Telomere Dysfunction and Senescence-associated Pathways in Bronchiectasis

Birch, Jodie; Victorelli, Stella; Rahmatika, Dina; Anderson, Rosaleen J.; Jiwa, Kasim; Moisey, Elizabeth; Ward, Chris; Fisher, Andrew J.; Soyza, Anthony De; Passos, João F.

doi:10.1164/rccm.201510-2035le

Cited by 35 publications

(24 citation statements)

References 11 publications

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“…Age-associated pathways including WNT signalling, mTOR and Toll-like receptors (TLRs) all have possible roles in COPD and IPF pathogenesis and could explain age-associated severity in bronchiectasis. Telomere dysfunction and senescence associated pathways have been described in explants studied from patients with bronchiectasis [18]. As such, this represents an important area of future interest and research [19][20][21].…”

Section: Ageing and Its Impact On Bronchiectasismentioning

confidence: 88%

Geographic variation in the aetiology, epidemiology and microbiology of bronchiectasis

et al. 2018

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Bronchiectasis is a disease associated with chronic progressive and irreversible dilatation of the bronchi and is characterised by chronic infection and associated inflammation. The prevalence of bronchiectasis is age-related and there is some geographical variation in incidence, prevalence and clinical features. Most bronchiectasis is reported to be idiopathic however post-infectious aetiologies dominate across Asia especially secondary to tuberculosis. Most focus to date has been on the study of airway bacteria, both as colonisers and causes of exacerbations. Modern molecular technologies including next generation sequencing (NGS) have become invaluable tools to identify microorganisms directly from sputum and which are difficult to culture using traditional agar based methods. These have provided important insight into our understanding of emerging pathogens in the airways of people with bronchiectasis and the geographical differences that occur. The contribution of the lung microbiome, its ethnic variation, and subsequent roles in disease progression and response to therapy across geographic regions warrant further investigation. This review summarises the known geographical differences in the aetiology, epidemiology and microbiology of bronchiectasis. Further, we highlight the opportunities offered by emerging molecular technologies such as -omics to further dissect out important ethnic differences in the prognosis and management of bronchiectasis.

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Section: Ageing and Its Impact On Bronchiectasismentioning

confidence: 88%

Geographic variation in the aetiology, epidemiology and microbiology of bronchiectasis

et al. 2018

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“…Cellular senescence may also be linked to an independent increase in risk of lung cancer in COPD, IPF and combined pulmonary fibrosis-emphysema patients (19). Increased lung senescent cells are also seen patients with other chronic lung conditions, including adult cystic fibrosis (20), bronchiectasis (21) and pulmonary arterial hypertension (22), although so far little research into the role of senescence in these diseases. and increased susceptibility to infections, cancer and autoimmunity (26).…”

Section: Cellular Senescencementioning

confidence: 99%

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases

Barnes

Baker

Donnelly

2019

Am J Respir Crit Care Med

369

264

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Cellular senescence is now considered an important driving mechanism for chronic lung diseases, particularly COPD and idiopathic pulmonary fibrosis. Cellular senescence is due to replicative and stress-related senescence with activation of p53 and p16 INK4a respectively, leading to activation of p21 CIP1 and cell cycle arrest. Senescent cells secrete multiple inflammatory proteins known as the senescence-associated secretory phenotype (SASP), leading to low grade chronic inflammation, which further drives senescence. Loss of key anti-aging molecules sirtuin-1 and sirtuin-6 may be important in acceleration of aging and arises from oxidative stress reducing phosphatase PTEN, thereby activating PI3K (phosphoinositide-3-kinase) and mTOR (mammalian target of rapamycin). MicroRNA-34a, which is regulated by PI3K-mTOR signaling, plays a pivotal role in reducing sirtuin-1/6 and its inhibition with an antagomir results in their restoration, reducing markers of senescence, reducing SASP and reversing cell cycle arrest in epithelial cells from peripheral airways of COPD patients. MiR-570 is also involved in reduction of sirtuin-1 and cellular senescence and is activated by p38 MAP kinase. These miRNAs may be released from cells in extracellular vesicles that are taken up by other cells, thereby spreading senescence locally within the lung but outside the lung through the circulation; this may account for comorbidities of COPD and other lung diseases. Understanding the mechanisms of cellular senescence may result in new treatments for chronic lung disease, either by inhibiting PI3K-mTOR signaling, by inhibiting specific miRNAs or by deletion of senescent cells with senolytic therapies, already shown to be effective in experimental lung fibrosis.

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“…Moreover, the work by Birch et al must also be stated since they discovered dysfunctional telomeres in airway epithelial cells from patients with COPD, which can be accelerated from smoking and may be associated with the secretion of inflammatory cytokines IL-6 and Il-8 [ 80 ]. The same group of researchers also reported dysfunctional telomeres and the activation of senescence pathways in the airways of patients with bronchiectasis [ 81 ].…”

Section: The Telomere/telomerase System In Chronic Disorders Is Imentioning

confidence: 99%

The Telomere/Telomerase System in Chronic Inflammatory Diseases. Cause or Effect?

Kordinas

Ioannidis

Chatzipanagiotou

2016

Genes

119

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Telomeres are specialized nucleoprotein structures located at the end of linear chromosomes and telomerase is the enzyme responsible for telomere elongation. Telomerase activity is a key component of many cancer cells responsible for rapid cell division but it has also been found by many laboratories around the world that telomere/telomerase biology is dysfunctional in many other chronic conditions as well. These conditions are characterized by chronic inflammation, a situation mostly overlooked by physicians regarding patient treatment. Among others, these conditions include diabetes, renal failure, chronic obstructive pulmonary disease, etc. Since researchers have in many cases identified the association between telomerase and inflammation but there are still many missing links regarding this correlation, the latest findings about this phenomenon will be discussed by reviewing the literature. Our focus will be describing telomere/telomerase status in chronic diseases under the prism of inflammation, reporting molecular findings where available and proposing possible future approaches.

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Telomere Dysfunction and Senescence-associated Pathways in Bronchiectasis

Cited by 35 publications

References 11 publications

Geographic variation in the aetiology, epidemiology and microbiology of bronchiectasis

Geographic variation in the aetiology, epidemiology and microbiology of bronchiectasis

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases

The Telomere/Telomerase System in Chronic Inflammatory Diseases. Cause or Effect?

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