Telomere-mediated lung disease

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.

Keywords: emphysema; pulmonary fibrosis; senescence; stem cells; telomerase.

Graphical abstract

FIGURE 1.

Telomere-mediated lung disease may appear as fibrosis or emphysema, with the latter appearing in smokers. Representative computed tomography images from 2 patients from a single family with a telomerase mutation; representative computed tomography images of idiopathic pulmonary fibrosis and emphysema associated with inherited mutations in telomerase genes. The overall estimated prevalence in the United States of each of the disease phenotypes, the percentage of patients with mutations in telomerase or other telomere maintenance genes, and the male-female distribution among those telomerase mutation carriers are shown. Only smokers with telomerase mutations develop emphysema, and this phenotype is more common among females.

FIGURE 2.

Pie chart shows relative proportion of patients with germline Mendelian mutations in familial pulmonary fibrosis. The largest subset is attributed to carriers of mutations in the telomerase reverse transcriptase, TERT. This is followed by carriers of mutations in 7 other telomere maintenance genes. A subset of patients also carries mutations in surfactant genes as listed.

FIGURE 3.

Eight telomerase and telomere maintenance genes are mutated in familial pulmonary fibrosis. Mutant components are shown in color. Genes are organized by their functions where known. The large subset of mutations (5 of 8) affect telomerase RNA (TR) or its biogenesis and localization (ZCCHC8, dyskerin, NAF1, and PARN).

FIGURE 4.

Short telomere length is a common and shared susceptibility factor for sporadic and familial idiopathic pulmonary fibrosis (IPF) and predisposes to extrapulmonary disease. A: telogram showing the normal distribution of telomere length in healthy populations, with each dot representing the average lymphocyte telomere length in a single patient. The distribution of dots schematically shows the distribution of telomere length among sporadic and familial cohorts of patients with IPF. They generally cluster across the lowest decile of the normal age-adjusted distribution relative to healthy control subjects. The colored lines representing the percentiles are labeled on right. B: Venn diagram shows overlap in the susceptibility between sporadic IPF and genetic determinants of short telomere length and familial forms of IPF caused by germline mutations. The 3 overlapping genes in the center, TERT, TR, and RTEL1, also cause autosomal dominant pulmonary fibrosis, and common variants near these genes predispose to short telomere length and are associated with sporadic forms of IPF. These observations highlight overlaps between the susceptibility of common and more rare forms of IPF with the genetic determinants of short telomere length. C: three most common categories of clinically relevant extrapulmonary manifestations of short telomere syndromes in patients with IPF.

FIGURE 5.

Advantages and limitations of 4 commonly used methods to estimate average telomere length in leukocytes. Southern blot was historically the first method developed. Southern blotting, quantitative PCR, and whole genome sequencing measure the average telomere length in bulk populations of cells. In contrast, flow cytometry and fluorescence in situ hybridization (flowFISH) is clinically used to measure telomere length separately in lymphocyte and granulocyte leukocyte lineages and has predictive and prognostic value in patient care decisions.

FIGURE 6.

Multi-“hit” model for telomere-mediated epithelium-driven lung disease. Schematic depicting the burden of telomere shortening in the lung with age. It is overall genetically determined and modestly changes with age given the slow turnover in lung alveolar epithelial compartments. On the other hand, acquired damage is cumulative and additive and includes endogenous sources such as endoplasmic reticulum stress as well as exogenous sources such as cigarette smoking or other cumulative damage related to oxygen exposure. The genetically determined short length lowers the threshold to fibrosis with age.

FIGURE 7.

Key differences in lung biology that impact modeling of human telomere-mediated lung disease in short-lived animals. This figure illustrates relevant life span, genetic, and physiological differences between mice and humans that pose challenges for the development of a faithful murine model of pulmonary fibrosis or emphysema, which evolve over decades in humans. The telomere length in most laboratory mice is longer and has a wide distribution posing a challenge to conditional studies.

FIGURE 8.

Cigarette causes additive genotoxic damage to short telomeres to provoke emphysema. Representative images of mouse lung micrographs showing intact alveolar architecture de novo in mice with short telomeres but a susceptibility to emphysema after cigarette smoke exposure. The cigarette smoke exposure causes telomere-independent cumulative DNA damage that leads to proliferative defects in epithelial cells and a senescence-like phenotype. Diagram is based on data reported in Ref. .

FIGURE 9.

Alveolar stem cell senescence and its role in fibrosis and lung remodeling. Model schematizing how telomere dysfunction limits the self-renewal potential of type 2 alveolar epithelial cells as well as differentiation into type 1 alveolar epithelial cells. With the accumulation of endogenous and exogenous “2nd hits” during aging, stem cell senescence drives lung remodeling, which appears as fibrosis (although among female smokers lung remodeling may appear as emphysema). The telomere dysfunction also concurrently drives a senescence-associated secretory phenotype (SASP) and an epithelium-derived signal that recruits inflammation, although the role of these events in lung remodeling directly is less clear and they may be bystander effects of epithelial senescence. The mechanisms by which stem cell senescence signals collagen synthesis are not understood. Image prepared with BioRender.com, with permission.