Vitamin D prevents experimental lung fibrosis and predicts survival in patients with idiopathic pulmonary fibrosis

Tzilas, Vasilios; Bouros, Evangelos; Barbayianni, Ilianna; Karampitsakos, Thodoris; Kourtidou, Sofia; Ntassiou, Maria; Ninou, Ioanna; Aidinis, Vassilis; Τzouvelekis, Αrgyris

doi:10.1016/j.pupt.2019.01.003

Cited by 71 publications

(59 citation statements)

References 58 publications

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“…Of interest, the reduced VDR levels detected in fibroblasts from damaged tissue of CD patients paralleled with an enhanced migration of these cells, and VD significantly prevented the enhanced migration. These observations, together with the significant correlations detected between the mRNA expression of VDR and MMP2 (positive) and α-SMA (negative), strongly support an anti-fibrotic effect of VD in intestinal tissue, previously reported in several other organs [35][36][37], and suggest a direct effect of this hormone on intestinal fibroblasts.…”

Section: Discussionsupporting

confidence: 88%

Diminished Vitamin D Receptor Protein Levels in Crohn’s Disease Fibroblasts: Effects of Vitamin D

et al. 2020

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Vitamin D (VD) deficiency has been associated to Crohn’s disease (CD) pathogenesis, and the exogenous administration of VD improves the course of the disease, but the mechanistic basis of these observations remains unknown. Vitamin D receptor (VDR) mediates most of the biological functions of this hormone, and we aim to analyze here the expression of VDR in intestinal tissue, epithelial cells, and fibroblasts from CD patients. The effects of VD on a fibroblast wound healing assay and murine intestinal fibrosis are also analyzed. Our data show diminished VDR protein levels in surgical resections and epithelial cells from CD patients. In intestinal fibroblasts isolated from damaged tissue of CD patients, we detected enhanced migration and decreased VDR expression compared with both fibroblasts from non-damaged tissue of the same CD patient or control fibroblasts. Treatment with VD increased VDR protein levels, avoided the accelerated migration in CD fibroblasts, and prevented murine intestinal fibrosis induced by the heterotopic transplant model. In conclusion, our study demonstrates diminished VDR protein levels associated with enhanced migration in intestinal fibroblasts from damaged tissue of CD patients. In these cells, VD accumulates VDR and normalizes migration, which supports that CD patients would benefit from the VD anti-fibrotic therapeutic value that we demonstrate in a murine experimental model.

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Section: Discussionsupporting

confidence: 88%

Diminished Vitamin D Receptor Protein Levels in Crohn’s Disease Fibroblasts: Effects of Vitamin D

et al. 2020

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“…A preventive role of vitamin D has also been demonstrated in DM1. In this autoimmune disease using calcitriol supplementation reduces serum levels of antibodies and slows the progression of β cell destruction down in the early stages of the disease [38], Interestingly, it has also been demonstrated that in Systemic Sclerosis (SSc) [39] the VDR could act as a negative regulator of TGF-β/ Hydroxyproline, col1a1, col3a1 and alfa-SMA mRNAs ↓ Prevention of bleomycin-induced lung fibrosis in a murine model [48] Smad signaling, thus making vitamin D a putative antifibrotic treatment in the early stages of the disease. Although the immunoregulatory function of activated vitamin D has been widely demonstrated, its role in modulating disease activity in patients with autoimmune diseases, such as rheumatoid arthritis was only recently showed [40,41].…”

Section: Vitamin D In Autoimmune Diseasesmentioning

confidence: 99%

“…Recently, it has been demonstrated that high levels of vitamin D (directly activated by respiratory tract cells through CYP27B1) could reduce pulmonary fibrosis by decreasing the levels of pro-inflammatory cytokines (IL-1 beta) produced by pulmonary fibroblast cell lines in a mouse model of bleomycin-induced lung fibrosis [47]. In another study vitamin D administration prevented bleomycin-induced lung fibrosis in mice, by decreasing the levels of hydroxyproline and col1a1, col3a1, and alfa-SMA mRNAs [48]. In the same study, pretreatment with vitamin D reduced profibrotic stimuli and restored TGFB1-induced downregulation of VDR mRNA levels.…”

