title: The role of proteases, endoplasmic reticulum stress and SERPINA1 heterozygosity in lung disease and α-1 anti-trypsin deficiency.
abstract: 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.
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland. cmgreene@rcsi.ie
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Greene
authors.forename: Tidi
authors.initials: T
authors.lastname: Hassan
authors.forename: Kevin
authors.initials: K
authors.lastname: Molloy
authors.forename: Noel G
authors.initials: NG
authors.lastname: McElvaney
mesh_terms: D000818:Animals; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008168:Lung / Q000201:enzymology* / Q000503:physiopathology; D008171:Lung Diseases / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D009154:Mutation; D010447:Peptide Hydrolases / Q000378:metabolism*; D010641:Phenotype; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology / Q000235:genetics; D018570:Risk Assessment; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D013312:Stress, Physiological; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism*; D019896:alpha 1-Antitrypsin Deficiency / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology
chemical_list: C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D010447:Peptide Hydrolases