Vitamin D High Doses Supplementation Could Represent A Promising ...

Anti-inflammatory and antioxidant actions of vitamin D at lung level

Lung epithelial cells have high expression of the 1-α-hydroxylase enzyme, which allows local synthesis of 1,25-dihydroxyvitamin D, the most active form of vitamin D, also called calcitriol. Calcitriol inhibits the production and secretion of many cytokines from bronchial smooth muscle cells, such as platelet-derived growth factor, RANTES (regulated on activation, normal T cell expressed and secreted) and matrix metalloproteinases, leading to a reduction in proliferation and inflammation in lung smooth muscle cells. Vitamin D stimulates the synthesis of IL-10 by CD4+, CD25+, Foxp3+ and T-regulatory cells. At the same time, it inhibits the activation of dendritic cells by negatively regulating the expression of CD80/86 and CD40. Furthermore, and as previously mentioned, vitamin D stimulates the expression of cathelicidin and many other anti-infectious molecules.34, 35

Supplementation with 1,25-dihydroxyvitamin D suppresses the recruitment of eosinophils and lymphocytes in the airways, decreases the production of IL-4 from the T cells and inhibits the migration of T cells by attenuating the inflammatory response.36 It also works as an adjuvant to other therapies, such as allergen immunotherapy.37 Simultaneous administration of vitamin D and dexamethasone in steroid-resistant asthma patients increased IL-10 synthesis to levels similar to those found in steroid-sensitive patients treated with dexamethasone alone.38

Significant reductions in serum IgE and eotaxin levels have also been described in an asthma model by treatment with vitamin D.39 In addition, airway infiltration of inflammatory cells, serum levels of IL-6, TNF-α and IL-1β, as well as expression of apoptotic protein associated with Bcl2, caspase-3, TLR4, NF-κB and phosphorylated NF-κB p65 were reduced. Thus, vitamin D raised serum levels of IL-10, reducing the inflammatory and apoptotic response in that asthmatic mouse model.40 Of interest, vitamin D suppressed the synthesis of 8-isoprostane (8-iso), IL-6 and granulocyte colony-stimulating factor and macrophages in human bronchial epithelial cells exposed to contaminating particles. In addition, it increased expression of the antioxidant pathway gene G6PD and levels of oxidised glutathione, and therefore it is inferred that vitamin D appears to protect the lungs and airways in asthmatic pathology through its anti-inflammatory and antioxidant effects.41

In a murine model of bleomycin-induced lung inflammation, calcitriol reduced early lung inflammation by attenuating immune cell infiltration, suppressing inflammatory cytokine secretion, blocking nuclear translocation of nuclear factor kappa B (NF-κB) p65, inhibiting phosphorylation of pulmonary p38 MAPK and protein kinase B (Akt), attenuating alpha-smooth muscle actin (a marker for epithelial-mesenchymal transition in the lungs, which promotes fibrosis), and decreased phosphorylation of transforming growth factor beta 1 (TGF-β1) regulated by augmentation and Smad.42 Calcitriol also caused a 40% reduction in neutrophil recruitment to the lungs in an acute lung injury animal model. This anti-inflammatory effect of vitamin D could be mediated by inhibition of IL-8 secretion at the pulmonary level.43

The administration of vitamin D to neonatal rats with hyperoxia-induced lung injury (as a model of bronchopulmonary dysplasia) caused attenuation of this injury through several protective actions, such as preserving the integrity of the lung structure, decreasing inflammation by negatively regulating TLR4 activation, reducing extracellular matrix deposition and inhibiting lung cell apoptosis.44 Vitamin D has also been shown to have immunomodulatory and anti-inflammatory effects in the treatment of cystic fibrosis of the respiratory tract by reducing the expression of CD279 (PD-1) on CD4+ and CD8 + T cells. In addition, vitamin D decreased the frequency of CD8+ and mucosa-associated invariant T cells that co-express CD38 and human leucocyte antigen D activation markers. Therefore, treatment with vitamin D would prevent the progression of lung damage associated with cystic fibrosis of the airways.45

Oxidative stress caused by tobacco smoke worsens the progression of chronic obstructive pulmonary disease (COPD). In this regard, vitamin D has also been proposed as a natural anti-inflammatory and antioxidant capable of improving the prognosis of this lung disease in patients who smoke.46 In fact, it has been observed that COPD patients have lower plasma levels of vitamin D than healthy patients, suggesting a possible correlation between poor antioxidant defence and the development of this lung disease.47 Of central interest to this review paper, some years ago our group raised for discussion a global pandemic of vitamin D deficiency as a possible explanation for the high cellular inflammatory activity induced by the RAAS.1 The original discussion involved a significant number of diseases, mainly cardiovascular, but all with a similar inflammatory basis. Now, with the focus on acute lung inflammation caused by COVID-19, the Irish Longitudinal Study on Ageing (TILDA 2020) reinforces the idea that appropriate supplementation of vitamin D, especially in older people, may be beneficial to the population of vulnerable groups during this COVID-19 pandemic.48 In this sense, vitamin D inhibits Skp2 protein, which plays a central role in the viral replication mechanism of COVID1949 and uses autophagy blockage for its accelerated replication and infectivity. The virus induces the abovementioned Skp2, which in turn inactivates Beclin-1, an essential component of the autophagy process (Fig. 1 ).

Open in a separate windowFigure 1

The figure gives a simple summary of the main pathways involved in the clinical progression at lung level of positive COVID-19 patients, its correlation with ACE/ACE2 receptors, and how their decoupling would determine a poor outcome at lung level. Furthermore, both RAAS blockage and vitamin D implementation are outlined, highlighting the potential impact of vitamin D on the restoration of signalling pathways and possible improved pulmonary clinical outcomes for COVID-19 positive patients.