Telomere Dysfunction Causes Sustained Inflammation in Chronic Obstructive Pulmonary Disease

Amsellem,; Gary-Bobo, Guillaume; Marcos, Élisabeth; Maître, Bernard; Chaar,; Validire, Pierre; Jb, Stern; Noureddine, Hiba; Sapin, E; Rideau, Dominique; Hüe, Sophie; Corvoisier, Philippe Le; Gouvello, Sabine Le; Jl, Dubois-Randé; Boczkowski, Jorge; Adnot, Serge

doi:10.1164/rccm.201105-0802oc

Cited by 207 publications

(179 citation statements)

References 33 publications

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“…With respect to COPD, this might be consistent with the observation that females appear to be more susceptible to COPD than males [34] but the causality certainly needs to be proved. Whereas our findings for asthma are novel, the results for COPD are in line with previous findings in case-control [14][15][16][17] and population-based studies [18]. This suggests that, as already shown for other chronic diseases [1,3,35], accelerated ageing may contribute to the pathogenesis of asthma and COPD.…”

Section: Discussionsupporting

confidence: 92%

“…Recent data suggest that shorter telomere length is associated with an increased risk of total and cancer mortality in COPD patients [13]. Shortened telomeres were found in pulmonary vascular endothelial cells, alveolar epithelial cells and circulating leukocytes of COPD patients [14][15][16][17][18], supporting the notion of accelerated ageing in COPD. RODE et al [18] reported multivariable-adjusted odds ratios of 1.15 (95% CI 1.06-1.25) for shortest versus longest telomere quartiles for COPD.…”

Section: Introductionmentioning

confidence: 78%

“…AMSELLEM et al [15] reported a higher percentage of pulmonary vascular endothelial cells stained for senescence markers in COPD patients than in lung healthy controls. This is in line with senescent-type growth characteristics of lung fibroblasts [36].…”

Section: Discussionmentioning

confidence: 97%

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Telomere length in circulating leukocytes is associated with lung function and disease

Albrecht¹,

Sillanpää²,

Karrasch³

et al. 2013

European Respiratory Journal

108

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Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function.Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status.We observed negative associations between telomere length and asthma (b5 -0.0452, p50.024) as well as COPD (b5 -0.0982, p50.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p51.07610 -7 ), FVC (p52.07610 -5 ), and FEV1/FVC (p55.27610 -3 ). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients.Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases. @ERSpublicationsTelomere length is decreased in asthma and COPD patients and positively associated with spirometric indices

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 78%

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Telomere length in circulating leukocytes is associated with lung function and disease

Albrecht¹,

Sillanpää²,

Karrasch³

et al. 2013

European Respiratory Journal

108

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“…These stimuli can act through two main different pathways: p53‐p21 and p16‐retinoblastoma protein (pRb), respectively (Campisi, 2005). In the lung, cell senescence leads to a decreased regenerative capacity and an increased cytokine production by structural cells (epithelium, fibroblasts) through a senescence‐associated secretome (Amsellem et al, 2011; Dagouassat et al, 2013; Noureddine et al, 2011; Tsuji, Aoshiba, & Nagai, 2010). However, other mechanisms, including mitochondrial dysfunction and defective mitophagy, may also contribute to ROS‐mediated senescence in COPD (Lerner, Sundar, & Rahman, 2016).…”

Section: Introductionmentioning

confidence: 99%

Heme oxygenase‐1 induction attenuates senescence in chronic obstructive pulmonary disease lung fibroblasts by protecting against mitochondria dysfunction

et al. 2018

Self Cite

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Chronic obstructive pulmonary disease (COPD) is associated with lung fibroblast senescence, a process characterized by an irreversible proliferation arrest associated with secretion of inflammatory mediators. ROS production, known to induce senescence, is increased in COPD fibroblasts and mitochondria dysfunction participates in this process. Among the battery of cellular responses against oxidative stress damage, heme oxygenase (HO)‐1 plays a critical role in defending the lung against oxidative stress and inflammation. Therefore, we investigated whether pharmacological induction of HO‐1 by chronic hemin treatment attenuates senescence and improves dysfunctional mitochondria in COPD fibroblasts. Fibroblasts from smoker controls (S‐C) and COPD patients were isolated from lung biopsies. Fibroblasts were long‐term cultured in the presence or absence of hemin, and/or ZnPP or QC‐15 (HO‐1 inhibitors). Lung fibroblasts from smokers and COPD patients displayed in long‐term culture a senescent phenotype, characterized by a reduced replicative capacity, an increased senescence and inflammatory profile. These parameters were significantly higher in senescent COPD fibroblasts which also exhibited decreased mitochondrial activity (respiration, glycolysis, and ATP levels) which led to an increased production of ROS, and mitochondria biogenesis and impaired mitophagy process. Exposure to hemin increased the gene and protein expression level of HO‐1 in fibroblasts and diminished ROS levels, senescence, the inflammatory profile and simultaneously rescued mitochondria dysfunction by restoring mitophagy in COPD cells. The effects of hemin were abolished by a cotreatment with ZnPP or QC‐15. We conclude that HO‐1 attenuates senescence in COPD fibroblasts by protecting, at least in part, against mitochondria dysfunction and restoring mitophagy.

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“…[39] Telomere dysfunction is one of the major processes perpetuating pulmonary inflammation in COPD. [40] COPD patients were reported to have shorter telomeres in leukocytes, out of 46,396 individuals from the Danish general population. Rode et al found that shortened telomere length was associated with higher risk of COPD, though the association was markedly attenuated after age and multivariable adjustment.…”

Section: Loss Of Telomeresmentioning

confidence: 99%

Genomic instability in chronic airway inflammatory diseases

Bao¹,

Xiong²,

Li³

et al. 2015

Biomed J

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Telomere Dysfunction Causes Sustained Inflammation in Chronic Obstructive Pulmonary Disease

Abstract: Telomere dysfunction and premature P-EC senescence are major processes perpetuating lung inflammation in COPD.

Cited by 207 publications

References 33 publications

Telomere length in circulating leukocytes is associated with lung function and disease

Telomere length in circulating leukocytes is associated with lung function and disease

Heme oxygenase‐1 induction attenuates senescence in chronic obstructive pulmonary disease lung fibroblasts by protecting against mitochondria dysfunction

Genomic instability in chronic airway inflammatory diseases

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