From Organ to Cell: Multi-level Telomere Assessment in Patients with Idiopathic Pulmonary Fibrosis
Cellular and molecular mechanisms (English)Rationale: A subset of Idiopathic pulmonary fibrosis (IPF) cases contain short leukocyte telomeres or telomere related mutations. It is therefore thought that telomere shortening contribute to disease development in a subgroup of patients with IPF.
Objectives: To better understand how telomere shortening affects patients with IPF and determine a subset of IPF patients with a telomere syndrome.
Methods: telomere length was determined in multiple organs, peripheral blood leukocytes, basal and apical lung, diagnostic and end-stage lung, and in alveolar type 2 cells in fibrotic and non-fibrotic areas of IPF lungs.
Results: In IPF but not in controls, telomere length in lung was shorter than in kidney, thyroid, liver and bladder tissue. No difference in telomere length was found between diagnostic and explant lung or between basal and apical lung, irrespective of the presence of a radiological apicobasal gradient. 13 out of 28 IPF patients had lung telomere length comparable to patients with a telomerase (TERT) mutation. Only in this IPFshort and TERT group we found that telomeres of alveolar type 2 cells in fibrotic areas were significantly shorter than in non-fibrotic areas. Additionally, whole exome sequencing of all IPF cases revealed two genetic variations in RTEL1 and one in PARN in the IPFshort group.
Conclusions: In IPF, organ telomere length is shortest in lung and independent of lung localization or disease duration. Excessive lung telomere shortening is present in approximately half of IPF patients and associates with short alveolar type 2 cell telomeres in fibrotic areas and telomere related mutations.