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Telomere-mediated lung disease

Alder, Jonathan K., Armanios, Mary·2022·Physiological Reviews
DOI 10.1152/physrev.00046.2021PMC PMC9306791
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Abstract

Parenchymal lung disease is the fourth leading cause of death in the United States; among the top causes, it continues on the rise. Telomeres and telomerase have historically been linked to cellular processes related to aging and cancer, but surprisingly, in the recent decade genetic discoveries have linked the most apparent manifestations of telomere and telomerase dysfunction in humans to the etiology of lung disease: both idiopathic pulmonary fibrosis (IPF) and emphysema. The short telomere defect is pervasive in a subset of IPF patients, and human IPF is the phenotype most intimately tied to germline defects in telomere maintenance. One-third of families with pulmonary fibrosis carry germline mutations in telomerase or other telomere maintenance genes, and one-half of patients with apparently sporadic IPF have short telomere length. Beyond explaining genetic susceptibility, short telomere length uncovers clinically relevant syndromic extrapulmonary disease, including a T-cell immunodeficiency and a propensity to myeloid malignancies. Recognition of this subset of patients who share a unifying molecular defect has provided a precision medicine paradigm wherein the telomere-mediated lung disease diagnosis provides more prognostic value than histopathology or multidisciplinary evaluation. Here, we critically evaluate this progress, emphasizing how the genetic findings put forth a new pathogenesis paradigm of age-related lung disease that links telomere abnormalities to alveolar stem senescence, remodeling, and defective gas exchange.

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Metadata

Authors
Alder, J. K., & Armanios, M.
Affiliations
  • Division of Pulmonary and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
  • Departments of Oncology and Genetic Medicine, Telomere Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland
ORCID
Venue
Physiological Reviews
Publisher
American Physiological Society
Published
2022-10-01
Volume
102
Issue
4
Pages
1703-1720
ISSN
  • 0031-9333
  • 1522-1210
DOI
10.1152/physrev.00046.2021
PMC
PMC9306791
Cited by
130
References
29
Language
en
Funders
  • HHS | NIH | National Cancer Institute (CA225027)
  • HHS | NIH | National Heart, Lung, and Blood Institute (HL119476, HL135062)
  • S&R Kuno Foundation

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