title: Z α1-antitrypsin confers a proinflammatory phenotype that contributes to chronic obstructive pulmonary disease.
abstract: BACKGROUND
  Severe α1-antitrypsin deficiency caused by the Z variant (Glu342Lys; ZZ-AT) is a well-known genetic cause for emphysema. Although severe lack of antiproteinase protection is the critical etiologic factor for ZZ-AT-associated chronic obstructive pulmonary disease (COPD), some reports have suggested enhanced lung inflammation as a factor in ZZ-AT homozygotes.
  
  
  OBJECTIVE
  To provide molecular characterization of inflammation in ZZ-AT.
  
  
  METHODS
  Inflammatory cell and cytokine profile (nuclear factor-κB, IL-6, tumor necrosis factor-α), intracellular polymerization of Z-AT, and endoplasmic reticulum (ER) stress markers (protein kinase RNA-like ER kinase, activator transcription factor 4) were assessed in transgenic mice and transfected cells in response to cigarette smoke, and in explanted lungs from ZZ and MM individuals with severe COPD.
  
  
  RESULTS
  Compared with M-AT, transgenic Z-AT mice lungs exposed to cigarette smoke had higher levels of pulmonary cytokines, neutrophils, and macrophages and an exaggerated ER stress. Similarly, the ER overload response was greater in lungs from ZZ-AT homozygotes with COPD, and was particularly found in pulmonary epithelial cells. Cigarette smoke increased intracellular Z-AT polymers, ER overload response, and proinflammatory cytokine release in Z-AT-expressing pulmonary epithelial cells, which could be prevented with an inhibitor of polymerization, an antioxidant, and an inhibitor of protein kinase RNA-like ER kinase.
  
  
  CONCLUSIONS
  We show here that aggregation of intracellular mutant Z-AT invokes a specific deleterious cellular inflammatory phenotype in COPD. Oxidant-induced intracellular polymerization of Z-AT in epithelial cells causes ER stress, and promotes excess cytokine and cellular inflammation. This pathway is likely to contribute to the development of COPD in ZZ-AT homozygotes, and therefore merits further investigation.
authors.affiliation: 1 Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Samuel
authors.initials: S
authors.lastname: Alam
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Li
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.forename: Danny
authors.initials: D
authors.lastname: Jonigk
authors.forename: Sabina
authors.initials: S
authors.lastname: Janciauskiene
authors.forename: Ravi
authors.initials: R
authors.lastname: Mahadeva
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D018698:Glutamic Acid; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D008239:Lysine; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010641:Phenotype; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000378:metabolism; D014028:Tobacco Smoke Pollution / Q000009:adverse effects; D014361:Trypsin Inhibitors / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D000515:alpha 1-Antitrypsin / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D015850:Interleukin-6; D016328:NF-kappa B; D014028:Tobacco Smoke Pollution; D014361:Trypsin Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; D018698:Glutamic Acid; D008239:Lysine