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 MAIN 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.
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 MAIN 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: Rayjean J Hung; Cornelia M Ulrich; Ellen L Goode; Yonathan Brhane; Kenneth Muir; Andrew T Chan; Loic Le Marchand; Joellen Schildkraut; John S Witte; Rosalind Eeles; Paolo Boffetta; Margaret R Spitz; Julia G Poirier; David N Rider; Brooke L Fridley; Zhihua Chen; Christopher Haiman; Fredrick Schumacher; Douglas F Easton; Maria Teresa Landi; Paul Brennan; Richard Houlston; David C Christiani; John K Field; Heike Bickeböller; Angela Risch; Zsofia Kote-Jarai; Fredrik Wiklund; Henrik Grönberg; Stephen Chanock; Sonja I Berndt; Peter Kraft; Sara Lindström; Ali Amin Al Olama; Honglin Song; Catherine Phelan; Nicholas Wentzensen; Ulrike Peters; Martha L Slattery; Thomas A Sellers; Graham Casey; Stephen B Gruber; David J Hunter; Christopher I Amos; Brian Henderson Journal: J Natl Cancer Inst Date: 2015-08-29 Impact factor: 13.506
Authors: Linda Kachuri; Jens Helby; Stig Egil Bojesen; David C Christiani; Li Su; Xifeng Wu; Adonina Tardón; Guillermo Fernández-Tardón; John K Field; Michael P Davies; Chu Chen; Gary E Goodman; Frances A Shepherd; Natasha B Leighl; Ming S Tsao; Yonathan Brhane; M Catherine Brown; Kevin Boyd; Daniel Shepshelovich; Lei Sun; Christopher I Amos; Geoffrey Liu; Rayjean J Hung Journal: Cancer Epidemiol Biomarkers Prev Date: 2019-07 Impact factor: 4.254
Authors: Kaori Fujishiro; Ana V Diez-Roux; Paul A Landsbergis; Nancy Swords Jenny; Teresa Seeman Journal: Occup Environ Med Date: 2013-05-18 Impact factor: 4.402