Detrimental pro-senescence effects of vitamin D on lung fibrosis

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.

Dual Effects of Hypoxia-Inducible Factors-1 Alpha in Bleomycin-Induced Pulmonary Fibrosis Treated by Human Umbilical Cord Mesenchymal Stem Cells

“…Therefore, the mechanism of pathogenesis of pulmonary fibrosis was investigated in bleomycin-induced A549 cells. In our results, the expression changes of cellular senescence marker γH2AFX, cell damage marker TP53BP1, and cell fibrosis marker α-SMA were consistent with the former studies of bleomycin on A549 cells [11]. Our results verified the protein expression of HIF-1α had a positive correlation with the content of ROS in A549 cells.…”

Effects of Hypocalcemic Vitamin D Analogs in the Expression of DNA Damage Induced in Minilungs from Hescs: Implications for Lung Fibrosis

“…DD foci are rapidly visualized as discrete foci in a pan-nuclear pattern (Figure 1A). As previously reported (10) , the exposure of A549 cells to vitamin D, in the presence of bleomycin, increased the levels of DD foci, both the percentage of damaged cells and the levels of severely damaged cells harboring more than 20 DD foci per nucleus (Figure 1B-D) (n=3; >150 cells were analyzed; P<0,001). However, the two hypocalcemic vitamin D analogs tested (paricalcitol and calcipotriol) were able to drastically reduce the bulk of DD expression compared to vitamin D in the presence of bleomycin (Figure 2C-D; n=3; >150 cells were analyzed; ANOVA P<0,001).…”

“…DSBs were also observed in cells throughout respiratory bronchioles or immersed in alveolar elds. The bulk of DNA damage was preferably associated to epithelial cells; broblasts, however seemed to be more resistant to DNA damage than epithelial cells (10). Senescence can be induced prematurely as a result of a persistent DNA damage response (DDR) secondary to oxidative stress that induces double-strand breaks DSBs (11).…”

Effect and mechanism of vitamin D activation disorder on liver fibrosis in biliary atresia

“…VDR is a member of the nuclear receptor superfamily, and its classical biological effects are mainly to maintain calcium homeostasis and calcium deposition in bone. In recent years, vitamin D has been found to have antifibrotic effects in lung, kidney and other tissues 13 – 18 . VDR is not expressed in liver tissue, so the role of vitamin D in liver fibrosis has not been studied in depth for a long time.…”