Pathology, Radiology, and Genetics of Interstitial Lung Disease in Patients With Shortened Telomeres

Cecchini, Matthew J.; Tarmey, Tara; Ferreira, Allison J.; Mangaonkar, Abhishek A.; Ferrer, Alejandro; Patnaik, Mrinal M.; Wylam, Mark E.; Jenkins, Sarah M.; Spears, Grant M.; Yi, Eunhee S.; Hartman, Thomas E.; Scott, John; Roden, Anja C.

doi:10.1097/pas.0000000000001725

Cited by 14 publications

(13 citation statements)

References 48 publications

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“…DSP analysis demonstrated a greater upregulation of p21 than p16 in fibroblastic foci. This is unsurprising, since recent studies have highlighted increased levels of both p16 [ 39 ] and p21 [ 34 ] in response to critically shortened telomeres, and various drivers of senescence via the p53-dependent cellular senescence pathway [ 18 ]. Other groups have been able to highlight p21-positive cells with immunofluorescence in cases of IPF [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Digital quantification of p16-positive foci in fibrotic interstitial lung disease is associated with a phenotype of idiopathic pulmonary fibrosis with reduced survival

et al. 2022

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Background Idiopathic pulmonary fibrosis (IPF) is associated with increased expression of cyclin-dependent kinase inhibitors such as p16 and p21, and subsequent induction of cell cycle arrest, cellular senescence, and pro-fibrotic gene expression. We sought to link p16-expression with a diagnosis of IPF or other fibrotic interstitial lung diseases (ILDs), radiographic pattern, senescent foci-specific gene expression, antifibrotic therapy response, and lung transplant (LTx)-free survival. Methods Eighty-six cases of fibrosing ILD were identified with surgical lung biopsy. Immunohistochemistry for p16 was performed on sections with the most active fibrosis. p16-positive foci (loose collection of p16-positive fibroblasts with overlying p16-positive epithelium) were identified on digital slides and quantified. Cases were scored as p16-low (≤ 2.1 foci per 100 mm2) or p16-high (> 2.1 foci per 100 mm2). Twenty-four areas including senescent foci, fibrotic and normal areas were characterized using in situ RNA expression analysis with digital spatial profiling (DSP) in selected cases. Results The presence of p16-positive foci was specific for the diagnosis of IPF, where 50% of cases expressed any level of p16 and 26% were p16-high. There was no relationship between radiographic pattern and p16 expression. However, there was increased expression of cyclin-dependent kinase inhibitors, collagens and matrix remodeling genes within p16-positive foci, and cases with high p16 expression had shorter LTx-free survival. On the other hand, antifibrotic therapy was significantly protective. DSP demonstrated that fibroblastic foci exhibit transcriptional features clearly distinct from that of normal-looking and even fibrotic areas. Conclusions We demonstrated the potential clinical applicability of a standardized quantification of p16-positive fibroblastic foci. This method identifies an IPF phenotype associated with foci-specific upregulation of senescence-associated and matrix remodeling gene expression. While these patients have reduced LTx-free survival, good response to antifibrotic therapies was observed in those who were treated.

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Section: Discussionmentioning

confidence: 99%

Digital quantification of p16-positive foci in fibrotic interstitial lung disease is associated with a phenotype of idiopathic pulmonary fibrosis with reduced survival

et al. 2022

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“…Telomere shortening is associated with cellular senescence and aging, as well as the progression of various diseases, including pneumonia [ 12 ]. Telomerase, the enzyme responsible for telomere elongation, counteracts telomere shortening by adding repeated DNA sequences to the ends of chromosomes [ 13 ]. Recent studies have shown that modulation of telomerase activity can influence immune responses, including those involved in the pathogenesis of pneumonia [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Melatonin-induced upregulation of telomerase activity interferes with macrophage mitochondrial metabolism and suppresses NLRP3 inflammasome activation in the treatment of Pneumonia

Jiang,

Liu,

Zhao

et al. 2024

Heliyon

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“…Patients with IPF have an annual decline in forced vital capacity of 130-210 mL, short telomeres caused by mutations in telomere-related genes, and forced vital capacity is reduced by an average of 300 mL per year 47 . Short telomeres are associated with increased fibrosis, histological patterns, and mortality 95 . These data support the notion that telomere function is involved in the development and progression of PF.…”

Section: Introductionmentioning

confidence: 99%

Genomic Fingerprint Associated with Familial Idiopathic Pulmonary Fibrosis: A Review

Ding¹,

Gao²,

Xue³

et al. 2023

Int. J. Med. Sci.

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Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease; although the recent introduction of two anti-fibrosis drugs, pirfenidone and Nidanib, have resulted in a significant reduction in lung function decline, IPF is still not curable. Approximately 2-20% of patients with IPF have a family history of the disease, which is considered the strongest risk factor for idiopathic interstitial pneumonia. However, the genetic predispositions of familial IPF (f-IPF), a particular type of IPF, remain largely unknown. Genetics affect the susceptibility and progression of f-IPF. Genomic markers are increasingly being recognized for their contribution to disease prognosis and drug therapy outcomes. Existing data suggest that genomics may help identify individuals at risk for f-IPF, accurately classify patients, elucidate key pathways involved in disease pathogenesis, and ultimately develop more effective targeted therapies. Since several genetic variants associated with the disease have been found in f-IPF, this review systematically summarizes the latest progress in the gene spectrum of the f-IPF population and the underlying mechanisms of f-IPF. The genetic susceptibility variation related to the disease phenotype is also illustrated. This review aims to improve the understanding of the IPF pathogenesis and facilitate his early detection.

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Pathology, Radiology, and Genetics of Interstitial Lung Disease in Patients With Shortened Telomeres

Cited by 14 publications

References 48 publications

Digital quantification of p16-positive foci in fibrotic interstitial lung disease is associated with a phenotype of idiopathic pulmonary fibrosis with reduced survival

Digital quantification of p16-positive foci in fibrotic interstitial lung disease is associated with a phenotype of idiopathic pulmonary fibrosis with reduced survival

Melatonin-induced upregulation of telomerase activity interferes with macrophage mitochondrial metabolism and suppresses NLRP3 inflammasome activation in the treatment of Pneumonia

Genomic Fingerprint Associated with Familial Idiopathic Pulmonary Fibrosis: A Review

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