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Vitamin D, an Ally in the Treatment of Asthma

September 6, 2018 By Helly Bartolome Hernandez Marin, M.D

Vitamin D exerts various functions throughout the body including the immune system. This vitamin is synthesized in the skin when exposed to sunlight. The wide use of sunscreen, a characteristic of modern life, would partly explain the increase in the prevalence of vitamin D insufficiency.

Multiple epidemiological studies have shown strong associations between asthma and reduced serum levels of 25-hydroxyvitamin D (25 [OH] D), the main precursor in the circulation of vitamin D.

More severe asthma has been observed in patients with low vitamin D levels, but it is unknown at this time whether the linkages express causality or inverse causality. It is possible that the association between asthma and vitamin D is complex. The information as a whole supports the therapeutic role of vitamin D in reducing the risk of asthma exacerbations.

In the Childhood Asthma Management Program, an association was observed between baseline vitamin D insufficiency (<30 ng / ml) and the risk of severe exacerbations over four years.

Asthma triggered by allergens

The asthmatic inflammation was essentially due to immunological reactions in response to aeroallergens. In this situation, T-helper lymphocytes phenotype 2 (Th2), B lymphocytes (producers of antibodies) and mast cells have a fundamental role.

Th2 lymphocytes synthesize various interleukins (IL), such as IL-4, IL-5, and IL-13, involved in the etiopathogenesis of asthma. IL-4, in particular, induces the synthesis of immunoglobulin (Ig) E by B lymphocytes.

IgE binds to mast cells, and cross-linking induces rapid release of proinflammatory mediators such as leukotrienes and histamine, which cause bronchial obstruction and mucus production.

Adaptive immune responses are regulated by various classes of regulatory T lymphocytes (Treg), for example, Foxp3 positive Treg lymphocytes and Treg lymphocytes that synthesize IL-10. In healthy subjects, both lymphocyte subpopulations participate in the emergence of tolerance towards non-harmful antigens.

Vitamin D plays a decisive role in the function of responses mediated by Treg lymphocytes. In several studies, it has been observed that vitamin D is favorably associated with the frequency of Foxp3 positive Treg lymphocytes and with the levels of IL-10 in the airways of patients with asthma.

Likewise, the stimulation and the signals derived from dendritic cells (DC) determine the induction of tolerance or the appearance of inflammatory responses; Vitamin D regulates multiple functions of DC.

In vitro, vitamin D suppresses the synthesis of IgE by B lymphocytes and increases the synthesis of IL-10 with induction of a regulatory B phenotype. In children, vitamin D deficiency is associated with increased levels of specific IgE against aeroallergens.

Vitamin D inhibits the activation of mast cells so that it reduces the synthesis of histamine and tumor necrosis factor alpha; it can also increase the production of IL-10 with anti-inflammatory properties.

Epithelial damage and asthmatic inflammation mediated by cytokines

The epithelial damage is accompanied by the release of IL-25, IL-33, and thymic stromal lymphopoietin, which directly stimulate various cell subtypes, including innate lymphoid cells type 2 (ILC2) and mast cells. ILC2 synthesize Th2-type cytokines, for example, IL-5, which induce eosinophilic inflammation.

Vitamin D modulates the epithelial response, especially by inducing synthesis in bronchial epithelial cells of soluble ST2, a suppressor of IL-33, associated with proinflammatory effects on effector cells, such as mast cells.

Viral infections induce the epithelial release of IL-33; in asthma, the mechanisms dependent on the Th2 phenotype alter the antiviral responses. Vitamin D is associated with increased immunological antimicrobial responses, through various mechanisms, including the increased production of antimicrobial peptides, such as cathelicidin, and autophagy, an important mechanism in viral and bacterial infections.

In a meta-analysis, the intake of vitamin D reduced the incidence of acute respiratory tract infections in selected patients with asthma.

Asthma resistant to steroids and IL-17

The physiopathological mechanisms involved in corticosteroid-resistant asthma would be somewhat different. The colonization of the airways with proinflammatory bacteria such as Haemophilusinfluenzae, oxidative stress (associated with air pollution) and vitamin D deficiency would play an important role in this type of asthma. Vitamin D increases the antimicrobial pathways and induces antioxidant responses.

Patients with asthma resistant to corticosteroids synthesize less IL-10. In these patients, the contribution of calcitriol is associated with the recovery of the clinical and immunological response of IL-10. Likewise, in patients with asthma resistant to corticosteroids, IL-17 would induce pathological neutrophilic inflammation, a phenomenon that reverts after the administration of vitamin D.

Vitamin D and remodeling of the airways

The final result of the abnormal immunological responses in asthma is the remodeling of the airways, associated with smooth muscle contraction and mucus secretion in the short term, and with remodeling and fibrosis in the long term. Vitamin D prevents the proliferation of smooth muscle cells in the airways.

Clinical data on the use of vitamin D for the treatment of asthma

In the study, Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma (VIDA), showed that for every 10 ng / ml increase in serum levels of 25 (OH) D, the rate of therapeutic failures and exacerbations was reduced in a meaningful way.

Although the rate of asthma exacerbations did not decrease significantly in the total group assigned to vitamin D therapy, the exploratory analysis revealed a significant decrease in the frequency of exacerbations in the group of patients who reached levels of 25 (OH ) D3 ≥ 30 ng/ml.

In multiple investigations and Meta-analyses, it was observed that vitamin D supplements substantially decreased the rate of severe asthmatic exacerbations in patients with asthma.

With the exception of asthma resistant to corticosteroids, the different asthma endotypes have not been studied in detail in controlled clinical studies. Although more work will undoubtedly be required to answer these questions, the information as a whole suggests that the optimal state of vitamin D is important regarding the appearance and clinical evolution of asthma.

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