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

Respir Res. 2014 Sep 14;15(1):112. doi: 10.1186/s12931-014-0112-3.

Abstract

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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Bronchi / enzymology*
  • Bronchi / physiopathology
  • Cell Line
  • Epithelial Cells / enzymology*
  • Female
  • Homozygote
  • Humans
  • Male
  • Middle Aged
  • Protein Multimerization
  • Pulmonary Disease, Chronic Obstructive / enzymology*
  • Pulmonary Disease, Chronic Obstructive / genetics
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • Pulmonary Emphysema / enzymology*
  • Pulmonary Emphysema / genetics
  • Pulmonary Emphysema / physiopathology
  • Respiratory Mucosa / enzymology*
  • Respiratory Mucosa / physiopathology
  • Transfection
  • Up-Regulation
  • alpha 1-Antitrypsin / genetics
  • alpha 1-Antitrypsin / metabolism*
  • alpha 1-Antitrypsin Deficiency / complications
  • alpha 1-Antitrypsin Deficiency / enzymology*
  • alpha 1-Antitrypsin Deficiency / genetics
  • alpha 1-Antitrypsin Deficiency / physiopathology

Substances

  • SERPINA1 protein, human
  • alpha 1-Antitrypsin