animal and ex vivo studies indicate that intrapulmonary polymerisation of α1-AT and inflammatory positive feedback loops may augment the destructive effects of decreased antiprotease levels in the lung. This review integrates the findings from these different approaches and highlights how multiple pathways may converge to give the severe, panacinar emphysema phenotype seen in α1-AT deficiency.
Metadata
| Item Type: | Article |
|---|---|
| Keyword(s) / Subject(s): | α1-Antitrypsin, deficiency, elastase, interstitial, inflammation, lung, mechanism of emphysema, serpin, polymer |
| School: | Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences |
| Research Centres and Institutes: | Structural Molecular Biology, Institute of (ISMB) |
| Depositing User: | Administrator |
| Date Deposited: | 24 Jun 2015 14:56 |
| Last Modified: | 02 Aug 2023 17:17 |
| URI: | https://eprints.bbk.ac.uk/id/eprint/12434 |
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