Telomere Shortening in Familial and Sporadic Pulmonary Fibrosis

Cronkhite, Jennifer T.; Xing, Chao; Raghu, Ganesh; Chin, Kelly; Torres, Fernando; Rosenblatt, Randall L.; Garcia, Christine Kim

doi:10.1164/rccm.200804-550oc

Cited by 469 publications

(422 citation statements)

References 40 publications

(59 reference statements)

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“…Indeed, the TERT and TERC mutational status could not be analysed retrospectively in the control group. However TERT mutations were previously found in no more than 1-3% of sporadic IPF cases [34][35]. The diagnosis of myelodysplastic syndrome in the control group was retrieved by querying physicians, possibly underestimating its frequency.…”

Section: Discussionmentioning

confidence: 99%

Severe hematologic complications after lung transplantation in patients with telomerase complex mutations

Borie

Kannengiesser

Hirschi

et al. 2015

The Journal of Heart and Lung Transplantation

109

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Section: Discussionmentioning

confidence: 99%

Severe hematologic complications after lung transplantation in patients with telomerase complex mutations

Borie

Kannengiesser

Hirschi

et al. 2015

The Journal of Heart and Lung Transplantation

109

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“…The pathogenesis is unknown, although some recent studies have identified telomerase mutations in almost 10% of patients with familial IPF, which suggests that telomere shortening in epithelial and mesenchymal cell compartments may limit lung regenerative capacity (25)(26)(27)(28). A recent study by Larsson et al (23) showed that myofibroblasts are in greater abundance in IPF fibroblast populations versus control fibroblast populations and exhibit genome-wide abnormalities in translational control, which may confer an anti-apoptotic phenotype.…”

Section: Discussionmentioning

confidence: 99%

SPARC Suppresses Apoptosis of Idiopathic Pulmonary Fibrosis Fibroblasts through Constitutive Activation of β-Catenin

Chang

Wei

Jacobs

et al. 2010

Journal of Biological Chemistry

107

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Idiopathic pulmonary fibrosis (IPF) is a poorly understood progressive disease characterized by the accumulation of scar tissue in the lung interstitium. A hallmark of the disease is areas of injury to type II alveolar epithelial cells with attendant accumulation of fibroblasts in areas called fibroblastic foci. In an effort to better characterize the lung fibroblast phenotype in IPF patients, we isolated fibroblasts from patients with IPF and looked for activation of signaling proteins, which could help explain the exaggerated fibrogenic response in IPF. We found that IPF fibroblasts constitutively expressed increased basal levels of SPARC, plasminogen activator inhibitor-1 (PAI-1), and active ␤-catenin compared with control cells. Control of basal PAI-1 expression in IPF fibroblasts was regulated by SPARCmediated activation of Akt, leading to inhibition of glycogen synthase kinase-3␤ and activation of ␤-catenin. Additionally, IPF fibroblasts (but not control fibroblasts) were resistant to plasminogen-induced apoptosis and were sensitized to plasminogen-mediated apoptosis by inhibition of SPARC or ␤-catenin. These findings uncover a newly discovered regulatory pathway in IPF fibroblasts that is characterized by elevated SPARC, giving rise to activated ␤-catenin, which regulates expression of downstream genes, such as PAI-1, and confers an apoptosisresistant phenotype. Disruption of this pathway may represent a novel therapeutic target in IPF.

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“…Mutations in TINF2, a telomere-binding protein, cause telomere shortening via a dominant negative mechanism (28), while mutations in RTEL1, which encodes a DNA helicase, disturb telomere length through mechanisms that are still incompletely understood (29). Abnormally short telomere length is also constitutional in at least half of individuals with sporadic IPF (30,31), suggesting that it is a pervasive contributor to disease risk, even beyond familial cases (30).…”

Section: Telomerase and Telomere Gene Mutations Explain The Genetic Bmentioning

confidence: 99%

Telomerase and the Genetics of Emphysema Susceptibility. Implications for Pathogenesis Paradigms and Patient Care

2016

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In the past five decades, alpha-1 antitrypsin deficiency has been the only known genetic cause of emphysema, yet it explains the genetics in only 1-2% of severe cases. Recently, mutations in telomerase genes were found to induce susceptibility to young-onset, severe, and familial emphysema at a frequency comparable to that of alpha-1 antitrypsin deficiency. Telomerase mutation carriers with emphysema report a family history of idiopathic pulmonary fibrosis, and both lung phenotypes show autosomal dominant inheritance within families. The data so far point to a strong gene-environment interaction that determines the lung disease type. In never-smokers, pulmonary fibrosis predominates, while smokers, especially females, are at risk for developing emphysema alone or in combination with pulmonary fibrosis. The telomere-mediated emphysema phenotype appears to have clinically recognizable features that are distinct from alpha-1 antitrypsin deficiency, and patients are prone to developing short telomere syndrome comorbidities that influence clinical outcomes. In animal models, telomere dysfunction causes alveolar epithelial stem cell senescence, which is sufficient to drive lung remodeling and recruit inflammation. Here, we review the implications of these discoveries for understanding emphysema biology as well as for patient care.Keywords: aging; alpha-1 antitrypsin deficiency; senescence; idiopathic pulmonary fibrosis; hepatopulmonary syndrome

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Telomere Shortening in Familial and Sporadic Pulmonary Fibrosis

Cited by 469 publications

References 40 publications

Severe hematologic complications after lung transplantation in patients with telomerase complex mutations

Severe hematologic complications after lung transplantation in patients with telomerase complex mutations

SPARC Suppresses Apoptosis of Idiopathic Pulmonary Fibrosis Fibroblasts through Constitutive Activation of β-Catenin

Telomerase and the Genetics of Emphysema Susceptibility. Implications for Pathogenesis Paradigms and Patient Care

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