title: The role of bronchial epithelial cells in the pathogenesis of COPD in Z-alpha-1 antitrypsin deficiency.
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.
authors.forename: Laura
authors.initials: L
authors.lastname: Pini
authors.forename: Laura
authors.initials: L
authors.lastname: Tiberio
authors.forename: Narayanan
authors.initials: N
authors.lastname: Venkatesan
authors.forename: Michela
authors.initials: M
authors.lastname: Bezzi
authors.forename: Luciano
authors.initials: L
authors.lastname: Corda
authors.forename: Maurizio
authors.initials: M
authors.lastname: Luisetti
authors.forename: Ilaria
authors.initials: I
authors.lastname: Ferrarotti
authors.forename: Mario
authors.initials: M
authors.lastname: Malerba
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Sabina
authors.initials: S
authors.lastname: Janciauskiene
authors.forename: Enrico
authors.initials: E
authors.lastname: Vizzardi
authors.forename: Denise
authors.initials: D
authors.lastname: Modina
authors.forename: Luisa
authors.initials: L
authors.lastname: Schiaffonati
authors.forename: Claudio
authors.initials: C
authors.lastname: Tantucci
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001980:Bronchi / Q000201:enzymology* / Q000503:physiopathology; D002460:Cell Line; D004847:Epithelial Cells / Q000201:enzymology*; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D055503:Protein Multimerization; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D011656:Pulmonary Emphysema / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D020545:Respiratory Mucosa / Q000201:enzymology* / Q000503:physiopathology; D014162:Transfection; D015854:Up-Regulation; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism*; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology
chemical_list: C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin