title: Telomere dysfunction causes sustained inflammation in chronic obstructive pulmonary disease.
abstract: BACKGROUND
  Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation of unknown pathogenesis.
  
  
  OBJECTIVE
  To investigate whether telomere dysfunction and senescence of pulmonary vascular endothelial cells (P-ECs) induce inflammation in COPD.
  
  
  METHODS
  Prospective comparison of patients with COPD and age- and sex-matched control smokers. Investigation of mice null for telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes.
  
  
  RESULTS
  In situ lung specimen studies showed a higher percentage of senescent P-ECs stained for p16 and p21 in patients with COPD than in control subjects. Cultured P-ECs from patients with COPD exhibited early replicative senescence, with decreased cell-population doublings, a higher percentage of β-galactosidase-positive cells, reduced telomerase activity, shorter telomeres, and higher p16 and p21 mRNA levels at an early cell passage compared with control subjects. Senescent P-ECs released cytokines and mediators: the levels of IL-6, IL-8, monocyte chemotactic protein (MCP)-1, Hu-GRO, and soluble intercellular adhesion molecule (sICAM)-1 were elevated in the media of P-ECs from patients compared with control subjects at an early cell passage, in proportion to the senescent P-EC increase and telomere shortening. Up-regulation of MCP-1 and sICAM-1 led to increased monocyte adherence and migration. The elevated MCP-1, IL-8, Hu-GROα, and ICAM-1 levels measured in lungs from patients compared with control subjects correlated with P-EC senescence criteria and telomere length. In Tert(-/-) and/or Terc(-/-) mouse lungs, levels of the corresponding cytokines (MCP-1, IL-8, Hu-GROα, and ICAM-1) were also altered, despite the absence of external stimuli and in proportion to telomere dysfunction.
  
  
  CONCLUSIONS
  Telomere dysfunction and premature P-EC senescence are major processes perpetuating lung inflammation in COPD.
authors: Institut National de la Santé et de la Recherche Médicale, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France.
authors: Valerie
authors: V
authors: Amsellem
authors: Guillaume
authors: G
authors: Gary-Bobo
authors: Elisabeth
authors: E
authors: Marcos
authors: Bernard
authors: B
authors: Maitre
authors: Vicky
authors: V
authors: Chaar
authors: Pierre
authors: P
authors: Validire
authors: Jean-Baptiste
authors: JB
authors: Stern
authors: Hiba
authors: H
authors: Noureddine
authors: Elise
authors: E
authors: Sapin
authors: Dominique
authors: D
authors: Rideau
authors: Sophie
authors: S
authors: Hue
authors: Philippe
authors: P
authors: Le Corvoisier
authors: Sabine
authors: S
authors: Le Gouvello
authors: Jean-Luc
authors: JL
authors: Dubois-Randé
authors: Jorge
authors: J
authors: Boczkowski
authors: Serge
authors: S
authors: Adnot
mesh_terms: D000328:Adult; D000818:Animals; D016022:Case-Control Studies; D004730:Endothelium, Vascular / Q000648:ultrastructure*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D016018:Least-Squares Analysis; D008297:Male; D016555:Matched-Pair Analysis; D051379:Mice; D018345:Mice, Knockout; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000473:pathology*; D012907:Smoking / Q000009:adverse effects; D059506:Telomere Shortening