A role for telomere length and chromosomal damage in idiopathic pulmonary fibrosis

Respiratory Research

Dries S. Martens¹  Tim S. Nawrot¹  Karen Maes²  Geert M. Verleden²  Stijn E. Verleden²  Wim A. Wuyts²  John E. McDonough²  Bart M. Vanaudenaerde²  Farida Ahangari³  Naftali Kaminski³  Naoya Tanabe⁴  James C. Hogg⁴ 

[1] Centre for Environmental Sciences, Hasselt University;Laboratory of Respiratory Diseases, Department of Chronic Diseases, Metabolism, and Ageing, KU Leuven;Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University;University of British Columbia, Centre for Heart Lung Innovation;

关键词: IPF;    Telomere length;    Gamma-H2AX;    Fibrosis;    Collagen 1;    Elastin;   

DOI  :  10.1186/s12931-018-0838-4

来源: DOAJ

【 摘 要 】

Abstract Background Idiopathic pulmonary fibrosis is a fatal lung disease characterized by a progressive formation of fibroblastic foci in the interstitium. This disease is strongly associated with telomere dysfunction but the extent of telomere shortening and consequent chromosomal damage within IPF lungs and with regional disease severity remains unknown. Methods Explanted IPF lungs (n = 10) were collected from transplant surgeries with six samples per lung analysed to capture the regional heterogeneity ranging from mild to severe disease. Non-used donor lungs (n = 6) were collected as “healthy” controls. Structural changes related to disease severity (microCT surface density), relative telomere length (real-time qPCR), and quantitative histology of chromosomal damage (γ-H2A.X) and extracellular matrix (elastin, total collagen, collagen 1, and collagen 3) were measured. A multivariate linear mixed-effects model controlling for subject was used to identify association of disease severity or fibrotic markers with telomere length and chromosomal damage. Results We observed shorter telomere length (p = 0.001) and increased chromosomal damage (p = 0.018) in IPF lungs compared to controls. In IPF lungs, telomere length was associated with total collagen (p < 0.001) but not with structural changes of disease severity. Chromosomal damage was positively associated with increased elastin (p = 0.006) and negatively with structural disease severity (p = 0.046). Extensive γ-H2A.X staining was also present in airway epithelial cells. Conclusions Telomere length and chromosomal damage are involved in IPF with regional variation in telomere length and chromosomal damage associated with pathological changes in tissue structure and the extracellular matrix.

【 授权许可】

Unknown