The role of proteases, endoplasmic reticulum stress and SERPINA1 heterozygosity in lung disease and α-1 anti-trypsin deficiency.

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Expert review of respiratory medicine, ISSN: 1747-6356, Vol: 5, Issue: 3, Page: 395-411

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Greene, Catherine M; Hassan, Tidi; Molloy, Kevin; McElvaney, Noel G
Informa UK Limited; Taylor & Francis Group
Medicine; Animals; Endoplasmic Reticulum; Genetic Predisposition to Disease; Heterozygote; Humans; Lung; Lung Diseases; Mutation; Peptide Hydrolases; Phenotype; Pulmonary Disease; Chronic Obstructive; Risk Assessment; Risk Factors; Smoking; Stress; Physiological; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; Medicine and Health Sciences
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The serine proteinase inhibitor α-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.