[Pathophysiology of pulmonary fibrosis associated with monogenic defects of telomere homeostasis]

Fibrosing interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF), are frequently associated with abnormalities in telomere homeostasis. Heterozygous pathogenic variants in telomere-related genes (TRGs) are found in 20-35% of patients with familial pulmonary fibrosis. These genetic defects are associated with impaired telomere homeostasis, which can lead to cellular senescence. Type II pneumocytes, the progenitor cells of the alveolar epithelium, are particularly sensitive to these genetic defects. Their senescence disrupts alveolar regeneration and promotes fibrosis by the production of profibrotic mediators. Autosomal dominant PARN deficiency provides a model for understanding the molecular mechanisms underlying pulmonary fibrosis associated with monogenic defects in telomere homeostasis, and developing targeted therapies.