The Role of Telomerase and Telomeres in Interstitial Lung Diseases: From Molecules to Clinical Implications

Petukhov, Dmytro; Wallach-Dayan, Shulamit B.

doi:10.3390/ijms20122996

Cited by 35 publications

(26 citation statements)

References 93 publications

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“…Fibrosis from ARDS, in contrast to IPF, does not progress nor lead to a dominant pattern of honeycombing. Although the etiology of IPF remains obscure, the pathogenesis is best understood as a consequence of repetitive injuries followed by dysregulated repair processes, facilitated by telomere shortening, not intense inflammation (44)(45)(46).…”

Section: Putting Scarring and Lung Fibrosis Into Contextmentioning

confidence: 99%

Antifibrotics in COVID-19 Lung Disease: Let Us Stay Focused

et al. 2020

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After decades of research, two therapies for chronic fibrotic lung disease are now approved by the FDA, with dozens more anti-fibrotic therapies in the pipeline. A great deal of enthusiasm has been generated for the use of these drugs, which are by no means curative but clearly have a favorable impact on lung function decline over time. Amidst a flurry of newly developed and repurposed drugs to treat the coronavirus disease 2019 (COVID-19) and its accompanying acute respiratory distress syndrome (ARDS), few have emerged as effective. Historically, survivors of severe viral pneumonia and related acute lung injury with ARDS often have near full recovery of lung function. While the pathological findings of the lungs of patients with COVID-19 can be diverse, current reports have shown significant lung fibrosis predominantly in autopsy studies. There is growing enthusiasm to study anti-fibrotic therapy for inevitable lung fibrosis, and clinical trials are underway using currently FDA-approved anti-fibrotic therapies. Given the relatively favorable outcomes of survivors of virus-mediated ARDS and the low prevalence of clinically meaningful lung fibrosis in survivors, this perspective examines if there is a rationale for testing these repurposed antifibrotic agents in COVID-19-associated lung disease.

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Section: Putting Scarring and Lung Fibrosis Into Contextmentioning

confidence: 99%

Antifibrotics in COVID-19 Lung Disease: Let Us Stay Focused

et al. 2020

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“…A major contributor to cellular senescence in lung fibrosis is telomere dysfunction [93,104]. Telomeres protect the ends of chromosomes from replicative loss through providing a mechanism for telomerase-dependent repeat expansion, thus maintaining the proliferative potential of stem and progenitor cells [105].…”

Section: Impaired At2 Self-renewal In Ipfmentioning

confidence: 99%

“…Smoking, a risk factor for IPF, also causes a dose-dependent shortening of telomeres [108]. Similarly, telomere attrition also occurs with aging, another risk for the development of IPF [104].…”

Section: Impaired At2 Self-renewal In Ipfmentioning

confidence: 99%

Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

Parimon

Yao

Stripp

et al. 2020

IJMS

241

172

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: Alveolar epithelial type II cells (AT2) are a heterogeneous population that have critical secretory and regenerative roles in the alveolus to maintain lung homeostasis. However, impairment to their normal functional capacity and development of a pro-fibrotic phenotype has been demonstrated to contribute to the development of idiopathic pulmonary fibrosis (IPF). A number of factors contribute to AT2 death and dysfunction. As a mucosal surface, AT2 cells are exposed to environmental stresses that can have lasting effects that contribute to fibrogenesis. Genetical risks have also been identified that can cause AT2 impairment and the development of lung fibrosis. Furthermore, aging is a final factor that adds to the pathogenic changes in AT2 cells. Here, we will discuss the homeostatic role of AT2 cells and the studies that have recently defined the heterogeneity of this population of cells. Furthermore, we will review the mechanisms of AT2 death and dysfunction in the context of lung fibrosis.

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“…Mutations in telomere-related genes (TERT, TERC, RTEL1, PARN, TINF2, NAF1 and DKC1) have been associated with a broad range of ILDs, including IPF, iNSIP, RA-ILD, acute interstitial pneumonia, cryptogenic organising pneumonia, chronic hypersensitivity pneumonitis and PPFE. [97][98][99] Telomeres are distal regions of chromosomes associated with specific protein complexes, which protect the chromosome against degradation and aberration. It is believed that loss of function in the telomerase complex may influence the turnover and healing of alveolar epithelial cells after an initial damaging stimulus, thereby triggering fibrosis.…”

Section: Genetic Mechanisms Driving Progressive Pulmonary Fibrosismentioning

confidence: 99%

Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstitial lung diseases (ILDs)

et al. 2020

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Interstitial lung diseases (ILDs), which can arise from a broad spectrum of distinct aetiologies, can manifest as a pulmonary complication of an underlying autoimmune and connective tissue disease (CTD-ILD), such as rheumatoid arthritis-ILD and systemic sclerosis (SSc-ILD). Patients with clinically distinct ILDs, whether CTD-related or not, can exhibit a pattern of common clinical disease behaviour (declining lung function, worsening respiratory symptoms and higher mortality), attributable to progressive fibrosis in the lungs. In recent years, the tyrosine kinase inhibitor nintedanib has demonstrated efficacy and safety in idiopathic pulmonary fibrosis (IPF), SSc-ILD and a broad range of other fibrosing ILDs with a progressive phenotype, including those associated with CTDs. Data from phase II studies also suggest that pirfenidone, which has a different—yet largely unknown—mechanism of action, may also have activity in other fibrosing ILDs with a progressive phenotype, in addition to its known efficacy in IPF. Collectively, these studies add weight to the hypothesis that, irrespective of the original clinical diagnosis of ILD, a progressive fibrosing phenotype may arise from common, underlying pathophysiological mechanisms of fibrosis involving pathways associated with the targets of nintedanib and, potentially, pirfenidone. However, despite the early proof of concept provided by these clinical studies, very little is known about the mechanistic commonalities and differences between ILDs with a progressive phenotype. In this review, we explore the biological and genetic mechanisms that drive fibrosis, and identify the missing evidence needed to provide the rationale for further studies that use the progressive phenotype as a target population.

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The Role of Telomerase and Telomeres in Interstitial Lung Diseases: From Molecules to Clinical Implications

Cited by 35 publications

References 93 publications

Antifibrotics in COVID-19 Lung Disease: Let Us Stay Focused

Antifibrotics in COVID-19 Lung Disease: Let Us Stay Focused

Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstitial lung diseases (ILDs)

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