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.