TY - JOUR
T1 - Mechanisms of emphysema in α1-antitrypsin deficiency
T2 - Molecular and cellular insights
AU - Gooptu, Bibekbrata
AU - Ekeowa, U.I.
AU - Lomas, D.A.
PY - 2008/8/1
Y1 - 2008/8/1
N2 - The severe, early onset emphysema that occurs in patients with circulating deficiency of α-antitrypsin (α-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 α-AT to self-associate into polymer chains that accumulate intracellularly rather than proceeding along the secretory pathway. Polymerisation of α-AT abolishes antiprotease activity and confers toxic gain-of-function effects. Since α-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 α-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 α-AT deficiency. Copyright
AB - The severe, early onset emphysema that occurs in patients with circulating deficiency of α-antitrypsin (α-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 α-AT to self-associate into polymer chains that accumulate intracellularly rather than proceeding along the secretory pathway. Polymerisation of α-AT abolishes antiprotease activity and confers toxic gain-of-function effects. Since α-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 α-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 α-AT deficiency. Copyright
UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-69249124617&md5=60a45ee250c95a4916675e384e56c702
U2 - 10.1183/09031936.00096508
DO - 10.1183/09031936.00096508
M3 - Article
AN - SCOPUS:69249124617
SN - 0903-1936
VL - 34
SP - 475
EP - 488
JO - European Respiratory Journal
JF - European Respiratory Journal
IS - 2
ER -