Telomere dysfunction causes sustained inflammation in chronic obstructive pulmonary disease
| Autor: | Serge Adnot, Jean-Baptiste Stern, Dominique Rideau, Jorge Boczkowski, Le Corvoisier P, Le Gouvello S, Sophie Hue, Guillaume Gary-Bobo, Elisabeth Marcos, Pierre Validire, Jean-Luc Dubois-Randé, Chaar, Bernard Maitre, Amsellem, Hiba Noureddine, Sapin E |
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| Rok vydání: | 2011 |
| Předmět: |
Pulmonary and Respiratory Medicine
Senescence Adult Male Telomerase Matched-Pair Analysis Inflammation Critical Care and Intensive Care Medicine Telomerase RNA component Mice Pulmonary Disease Chronic Obstructive Medicine Animals Humans Telomerase reverse transcriptase Prospective Studies Least-Squares Analysis Telomere Shortening Mice Knockout COPD Lung business.industry Smoking medicine.disease respiratory tract diseases Telomere medicine.anatomical_structure Case-Control Studies Immunology Female Endothelium Vascular medicine.symptom business |
| Zdroj: | American journal of respiratory and critical care medicine. 184(12) |
| ISSN: | 1535-4970 |
| Popis: | Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation of unknown pathogenesis.To investigate whether telomere dysfunction and senescence of pulmonary vascular endothelial cells (P-ECs) induce inflammation in COPD.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.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.Telomere dysfunction and premature P-EC senescence are major processes perpetuating lung inflammation in COPD. |
| Databáze: | OpenAIRE |
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