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Mechanisms of emphysema in ₁-antitrypsin deficiency: molecular and cellular insights

¹ School of Crystallography, Institute of Structural Molecular Biology, Birkbeck College, University of London, London, and ² Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.

CORRESPONDENCE: B. Gooptu, School of Crystallography, Institute of Structural Molecular Biology, Birkbeck College, University of London, London, WC1E 7HX, UK. E-mail: bibek.gooptu{at}doctors.org.uk

Keywords: ₁-Antitrypsin deficiency, elastase, interstitial inflammation, lung, mechanism of emphysema, serpin polymer

Received: June 26, 2008
Accepted January 26, 2009

The severe, early onset emphysema that occurs in patients with circulating deficiency of ₁-antitrypsin (₁-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 ₁-AT to self-associate into polymer chains that accumulate intracellularly rather than proceeding along the secretory pathway. Polymerisation of ₁-AT abolishes antiprotease activity and confers toxic gain-of-function effects. Since ₁-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 ₁-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 ₁-AT deficiency.