Study: Treatment of pulmonary fibrosis should focus on the telomeres of the cells that regenerate the lungs

Treatment of pulmonary fibrosis should focus on the telomeres of the cells that regenerate the lungs, according to a new study b
Efficient Trf1 deletion in lung fibroblasts upon tamoxifen administration. a Generation of the conditional knockout mouse model in which Trf1 was deleted in fibroblasts using the Cre recombinase driven by the Col1a2 promoter. Trf1lox, KFPLox-LSL-Lox, and Col1a2-CreERT2 alleles are depicted before and after Cre-mediated excision. b Tamoxifen (TMX) treatment, survival rate assessment and sample collection. Eight-to 10-week-old male Trf1+/+ KFP+/t Cre+/t (Col1a2-Cre; Trf1+/+) and Trf1lox/lox KFP+/t Cre+/t (Col1a2-Cre; Trf1lox/lox) mice were i.p. injected with TMX for five consecutive days during the first week and once a week until the sacrifice and sample collection on week (W) 7, and during the follow-up of survival until W12. c Representative images of fluorescence intensity of katushka fluorescent protein (KFP) in Trf1+/+ KFP+/+ Cre+/t, Trf1+/+ KFP+/t Cre+/t and Trf1lox/lox KFP+/t Cre+/t mice. Representative immunostainings for KFP (d), and quantification of KFP positive cells per 40X high-power field (HPF) (e) in lung sections from Trf1+/+ KFP+/t Cre+/t and Trf1lox/lox KFP+/t Cre+/t mice. f Kaplan–Meier survival curves of Col1a2-Cre; Trf1+/+ (Trf1+/+, controls) and Col1a2-Cre; Trf1Δ/Δ (Trf1Δ/Δ) mice upon TMX treatment. g Representative immunofluorescence stainings for COL1A2 (green) and TRF1 (red) (white arrowheads indicate COL1A2+ fibroblasts with deletion of TRF1), and immune-telomere-Q-FISH in COL1A2+ fibroblasts (Cy3Tel probe (red), COL1A2+ cells (green), and nuclei stained with DAPI (blue)) in lung sections from Trf1+/+ and Trf1Δ/Δ mice. Quantification of the proportion of double COL1A2+-TRF1+ fibroblasts (h) and mean telomere spot intensity (i) and average number of telomeres (j) in COL1A2+ cells from Trf1+/+ and Trf1Δ/Δ mice. Data are expressed as mean ± SEM (the number of mice is indicated in each case). **p < 0.01 (Mann–Whitney or unpaired t tests). Animal survival was assessed by the Kaplan–Meier analysis, using the log Rank (Mantel–Cox) test. Credit: Nature Communications (2022). DOI: 10.1038/s41467-022-32771-6

Idiopathic pulmonary fibrosis could become the first degenerative disease to be treated through the science of aging.

It was known that this disease—like other —is associated with the aging process, but its molecular causes were unknown. The Telomeres and Telomerase Group at the Spanish National Cancer Research Centre (CNIO), led by Maria A. Blasco, has been working for years to unravel them. In their latest findings, they have narrowed down exactly which cells give rise to fibrosis when they undergo alterations due to the aging process: alveolar type II pneumocytes, the cells responsible for regenerating .

"The relevance of this finding is that it indicates which cells in particular should be targeted in any therapy against ," explains Blasco.

The paper is published today in Nature Communications, with Maria A. Blasco as senior author and CNIO Telomeres and Telomerase Group researchers Paula Martínez and Sergio Piñeiro-Hermida as first authors.

Telomere malfunctioning

People affected by pulmonary fibrosis suffer a progressive loss of breathing capacity because their lung tissue becomes stiff and scarred. The disease, currently untreatable, is potentially lethal and affects around 8,000 people in Spain.

In recent years, Blasco's group has shown that pulmonary fibrosis is triggered when telomeres, the molecular structures that protect the ends of chromosomes, no longer function properly in lung cells. Telomeres are linked to aging: they shorten over the course of a lifetime, which can cause them to lose their ability to work properly as the body ages.

However, there are several different cell types in the lungs, including alveolar type II, fibroblasts, so-called club cells and , and until now no studies have been done on which of these cells is the origin of lung fibrosis caused by non-functional telomeres.

Fibrosis is only produced when the telomeres in pneumocytes are damaged

The new study by this CNIO group investigates whether damaging the telomeres of different types of lung cells causes fibrosis. It does so by inactivating—in each of these —a gene called TRF1, which controls the synthesis of a protein that is essential for proper telomere functioning.

The finding confirms that the truly important cells for lung fibrosis are alveolar type II pneumocytes.

"We show that depletion of TRF1 in fibroblasts, Club and basal does not lead to interstitial lung fibrosis, underscoring alveolar type II pneumocytes as the relevant cell type for the origin of interstitial fibrosis," the authors write in Nature Communications.

CNIO researchers have also designed a therapeutic strategy to treat , based on a that activates the production of the enzyme that repairs telomeres in the body: telomerase. This therapy has resulted in patents and the creation of a new company, Telomere Therapeutics, involving the public bodies CNIO, the Autonomous University of Barcelona and the Centre for the Development of Industrial Technology (CTDI).

"Pulmonary is now the top disease for those researching aging," says Maria A. Blasco. "If we succeed in curing it, it will be the first time in which what is being treated is aging."

More information: Sergio Piñeiro-Hermida et al, Consequences of telomere dysfunction in fibroblasts, club and basal cells for lung fibrosis development, Nature Communications (2022). DOI: 10.1038/s41467-022-32771-6
Journal information: Nature Communications

Citation: Study: Treatment of pulmonary fibrosis should focus on the telomeres of the cells that regenerate the lungs (2022, October 6) retrieved 9 December 2022 from https://medicalxpress.com/news/2022-10-treatment-pulmonary-fibrosis-focus-telomeres.html
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