Pulmonary Artery Smooth Muscle Cell Senescence Is a Pathogenic Mechanism for Pulmonary Hypertension in Chronic Lung Disease

Noureddine, Hibo; Gary-Bobo, Guillaume; Alifano, Marco; Marcos, Élisabeth; Saker, Mirna; Vienney, Nora; Amsellem, Valérie; Maître, Bernard; Chaouat, Ari; Chouaïd, C.; Dubois‐Randé, Jean‐Luc; Damotte, Diane; Adnot, Serge

doi:10.1161/circresaha.111.241299

Cited by 127 publications

(141 citation statements)

References 20 publications

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“…This is in line with senescent-type growth characteristics of lung fibroblasts [36]. Furthermore, cellular senescence of pulmonary smooth muscle cells appears to be involved in the pathogenesis of pulmonary hypertension in COPD [37]. Several mechanisms have been proposed for abnormal ageing in COPD, including chronic inflammation, oxidative stress, mitochondrial dysfunction, altered energy metabolism, abnormal regulation of ageing processes, cellular and immunosenescence, and telomere dysfunction [3,[7][8][9]15].…”

Section: Discussionmentioning

confidence: 67%

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: Discussionmentioning

confidence: 67%

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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“…Reduced telomere length has been demonstrated in pulmonary vascular endothelial cells and pulmonary artery smooth muscle cells derived from COPD patients when compared to cells derived from smoking controls [84,85]. TSUJI et al [86] used fluorescent in situ hybridisation to assess telomere length in alveolar type II and endothelial cells and demonstrated decreased telomere length in COPD patients when compared to nonsmoking controls, but not compared to smoking controls.…”

Section: Telomere Shorteningmentioning

confidence: 99%

Lung ageing and COPD: is there a role for ageing in abnormal tissue repair?

et al. 2017

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Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide, with increasing prevalence, in particular in the elderly. COPD is characterised by abnormal tissue repair resulting in (small) airways disease and emphysema. There is accumulating evidence that ageing hallmarks are prominent features of COPD. These ageing hallmarks have been described in different subsets of COPD patients, in different lung compartments and also in a variety of cell types, and thus might contribute to different COPD phenotypes. A better understanding of the main differences and similarities between normal lung ageing and the pathology of COPD may improve our understanding of the mechanisms driving COPD pathology, in particular in those patients that develop the most severe form of COPD at a relatively young age, i.e. severe early-onset COPD patients.In this review, after introducing the main concepts of lung ageing and COPD pathology, we focus on the role of (abnormal) ageing in lung remodelling and repair in COPD. We discuss the current evidence for the involvement of ageing hallmarks in these pathological features of COPD. We also highlight potential novel treatment strategies and opportunities for future research based on our current knowledge of abnormal lung ageing in COPD.

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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

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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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Pulmonary Artery Smooth Muscle Cell Senescence Is a Pathogenic Mechanism for Pulmonary Hypertension in Chronic Lung Disease

Cited by 127 publications

References 20 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

Lung ageing and COPD: is there a role for ageing in abnormal tissue repair?

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

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