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

Laura Pini, Laura Tiberio, Narayanan Venkatesan, Michela Bezzi, Luciano Corda, Maurizio Luisetti, Ilaria Ferrarotti, Mario Malerba, David A. Lomas, Sabina Janciauskiene, Enrico Vizzardi, Denise Modina, Luisa Schiaffonati, Claudio Tantucci

Research output: Contribution to journalArticlepeer-review


Background: Alpha-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.Methods: Experiments 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.Results: Alpha-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).Conclusions: Polymers 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.

Original languageEnglish
Article number112
Pages (from-to)1-10
Number of pages10
JournalRespiratory Research
Issue number1
Publication statusPublished - Sep 14 2014


  • Bronchial epithelial cell dysfunction
  • Bronchial epithelial cells
  • Pathogenesis of COPD
  • Z-AAT polymers

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine


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