Abstract
BackgroundIdiopathic 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.MethodsExplanted 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.ResultsWe 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.ConclusionsTelomere 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.
Highlights
Idiopathic pulmonary fibrosis is a fatal lung disease characterized by a progressive formation of fibroblastic foci in the interstitium
Loss of normal parenchymal structures in Idiopathic pulmonary fibrosis (IPF) was seen as decreased surface density in IPF compared to control. (Figure 1a) PCR based measurement of telomere length demonstrated a ~ 27% reduction in relative telomere length (RTL) in IPF lungs compared to controls. (Figure 1b) Immunostaining of γ-H2A.X showed a 3-fold increase in tissue fraction stained in IPF compared to controls. (Figure 1c) Increased markers of fibrosis were present in IPF compared to control lungs as would be expected
Despite chromosomal damage being one of the consequences of telomere shortening, we found no correlation between regional measurements of RTL with γ-H2A.X in the IPF group (p = 0.95, r = 0.01). (Figure 2a) Multivariate linear mixed-effects models correlated surface density with γ-H2A.X (p = 0.046, r = − 0.35) (Fig. 2b) but not age-adjusted RTL (p = 0.40, r = − 0.06)
Summary
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. Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a median survival of 2 to 3 years after diagnosis and characterized by a restrictive respiratory function failure caused by formation of fibrotic foci within the lung interstitium [1]. Despite the significance of telomeres in IPF, few studies has directly measured telomere length in the lungs [6, 11]. The most recent of these studies found sporadic IPF subjects had shortened telomere lengths in AT2 cells in fibrotic regions compared to surrounding cells [11]
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