Section: Vitamin D and Pulmonary Fibrosismentioning

confidence: 99%

Possible role of vitamin D in Covid-19 infection in pediatric population

Panfili

Roversi

D’Argenio

et al. 2020

J Endocrinol Invest

122

116

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Purpose Covid-19 is a pandemic of unprecedented proportion, whose understanding and management is still under way. In the emergency setting new or available therapies to contrast the spread of COVID-19 are urgently needed. Elderly males, especially those affected by previous diseases or with comorbidities, are more prone to develop interstitial pneumonia that can deteriorate evolving to ARDS (acute respiratory distress syndrome) that require hospitalization in Intensive Care Units (ICUs). Even children and young patients are not spared by SARS-CoV 2 infection, yet they seem to develop a milder form of disease. In this setting the immunomodulatory role of Vitamin D, should be further investigated. Methods: We reviewed the literature about the immunomodulatory role of Vitamin D collecting data from the databases Medline and Embase. Results Vitamin D proved to interact both with the innate immune system, by activating Toll-like receptors (TLRs) or increasing the levels of cathelicidins and β-defensins, and adaptive immune system, by reducing immunoglobulin secretion by plasma cells and pro-inflammatory cytokines production, thus modulating T cells function. Promising results have been extensively described as regards the supplementation of vitamin D in respiratory tract infections, autoimmune diseases and even pulmonary fibrosis. Conclusions In this review, we suggest that vitamin D supplementation might play a role in the prevention and/or treatment to SARS-CoV-2 infection disease, by modulating the immune response to the virus both in the adult and pediatric population.

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“…Although evidence is limited, we can speculate that levels of 1,25(OH) 2 D and responses are also affected by disease-associated factors in mesenchymal cells that are present in the lung mucosa. One study that showed in a bleomycin fibrosis model and in primary lung mouse fibroblasts that TGF-β1 reduced expression of the VDR might support this assumption (88). It is currently insufficiently studied whether exposures to disease-associated factors promote or impair levels of 1,25(OH) 2 D and responses in immune-, mesenchymal and epithelial cells combined to give a better reflection of the in vivo situation.…”

Section: Lung Mucosamentioning

confidence: 99%

“…There are indications that 1,25(OH) 2 D counteracts various pathways leading to EMT. In mouse models and in airway epithelial cell lines, vitamin D supplementation and 1,25(OH) 2 D, respectively, has been shown to inhibit EMT and fibrosis, in particular when this process is induced by TGF-β1 (88,(103)(104)(105)(106).…”

Section: Anti-fibrotic Effects Of Vitamin Dmentioning

confidence: 99%

Impact of the Local Inflammatory Environment on Mucosal Vitamin D Metabolism and Signaling in Chronic Inflammatory Lung Diseases

2020

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Vitamin D plays an active role in the modulation of innate and adaptive immune responses as well as in the protection against respiratory pathogens. Evidence for this immunomodulatory and protective role is derived from observational studies showing an association between vitamin D deficiency, chronic airway diseases and respiratory infections, and is supported by a range of experimental studies using cell culture and animal models. Furthermore, recent intervention studies have now shown that vitamin D supplementation reduces exacerbation rates in vitamin D-deficient patients with chronic obstructive pulmonary disease (COPD) or asthma and decreases the incidence of acute respiratory tract infections. The active vitamin D metabolite, 1,25-dihydroxy-vitamin D (1,25(OH) 2 D), is known to contribute to the integrity of the mucosal barrier, promote killing of pathogens (via the induction of antimicrobial peptides), and to modulate inflammation and immune responses. These mechanisms may partly explain its protective role against infections and exacerbations in COPD and asthma patients. The respiratory mucosa is an important site of local 1,25(OH) 2 D synthesis, degradation and signaling, a process that can be affected by exposure to inflammatory mediators. As a consequence, mucosal inflammation and other disease-associated factors, as observed in e.g., COPD and asthma, may modulate the protective actions of 1,25(OH) 2 D. Here, we discuss the potential consequences of various disease-associated processes such as inflammation and exposure to pathogens and inhaled toxicants on vitamin D metabolism and local responses to 1,25(OH) 2 D in both immune-and epithelial cells. We furthermore discuss potential consequences of disturbed local levels of 25(OH)D and 1,25(OH) 2 D for chronic lung diseases. Additional insight into the relationship between disease-associated mechanisms and local effects of 1,25(OH) 2 D is expected to contribute to the design of future strategies aimed at improving local levels of 1,25(OH) 2 D and signaling in chronic inflammatory lung diseases.

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Vitamin D prevents experimental lung fibrosis and predicts survival in patients with idiopathic pulmonary fibrosis

Cited by 71 publications

References 58 publications

Diminished Vitamin D Receptor Protein Levels in Crohn’s Disease Fibroblasts: Effects of Vitamin D

Diminished Vitamin D Receptor Protein Levels in Crohn’s Disease Fibroblasts: Effects of Vitamin D

Possible role of vitamin D in Covid-19 infection in pediatric population

Impact of the Local Inflammatory Environment on Mucosal Vitamin D Metabolism and Signaling in Chronic Inflammatory Lung Diseases

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