The role of proteases, endoplasmic reticulum stress and SERPINA1 heterozygosity in lung disease and αα-1 anti-trypsin deficiency. (June 2011)

• Record Type: Journal Article
• Authors: Greene, Catherine M; Hassan, Tidi; Molloy, Kevin; McElvaney, Noel G
• Is Part Of: Expert review of respiratory medicine. Volume 5:Number 3(2010)
• Page Start: 395
• Page End: 411
• Publication Date: 2011-06
• Subjects: αα-1 anti-trypsin deficiency -- augmentation therapy -- endoplasmic reticulum stress -- serine antiprotease -- serine proteases -- SERPINA1 heterozygosity; Respiratory organs -- Diseases -- Periodicals; Respiratory organs -- Diseases -- Treatment -- Periodicals; 616.2005
• DOI: 10.1586/ers.11.20
• Languages: English
• ISSNs: 1747-6348

Abstract

The serine proteinase inhibitor αα-1 anti-trypsin (AAT) provides an antiprotease protective screen throughout the body. Mutations in the AAT gene ( SERPINA1 ) that lead to deficiency in AAT are associated with chronic obstructive pulmonary diseases. The Z mutation encodes a misfolded variant of AAT that is not secreted effectively and accumulates intracellularly in the endoplasmic reticulum of hepatocytes and other AAT-producing cells. Until recently, it was thought that loss of antiprotease function was the major cause of ZAAT-related lung disease. However, the contribution of gain-of-function effects is now being recognized. Here we describe how both loss- and gain-of-function effects can contribute to ZAAT-related lung disease. In addition, we explore how SERPINA1 heterozygosity could contribute to smoking-induced chronic obstructive pulmonary diseases and consider the consequences.