• Am. J. Respir. Crit. Care Med. · Dec 2011

    Telomere dysfunction causes sustained inflammation in chronic obstructive pulmonary disease.

    • Sophie Hue, Jean-Baptiste Stern, Pierre Validire, Jean-Luc Dubois-Randé, Sabine Le Gouvello, Serge Adnot, Jorge Boczkowski, Bernard Maitre, Valerie Amsellem, Guillaume Gary-Bobo, Elisabeth Marcos, Vicky Chaar, Hiba Noureddine, Elise Sapin, Dominique Rideau, and Philippe Le Corvoisier.
    • Institut National de la Santé et de la Recherche Médicale, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France.
    • Am. J. Respir. Crit. Care Med.. 2011 Dec 15;184(12):1358-66.

    RationaleChronic obstructive pulmonary disease (COPD) is associated with chronic inflammation of unknown pathogenesis.ObjectivesTo investigate whether telomere dysfunction and senescence of pulmonary vascular endothelial cells (P-ECs) induce inflammation in COPD.MethodsProspective 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.Measurements And Main ResultsIn 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.ConclusionsTelomere dysfunction and premature P-EC senescence are major processes perpetuating lung inflammation in COPD.

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