Telomere Dysfunction in Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis is an age-dependent progressive and fatal lung disease of unknown etiology, which is characterized by the excessive accumulation of extracellular matrix inside the interstitial layer of the lung parenchyma that leads to abnormal scar architecture and compromised lung function capacity. Recent genetic studies have attributed the pathological genes or genetic mutations associated with familial idiopathic pulmonary fibrosis (IPF) and sporadic IPF to telomere-related components, suggesting that telomere dysfunction is an important determinant of this disease. In this study, we summarized recent advances in our understanding of how telomere dysfunction drives IPF genesis. We highlighted the key role of alveolar stem cell dysfunction caused by telomere shortening or telomere uncapping, which bridged the gap between telomere abnormalities and fibrotic lung pathology. We emphasized that senescence-associated secretory phenotypes, innate immune cell infiltration, and/or inflammation downstream of lung stem cell dysfunction influenced the native microenvironment and local cell signals, including increased transforming growth factor-beta (TGF-β) signaling in the lung, to induce pro-fibrotic conditions. In addition, the failed regeneration of new alveoli due to alveolar stem cell dysfunction might expose lung cells to elevated mechanical tension, which could activate the TGF-β signaling loop to promote the fibrotic process, especially in a periphery-to-center pattern as seen in IPF patients. Understanding the telomere-related molecular and pathophysiological mechanisms of IPF would provide new insights into IPF etiology and therapeutic strategies for this fatal disease.

Research Progress in the Molecular Mechanisms, Therapeutic Targets, and Drug Development of Idiopathic Pulmonary Fibrosis

“…These common and rare genetic mutations mainly include mutations in telomeres, alveolar surfactant and muco-ciliary transportation system, immune and cytokine-related genes, cell adhesion and cell integrity-related genes ( Table 2 ). MUC5B and telomere related gene mutations are more common in IPF patients, which has inspired a very large number of studies to explore the pathogenic mechanisms of gene mutations ( Evans et al, 2016 ; Zhang et al, 2021 ). Besides, genetic variants have been associated with the imaging presentation of IPF.…”

“…The ends of telomeres are bonded with telomerase, which is comprised of the catalytic subunit of TERT, the telomerase RNA component of TERC, and accessory proteins. The telomerase exerts its effects by adding telomeric sequences to the telomeric ends ( Zhang et al, 2021 ). Telomere shortening is one of the important phenotypes of IPF.…”

“…The mechanism by which telomerase gene mutations lead to IPF is unclear. Available data suggest that cellular senescence or death of alveolar stem cells induced by telomere dysfunction is implicated in pulmonary fibrosis ( Zhang et al, 2021 ). Knockdown of telomerase related genes leads to lung stem cell regenerative capacity and the senescence/death of AEC II ( Jackson et al, 2011 ; Alder et al, 2015 ; Snetselaar et al, 2017 ; Wang et al, 2020 ).…”

Avances en la investigación de los mecanismos moleculares, los blancos terapéuticos y el desarrollo de fármacos para la fibrosis pulmonar idiopática

“…Estas mutaciones genéticas, sean comunes o raras, incluyen principalmente mutaciones en los telómeros, en el surfactante alveolar y en el sistema de transporte mucociliar, además de en genes relacionados con la inmunidad y las citocinas, y en genes relacionados con la adhesión y la integridad celular (Tabla 2). Las mutaciones genéticas relacionadas con MUC5B y los telómeros son más comunes en pacientes con FPI, lo que ha inspirado un gran número de estudios para explorar los mecanismos patogénicos de dichas mutaciones [96, 97]. Además, las variantes genéticas se han asociado con la presentación imagenológica de la FPI.…”

“…Los extremos de los telómeros se unen con la telomerasa, que está compuesta por la subunidad catalítica de TERT, el componente RNA telomerasa de TERC y proteínas accesorias. La telomerasa ejerce sus efectos añadiendo secuencias teloméricas a los extremos de los telómeros [97]. El acortamiento de los telómeros es un fenotipo importante de la FPI.…”