Telomeres in Interstitial Lung Disease: The Short and the Long of It

Abstract

Telomeres are repetitive nucleotide sequences that cap linear chromosomes, thereby limiting progressive chromosomal shortening during cell replication. In conjunction with environmental factors, common single-nucleotide polymorphisms and rare and ultra-rare telomere-related mutations are associated with accelerated telomere shortening resulting in organ dysfunction, including interstitial lung disease (ILD). The most common telomere-related mutation-associated ILD is idiopathic pulmonary fibrosis (IPF). Up to one-third of individuals with familial IPF have shortened telomeres and/or carry a telomererelated mutation, and 1 in 10 individuals with sporadic IPF have telomere-related mutations. Regardless of ILD phenotype, individuals with short telomeres and/or known telomere-related mutations have more rapid disease progression and shorter lung transplant-free survival. Management should include initiation of antifibrotic agents for those with an IPF phenotype and early referral to a transplant center. Patients with ILD being considered for transplant should be screened for short telomeres if there is a significant family history of pulmonary fibrosis or evidence of extrapulmonary organ dysfunction associated with a short telomere syndrome. Post-transplant management of recipients with telomere-related mutations should include careful adjustment of immunosuppression regimens on the basis of bone marrow reserve. Data on the impact of shortened telomeres on post-transplant outcomes, however, remain mixed.

Antifibrotics in COVID-19 Lung Disease: Let Us Stay Focused

“…Fibrosis from ARDS, in contrast to IPF, does not progress nor lead to a dominant pattern of honeycombing. Although the etiology of IPF remains obscure, the pathogenesis is best understood as a consequence of repetitive injuries followed by dysregulated repair processes, facilitated by telomere shortening, not intense inflammation ( 44 – 46 ).…”

Shorter telomere length following lung transplantation is associated with clinically significant leukopenia and decreased chronic lung allograft dysfunction-free survival

“…The normal telomere shortening that occurs with cellular division can eventually trigger cell senescence or apoptosis [1]. Individuals with short telomeres, with or without associated telomere-related mutations, are more susceptible to a range of premature organ dysfunctions, including interstitial lung disease (ILD) [2][3][4][5][6]. The most definitive treatment for ILD and other advanced lung diseases that progress despite standard therapy is lung transplantation.…”

The Role of Telomerase and Telomeres in Interstitial Lung Diseases: From Molecules to Clinical Implications

“…This is especially important since IPF remains incurable (short of lung transplantation), and telomerase or other telomere-targeted approaches may offer new clinical options [23]. Short telomere screening is proposed as a useful tool in preferential selection for a lung transplant in ILD, since patients with short telomeres have poorer lung-transplant-free survival times [72]. For example, it has been determined through patient cohorts with various ILDs that decreased telomere length is associated with faster lung function decline and worse transplant-free survival, thus confirming its credence as a prognostic tool [73].…”