Cellular Aging of Certain Lung Cells May Drive PF, Mouse Model Finds

Findings show which cells should be target of any new IPF therapy

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Mice play in a laboratory near a beaker and vials.

The cellular aging of a group of cells called alveolar type 2 pneumocytes — which work to promote airway stability, and play a key role in lung repair after injury — may be responsible for driving pulmonary fibrosis (PF).

That’s according to new findings from a team led by researchers at the Spanish National Cancer Research Centre (CNIO). The team had previously found that telomere dysfunction — a cellular sign of aging — in these cells leads to progressive and fatal PF in mice.

Now, once again using a mouse model, the researchers have demonstrated that telomere dysfunction in other lung cell types does not have the same effect.

“The relevance of this finding is that it indicates which cells in particular should be targeted in any therapy against idiopathic pulmonary fibrosis,” Maria A. Blasco, PhD, the study’s senior author and the director of the CNIO, said in a press release.

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The study, “Consequences of telomere dysfunction in fibroblasts, club and basal cells for lung fibrosis development,” was published in the journal Nature Communications.

Cellular aging in PF

Telomeres are the protective “caps” on the end of chromosomes that help maintain the stability of chromosomal DNA. These structures have long been linked to the normal aging process — they progressively shorten over the course of one’s lifetime, gradually losing their protective function as the body ages.

Shortened telomeres recently have been implicated in a number of degenerative diseases, including PF. About 8–15% of familial PF cases are associated with mutations in genes involved in telomere expansion or function. In sporadic cases of PF that are not linked to such mutations, telomeres are still found to be shorter than those in the general population.

The lungs are made up of many different types of cells. Blasco and her team previously found that inducing telomere dysfunction specifically in alveolar type 2 cells was sufficient to induce progressive and lethal PF in mice. However, it had not yet been established if other cell types in the lungs would be similarly involved.

Now, a team led by Blasco — and involving CNIO researchers and collaborators at AstraZeneca and the Complutense University of Madrid, Spain — aimed to identify other lung cell types in which telomere dysfunction might drive PF.

To that end, they examined three cell types, all of which play some role in tissue regeneration or repair: fibroblasts, club cells, and basal cells.

Mice were genetically engineered so that short-term telomere dysfunction could be induced in certain cell types when a chemical called tamoxifen was injected. Essentially, the injection would work to temporarily inactivate a gene called TRF1 that is necessary for telomeres to function.

Results showed that TRF1 deletion in any of the three cell types caused telomere damage, disruptions to cell growth, and reduced cellular proliferation, or growth.

In fibroblasts, no signs of inflammation, fibrosis (tissue scarring), or lung dysfunction were seen in the mice, suggesting that telomere damage in these cells is not the driver of PF.

For both club and basal cells, some changes in inflammation and airway remodeling were observed. Airway remodeling refers to structural changes that contribute to the thickening of airway walls and airway narrowing.

Notably, these changes were only seen in male mice, a finding consistent with the fact that IPF is more common in men than women, the researchers noted.

But TRF1 deletion in either cell type did not lead to signs of fibrosis in the lung parenchyma — the part of the lungs involved in gas exchange. According to researchers, these findings suggest that telomere dysfunction in either cell type is not sufficient to cause PF.

Deletion of TRF1 in any of the cell types did not affect telomere length, only their function, the researchers found.

“Noteworthy, depletion of TRF1 in fibroblasts, Club and basal cells did not lead to interstitial lung fibrosis, underscoring [alveolar type 2] cells as the relevant cell type for the origin of interstitial fibrosis,” the researchers wrote.

CNIO researchers are working on a therapeutic strategy to treat PF. It is a type of gene therapy that will activate telomerase, an enzyme that repairs telomeres and combats cellular aging.

“Pulmonary fibrosis is now the top disease for those researching ageing,” Blasco said. “If we succeed in curing pulmonary fibrosis, it will be the first time we are able to cure a disease by treating ageing.”

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