Abstract
BackgroundThe multiple biological effects of vitamin D and its novel activities on inflammation and redox homeostasis have raised high expectations on its use as a therapeutic agent for multiple fibrogenic conditions. We have assessed the therapeutic effects of 1α,25-Dihydroxyvitamin D3, the biologically active form of vitamin D, in the context of lung fibrosis.MethodsWe have used representative cellular models for alveolar type II cells and human myofibroblasts. The extension of DNA damage and cellular senescence have been assessed by immunofluorescence, western-blot and senescence-associated β-galactosidase activity. We have also set up a murine model for lung fibrosis by intraperitoneal injections of bleomycin.ResultsVitamin D induces cellular senescence in bleomycin-treated alveolar epithelial type II cells and aggravates the lung pathology induced by bleomycin. These effects are probably due to an alteration of the cellular DNA double-strand breaks repair in bleomycin-treated cells.ConclusionsThe detrimental effects of vitamin D in the presence of a DNA damaging agent might preclude its use as an antifibrogenic agent for pulmonary fibrosis characterized by DNA damage occurrence and cellular senescence.
Highlights
Vitamin D is a hydrophobic secosteroid involved in the homeostasis of calcium, magnesium, iron, phosphate and zinc
Effects of vitamin D and bleomycin in A549 cells and human lung fibroblasts Effects of vitamin D in A549 cells [alveolar type II cells (ATII)] A549 cells express the vitamin D receptor (VDR), which is overexpressed in the presence of 1α, 25-Dihydroxyvitamin D3, vitamin D on (Fig. 1a)
The treatment of A549 cells with 25 μg/mL of bleomycin for 48 h induced a drastic expression of DNA damage (DD) foci containing Tumor protein p53 binding protein 1 (TP53BP1), a reliable marker of DNA double-strand breaks (DSBs) (Zambrano et al 2014) (Fig. 1c)
Summary
Vitamin D is a hydrophobic secosteroid involved in the homeostasis of calcium, magnesium, iron, phosphate and zinc. Besides its role on mineral metabolism, vitamin D regulates some chronic conditions including autoimmune, cardiovascular and respiratory diseases (Finklea et al 2011). Vitamin D and its analogs are active in the regulation of fibrosis that characterizes multiple chronic diseases such as renal, cardiac, liver or pulmonary fibrosis (Ding et al 2013; Ito et al 2013; Meredith et al 2015; Zhang et al 2015). The multiple biological effects of vitamin D and its novel activities on inflammation and redox homeostasis have raised high expectations on its use as a therapeutic agent for multiple fibrogenic conditions. We have assessed the therapeutic effects of 1α,25-Dihydroxyvitamin D3, the biologically active form of vitamin D, in the context of lung fibrosis
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