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Abstract
Alpha-1 antitrypsin deficiency (AATD) is a genetic condition characterised by low circulating levels of alpha-1 antitrypsin (AAT), a serine proteinase inhibitor. The most common deficiency variants are the S and Z mutations, which cause the accumulation of misfolded AAT in hepatocytes resulting in endoplasmic reticular stress and insufficient release of AAT into the circulation (<11μmol/L). This leads to liver disease, as well as an increased risk of emphysema due to unopposed proteolytic activity of neutrophil-derived serine proteinases in the lungs. AATD has been traditionally viewed as an inflammatory disorder caused directly by a proteinase-antiproteinase imbalance in the lung, but increasing evidence suggests that low AAT levels may affect other cellular functions. Recently, AAT polymers have been identified in both monocytes and macrophages from AATD patients and evidence is building that these cells may also play a role in the development of AATD lung disease. Alveolar macrophages are phagocytic cells that are important in the lung immune response but are also implicated in driving inflammation. This review explores the potential implications of monocyte and macrophage involvement in non-liver AAT synthesis and the pathophysiology of AATD lung disease.
Highlights
Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant genetic con dition that is characterised by low circulating levels of alpha-1 antitrypsin (AAT) protein, a serine proteinase inhibitor synthesised and secreted mainly by hepato cytes, and by immune and other cells.[1]
AAT circulates in the blood and enters tissues including the lungs by diffusion, where it binds and inhibits proteinases including neutrophil elastase (NE), cathepsin G and proteinase 3, as well as potentially exhibiting anti-inflammatory properties.[2]
AAT is released as a single polypeptide chain that binds neutrophil elastase via a methionine residue at position 358 on the reactive centre loop of the protein
Summary
Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant genetic con dition that is characterised by low circulating levels of alpha-1 antitrypsin (AAT) protein, a serine proteinase inhibitor synthesised and secreted mainly by hepato cytes, and by immune and other cells.[1]. In non-AATD COPD, macrophages are believed to be the key drivers of processes leading to disease initiation and progression.[52] COPD macrophages are predominantly pro-inflammatory, display dysfunctional phagocytosis[53,54,55] and efferocytosis,[56] and have altered mitochondrial function.[57] This likely contributes to the chronic colonisa tion of the respiratory tract, due to an inability to clear invading bacteria and apoptotic cells, despite the 20 fold increase in macrophage number within the lungs.[52] Targeting macrophage function in COPD is a potential treatment strategy being explored Whether this is of importance in AATD macrophages requires exploration. There is no published data on the effectiveness of these drugs in humans.[75]
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