Telomere shortening and fibrotic remodeling in progressive fibrosing interstitial lung disease

Abstract

This summarizing discussion further addresses the question how telomere shortening is associated with IPF and other PF-ILDs at multiple levels, and the consequences of these findings for our understanding of pulmonary complications in short telomere syndromes. We have shown that at the organ level, average telomere length was most strongly declined in the lungs of patients with pulmonary fibrosis, compared to other organs. Within the lung, average telomere length did not differ between upper and lower lobes, or between diagnostic biopsies and explant lungs over time. At the cellular level, however, AT2 cells had significantly shorter telomeres than surrounding cells, such as club cells and myofibroblasts. Furthermore, AT2 cells in fibrotic areas had significantly shorter telomeres than AT2 cells in non-fibrotic areas. Next, at the patient level, approximately half of IPF patients showed excessive lung telomere shortening similar to that in pulmonary fibrosis driven by known telomerase mutations. In this “IPF short group” we found three cases with a genetic mutation in a telomere-related gene, which explains the disease. In these cases the “I” was removed from IPF. In addition to the above findings regarding short telomeres, we also found elevated levels of DNA damage in AT2 cells of IPF and TERT-PF lungs. Since critically short telomeres are recognized as DNA double-strand breaks and initiate pro-fibrotic DNA damage responses, the AT2 cell-specific DNA damage signals further substantiates the importance of this cell type in IPF/TERT-PF lungs. Interestingly, we did not find excessively short telomeres in fHP, another PF-ILD. Remarkably, however, also in these cases DNA damage levels in club cells were extremely high, corresponding to the bronchiolocentric localization of this disease. Lastly, in histological slides of diagnostic lung biopsies we found no significant difference in fibrotic and inflammatory features between sporadic IPF and familial IPF due to a SFTP- or TERT mutations. It was the degree of fibrosis, rather than inflammation, which correlated with survival, supporting the view that fibrogenesis is the most essential mechanism to be targeted in FPF. The following paragraphs further discuss our results in the context of the available literature, leading to the concept that malfunction of AT2 cells due to telomere shortening is the main driver of disease in PF-ILD. Furthermore, we postulate that also in 50 percent of IPF cases telomere shortening is the initial defect, causing maladaptive wound healing and repair response to injury with extensive deposition of extracellular matrix (ECM) proteins and fibrosis.