The role of bronchial epithelial cells in the pathogenesis of COPD in Z-alpha-1 antitrypsin deficiency

Abstract

BackgroundAlpha-1 antitrypsin is the main inhibitor of neutrophil elastase in the lung. Although it is principally synthesized by hepatocytes, alpha-1 antitrypsin is also secreted by bronchial epithelial cells. Gene mutations can lead to alpha-1 antitrypsin deficiency, with the Z variant being the most clinically relevant due to its propensity to polymerize. The ability of bronchial epithelial cells to produce Z-variant protein and its polymers is unknown.We investigated the expression, accumulation, and secretion of Z-alpha-1 antitrypsin and its polymers in cultures of transfected cells and in cells originating from alpha-1 antitrypsin-deficient patients.MethodsExperiments using a conformation-specific antibody were carried out on M- and Z-variant–transfected 16HBE cells and on bronchial biopsies and ex vivo bronchial epithelial cells from Z and M homozygous patients. In addition, the effect of an inflammatory stimulus on Z-variant polymer formation, elicited by Oncostatin M, was investigated. Comparisons of groups were performed using t-test or ANOVA. Non-normally distributed data were assessed by Mann–Whitney U test or the Kruskal-Wallis test, where appropriate. A P value of < 0.05 was considered to be significant.ResultsAlpha-1 antitrypsin polymers were found at a higher concentration in the culture medium of ex vivo bronchial epithelial cells from Z-variant homozygotes, compared with M-variant homozygotes (P < 0.01), and detected in the bronchial epithelial cells and submucosa of patient biopsies. Oncostatin M significantly increased the expression of alpha-1 antitrypsin mRNA and protein (P < 0.05), and the presence of Z-variant polymers in ex vivo cells (P < 0.01).ConclusionsPolymers of Z-alpha-1 antitrypsin form in bronchial epithelial cells, suggesting that these cells may be involved in the pathogenesis of lung emphysema and in bronchial epithelial cell dysfunction.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-014-0112-3) contains supplementary material, which is available to authorized users.

The pathological Trento variant of alpha‐1‐antitrypsin (E75V) shows nonclassical behaviour during polymerization

“…The consequent low‐circulating levels of AAT result in damage to lung parenchyma and early‐onset emphysema due to uncontrolled activity of neutrophil elastase ( and reviewed in ). In addition to liver tissue, polymers are found in the circulation and in lung bronchoalveolar lavage fluid , where they are thought to exert proinflammatory effects and thereby worsen pulmonary damage in AATD .…”

α1-Antitrypsin Polymerizes in Alveolar Macrophages of Smokers With and Without α1-Antitrypsin Deficiency

“…[12][13][14] To a minor extent other cells in the lung including lung epithelial cells, bronchial epithelial cells, endothelial cells, and the human A549 cell line of alveolar epithelial cells, as well as polymorphonuclear leukocytes and neutrophils, have also been found to produce AAT. [15][16][17][18][19] Alveolar macrophages develop from fetal liver under the control of granulocyte-macrophage colony-stimulating factor in the first days of life, paralleling the development of the alveoli, and then maintain themselves by in situ self-renewal. [20][21][22] Perhaps, because of their different origin, there is an important difference in production of AAT between blood monocytes (which produce threefold less AAT) and alveolar macrophages, 14 suggesting that alveolar macrophages are preprogramed by their liver origin or that, once in the lung milieu, they up-regulate AAT gene expression.…”

The important role of primary care providers in the detection of alpha-1 antitrypsin deficiency

“…Liver damage is probably accelerated in the presence of other hepatotoxic stimuli [38]. In addition to the liver, Z-AAT polymers can be found in the circulation and in some tissues [39]. These polymers are proinflammatory and likely reasons for other rarer AATD- • Recurring upper respiratory tract infections…”