People with idiopathic pulmonary fibrosis have shorter telomeres — the protective caps at the end of chromosomes — but shortening may occur prior to disease onset.
The study with that finding, “From organ to cell: Multi-level telomere length assessment in patients with idiopathic pulmonary fibrosis,” was published in the journal PLOS One.
Mutations in genes that regulate the telomeres of chromosomes have been reported in patients with pulmonary fibrosis.
Telomeres become shorter with aging, but the enzyme telomerase works to prevent their rapid shortening. Mutations in the gene that provides instructions for making telomerase reverse transcriptase (TERT) cause telomeres to become extremely shorter; that leads to problems in the repair of DNA. Eventually this causes cellular senescence, meaning cessation of cell division, which is a key process for wound healing that also promotes lung fibrosis (scarring).
Evidence suggests that IPF patients with shorter telomeres also have shorter survival. Previous studies have shown that telomeres’ length differs between organs, yet the lung rarely has been included in these earlier studies.
Now, a team of researchers at the St Antonius Hospital, Nieuwegein, in The Netherlands, investigated if telomeres in lung cells were affected by lung fibrosis, and how their length correlated with disease features.
In total, they analyzed 82 individuals, including 49 cases of sporadic IPF, 18 of IPF carrying mutations in the TERT gene, and 15 healthy controls.
The team first measured telomere size in the lung, kidney, thyroid, liver, and bladder in two patients with sporadic IPF, one IPF patient with a mutation in the TERT gene, and two matched controls. Results showed that lung telomeres were the shortest in IPF cases.
Researchers then looked at whether age was influencing lung telomeres’ length in a group of 32 sporadic IPF patients ranging in age from 35 to 75. Results showed no correlation between age and telomere length in sporadic IPF, while in controls they saw a correlation between increasing age and shortening of lung telomere length.
The results also suggested that despite disease progression, telomeres’ length remains constant over time, as researchers saw no differences in telomeres’ length in lung biopsy samples taken at diagnosis and after 45 months, at end-stage fibrosis in the same patient. (They performed this analysis in eight patients.)
Fibrosis in the lungs often follows an apicobasal gradient, accumulating more at the basal (bottom) than apical (top) of lung. By comparing patients with this fibrosis gradient (eight patients) to those without it (seven patients), researchers found that telomeres’ length was independent of this gradient. Also, no significant differences were found between lungs with and without an apicobasal gradient.
Next, in order to “identify a subgroup of IPF cases with possible telomere related pathology,” researchers compared 32 sporadic IPF cases to 17 patients with a TERT mutation. In the sporadic IPF cases, researchers saw a correlation in telomeres’ length in the blood and lungs, but no correlation was found in the TERT mutation carriers.
They then determined a threshold to define patients with short telomeres (less than 0.857, IPF short), and normal length (more than 0.857, IPF normal). Biopsy telomere length in IPF normal patients was in the same range as that of age-matched controls.
Also, in the IPF short and TERT carrier sub-groups, researchers observed that AT2 cells (alveolar type 2 progenitor cells that divide frequently) had shorter telomeres, compared to controls. Also, AT2 cells telomeres were particularly short in scarred (fibrotic) lung areas, especially of IPF short and TERT carrier sub-groups.
To identity other genetic alterations in telomere-related genes associated with pulmonary fibrosis, researchers sequenced telomere-related genes in all 32 sporadic IPF patients. They found three genetic variants, two in the RTEL1 gene and one in the PARN gene in the IPF short group that potentially could be involved in the fibrosis process.
Overall, “this study demonstrates that there is no difference in average lung telomere length in time and location, which make[s] it plausible that lung telomere shortening occurs prior to disease diagnosis,” researchers wrote.
“This opens up possibilities for early detection of patients at risk of developing IPF, if easily accessible markers would be available that associate with this process,” they stated.
“Future measurement of lung telomere length in IPF may aid discrimination between telomere-related and telomere-unrelated pulmonary fibrosis,” the team noted.
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