α₁-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies

TY - JOUR

T1 - α1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies

AU - Ekeowa, U.I.

AU - Gooptu, Bibek

AU - Belorgey, D.

AU - Hägglöf, P.

AU - Karlsson-Li, S.

AU - Miranda, E.

AU - Pérez, J.

AU - MacLeod, I.

AU - Kroger, H.

AU - Marciniak, S.J.

AU - Crowther, D.C.

AU - Lomas, D.A.

PY - 2009/6/1

Y1 - 2009/6/1

N2 - α-Antitrypsin is the prototypical member of the serine proteinase inhibitor or serpin superfamily of proteins. The family includes α-antichymotrypsin, C1 inhibitor, antithrombin and neuroserpin, which are all linked by a common molecular structure and the same suicidal mechanism for inhibiting their target enzymes. Point mutations result in an aberrant conformational transition and the formation of polymers that are retained within the cell of synthesis. The intracellular accumulation of polymers of mutant α-antitrypsin and neuroserpin results in a toxic gain-of-function phenotype associated with cirrhosis and dementia respectively. The lack of important inhibitors results in overactivity of proteolytic cascades and diseases such as COPD (chronic obstructive pulmonary disease) (α-antitrypsin and α- antichymotrypsin), thrombosis (antithrombin) and angio-oedema (C1 inhibitor). We have grouped these conditions that share the same underlying disease mechanism together as the serpinopathies. In the present review, the molecular and pathophysiological basis of α-antitrypsin deficiency and other serpinopathies are considered, and we show how understanding this unusual mechanism of disease has resulted in the development of novel therapeutic strategies.

AB - α-Antitrypsin is the prototypical member of the serine proteinase inhibitor or serpin superfamily of proteins. The family includes α-antichymotrypsin, C1 inhibitor, antithrombin and neuroserpin, which are all linked by a common molecular structure and the same suicidal mechanism for inhibiting their target enzymes. Point mutations result in an aberrant conformational transition and the formation of polymers that are retained within the cell of synthesis. The intracellular accumulation of polymers of mutant α-antitrypsin and neuroserpin results in a toxic gain-of-function phenotype associated with cirrhosis and dementia respectively. The lack of important inhibitors results in overactivity of proteolytic cascades and diseases such as COPD (chronic obstructive pulmonary disease) (α-antitrypsin and α- antichymotrypsin), thrombosis (antithrombin) and angio-oedema (C1 inhibitor). We have grouped these conditions that share the same underlying disease mechanism together as the serpinopathies. In the present review, the molecular and pathophysiological basis of α-antitrypsin deficiency and other serpinopathies are considered, and we show how understanding this unusual mechanism of disease has resulted in the development of novel therapeutic strategies.

UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-67649246879&md5=d5d3c59cf5c29c9fa3d4d0569b65b943

U2 - 10.1042/CS20080484

DO - 10.1042/CS20080484

M3 - Article

AN - SCOPUS:67649246879

SN - 0143-5221

VL - 116

SP - 837

EP - 850

JO - Clinical Science

JF - Clinical Science

IS - 12

ER -