Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis

Naikawadi, Ram P.; Disayabutr, Supparerk; Mallavia, Beñat; Donne, Matthew; Green, Gary; La, Janet; Rock, Jason R.; Looney, Mark R.; Wolters, Paul J.

doi:10.1172/jci.insight.86704

Cited by 206 publications

(201 citation statements)

References 37 publications

(47 reference statements)

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“…The additive effect of low, repeated doses of bleomycin induces higher susceptibility to the development of lung fibrosis in TERTdeficient mice 7 . By sharp contrast, telomere shortening in AEC2s through the defective expression of telomeric repeat-binding factor 1 (TRF1) or TRF2 is associated with the agerelated development of lung fibrosis or the recruitment of inflammatory cells, respectively 7,8,29 . Mice deficient for TRF1 only in fibroblasts do not develop fibrosis 8 .…”

Section: Telomere Attritionmentioning

confidence: 99%

“…By sharp contrast, telomere shortening in AEC2s through the defective expression of telomeric repeat-binding factor 1 (TRF1) or TRF2 is associated with the agerelated development of lung fibrosis or the recruitment of inflammatory cells, respectively 7,8,29 . Mice deficient for TRF1 only in fibroblasts do not develop fibrosis 8 . These findings are a reminder that cell type and biological context could also affect how telomerase changes can drive age-related susceptibility to lung fibrosis.…”

Section: Telomere Attritionmentioning

confidence: 99%

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Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Mora

Rojas

Pardo

et al. 2017

Nat Rev Drug Discov

280

212

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Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches.Fibrosis as a pathogenic mechanism occurs in numerous organs and diseases. Fibrosis results from abnormal tissue repair and is associated with persistent and/or severe tissue damage and cellular stress. Epithelial and/or endothelial injury caused by various insults triggers interrelated wound-healing pathways to restore homeostasis 1 . Failure to adequately contain or eliminate inciting factors can exacerbate inflammation and chronic woundCorrespondence to A.L.M. anamora@pitt.edu. Competing interests statementThe authors declare competing interests: see Web version for details. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript healing responses, resulting in continued tissue damage and inadequate regeneration and, ultimately, fibrosis 2 . Although their aetiology and causative mechanisms differ, the various fibrotic diseases all have abnormal and exaggerated accumulation of extracellular matrix (ECM) components, mainly fibrillar collagens. The resulting fibrosis disturbs the normal architecture of affected organs, which ultimately leads to their dysfunction and failure. Nearly 45% of deaths in the developed world are attributable to some type of chronic fibroproliferative disease, including idiopathic pulmonary fibrosis (IPF) and end-stage fibrotic liver, kidney and heart disease 2 . The progressive nature of these diseases and the absence of effective treatments mean that a better understanding of the cellular and molecular mechanisms that contribute to the development of fibrosis is needed.Although IPF was originally thought to be an inflammation-driven disorder, clinical trials with a combination of anti-inflammatory drugs (prednisone, azathioprine and N-acetyl-Lcysteine (NAC)), failed to improve outcomes and instead increased mortality 3 . In 2014, two drugs, pirfenidone, a drug with poorly understood mechanisms, and nintedanib, a tyrosine kinase inhibitor, were approved for the treatment of IPF ...

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Section: Telomere Attritionmentioning

confidence: 99%

Section: Telomere Attritionmentioning

confidence: 99%

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Mora

Rojas

Pardo

et al. 2017

Nat Rev Drug Discov

280

212

View full text Add to dashboard Cite

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“…5,62 One durable alteration is the critical shortening of telomeres in alveolar type II cells, 63,64 which can lead to molecular changes within lung epithelial cells sufficient to promote lung remodelling and fibrosis. 65 Other epithelial alter ations are activation of senescence pro gramming, 66–68 accumulation of dysfunctional mitochondria, 69 and activation of the unfolded protein response. 70 The abnormal epithelium expresses numerous mediators that might lead to mesenchymal-cell activation and lung remodelling.…”

Section: Primary Role Of Lung Epithelia In Disease Pathogenesismentioning

confidence: 99%

Time for a change: is idiopathic pulmonary fibrosis still idiopathic and only fibrotic?

Wolters

Blackwell

Eickelberg

et al. 2018

The Lancet Respiratory Medicine

158

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Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and typically fatal lung disease characterised by subpleural fibrosis, subepithelial fibroblast foci, and microscopic honeycombing. Although understanding of the pathogenic mechanisms continues to evolve, evidence indicates that distal airway and alveolar epithelial cells are central drivers of the disease. In this Viewpoint, we review the history of naming and classifications used to define the disease now referred to as IPF, in the context of understanding the clinical presentation, causes, and pathogenesis of the disease. We aim to generate discussion on whether, given the substantial progress made in understanding the clinical, genetic, cellular, and molecular mechanisms involved in the development of IPF, a change of name should be considered. To initiate this discussion, we offer new suggestions to update the name of this disease and new approaches to classify all forms of pulmonary fibrosis.

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“…Professor Paul Wolters (San Francisco, USA) showed that deletion of the telomere shelterin protein TRF1 in alveolar epithelial cells (AECs) leads to the spontaneous development of lung fibrosis in mice, suggesting that telomere dysfunction in AECs contributes directly to the development of lung fibrosis 22. He explained that the telomere link may extend beyond IPF and predispose to other fibrotic lung diseases.…”

Section: Interstitial Lung Diseasementioning

confidence: 99%

Review of the British Thoracic Society Winter Meeting 2017, 6–8 December 2017, London, UK

Singanayagam

Woodcock

Molyneaux

et al. 2018

Thorax

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Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis

Cited by 206 publications

References 37 publications

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Time for a change: is idiopathic pulmonary fibrosis still idiopathic and only fibrotic?

Review of the British Thoracic Society Winter Meeting 2017, 6–8 December 2017, London, UK

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