Telomere dysfunction causes sustained inflammation in chronic obstructive pulmonary disease.
Am J Respir Crit Care Med
; 184(12): 1358-66, 2011 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-21885626
ABSTRACT
RATIONALE Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation of unknown pathogenesis. OBJECTIVES:
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. MEASUREMENTS AND MAINRESULTS:
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 ß-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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Endotélio Vascular
/
Doença Pulmonar Obstrutiva Crônica
/
Encurtamento do Telômero
/
Inflamação
Tipo de estudo:
Etiology_studies
/
Observational_studies
/
Risk_factors_studies
Limite:
Adult
/
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Am J Respir Crit Care Med
Assunto da revista:
TERAPIA INTENSIVA
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
França