title: Mechanisms of emphysema in alpha1-antitrypsin deficiency: molecular and cellular insights.
abstract: The severe, early onset emphysema that occurs in patients with circulating deficiency of alpha(1)-antitrypsin (alpha(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 alpha(1)-AT to self-associate into polymer chains that accumulate intracellularly rather than proceeding along the secretory pathway. Polymerisation of alpha(1)-AT abolishes antiprotease activity and confers toxic gain-of-function effects. Since alpha(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 alpha(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 alpha(1)-AT deficiency.
authors: School of Crystallography, Institute of Structural Molecular Biology, Birkbeck College, University of London, London, UK. bibek.gooptu@doctors.org.uk
authors: B
authors: B
authors: Gooptu
authors: U I
authors: UI
authors: Ekeowa
authors: D A
authors: DA
authors: Lomas
mesh_terms: D000818:Animals; D004646:Emphysema / Q000150:complications* / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007249:Inflammation; D008168:Lung / Q000473:pathology; D008954:Models, Biological; D010196:Pancreatic Elastase / Q000096:biosynthesis; D011108:Polymers / Q000737:chemistry; D015843:Serpins / Q000737:chemistry; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications* / Q000235:genetics*
chemical_list: D011108:Polymers; D015843:Serpins; D000515:alpha 1-Antitrypsin; D010196:Pancreatic Elastase