Current Respiratory Medicine Reviews - Volume 7, Issue 6, 2011

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There is evidence of an association between early life vitamin D insufficiency and future risk of developing asthma. Given the high prevalence of vitamin D insufficiency in women during pregnancy when developmental programming is occurring, this may be of critical public health importance. There are plausible biological mechanisms for an association. Vitamin D is the pro-hormone of calcitriol, a secosteroid hormone with widespread pleiotropic actions. It is a powerful immune modulator and has been shown in animal and in vitro work to have a role in early lung development. Calcitriol may influence lung development through expression of the vitamin D receptor on lung and immune cells, and through epigenetic mechanisms. If the association between early life vitamin D status and childhood respiratory disease is shown to be causal, then this could have significant implications for public health policy. This hypothesis is currently being tested in a number of prospective intervention trials. The aim of this article is to review the evidence that vitamin D status influences early lung development, with a focus on early life mechanisms.

There is a large body of literature suggesting that the recent increase in the incidence of childhood asthma might be associated with vitamin D deficiency during lung development. There are also strong experimental animal data showing that vitamin D is one of the local alveolar paracrine factors that spatiotemporally modulates perinatal pulmonary maturation. However, the mechanistic link between vitamin D deficiency during pregnancy and childhood asthma is not known. In this review, we demonstrate how perinatal vitamin D deficiency could mechanistically drive both the proximal and distal airways to a myogenic phenotype, molecularly and structurally, predisposing the offspring to asthma. More specifically, we will review how perinatal vitamin D deficiency results in an increased abundance of mesenchymal myofibroblasts, a feature that is highly consistent with the pathophysiology of asthma. We also provide evolutionary insights as to how vitamin D deficiency might (re)activate the atavistic host defense mechanisms that could precipitate a lung phenotype consistent with asthma. Since vitamin D deficiency seems to alter the normal homeostatic epithelialmesenchymal signaling pathways in the developing lung, it offers a distinct translational opportunity to prevent this process through targeted molecular manipulations. While we wait for the results of on-going trials of vitamin D supplementation during pregnancy to get some definitive answers on its role in the pathogenesis of childhood asthma, we advocate studies to discover new vitamin D analogs and/or metabolites with optimal respiratory effects and without any significant side effects.

Widespread vitamin D insufficiency and vitamin D supplementation (even low dose rickets prophylaxis) have been hypothesised as contributory factors to the recent increase in asthma. These hypotheses are supported by reports of immunomodulatory effects of vitamin D on antigen presenting cells, regulatory T cells and T-helper cells and evidence that vitamin D influences fetal lung differentiation and epithelial-mesenchymal function. Studies of vitamin D in animal models confirm complex effects of vitamin D on asthma immunopathogenesis. In humans a majority of epidemiological studies support the hypothesis that vitamin D insufficiency during pregnancy increases the likelihood of childhood wheeze and possibly asthma, although some studies do report the converse. In children and adults with asthma, reduced serum vitamin 25-hydroxyvitamin D levels have been associated with parameters of increased asthma severity. Clinical trials are underway addressing whether maternal vitamin D supplementation during pregnancy reduces the likelihood of childhood asthma and if there is a role for vitamin D supplementation in established asthma.

Chronic Obstructive Pulmonary Disease (COPD) is a debilitating disease affecting an estimated 3 million people in the United Kingdom. It is characterised by progressive and irreversible airway obstruction and lung parenchymal damage, and by multisystem involvement including skeletal muscle impairment, systemic inflammation, and an increased prevalence of osteoporosis, cardiovascular disease and lung cancer. Patients with COPD have reduced dietary intake of vitamin D, spend a reduced amount of time outdoors and have been shown to have lower levels of 25-hydroxyvitamin D (25[OH]D) than age-matched subjects without COPD. The active metabolite of vitamin D, 1,25-dihydoxyvitamin D (1,25[OH]2D), is a pleiotropic hormone with effects on lung development and function, the immune system and musculoskeletal function; vitamin D deficiency also associates with increased prevalence of cardiovascular disease and cancer. This article focuses on the evidence that vitamin D deficiency is highly prevalent in patients with COPD and reviews associations between vitamin D status and lung function, muscle function and risk of osteoporosis, cardiovascular disease and cancer. The potential pathological mechanisms which may be involved are also discussed.

Acute respiratory tract infections (ARTI) generate a major disease burden worldwide, disproportionately affecting the elderly and the very young. A growing body of evidence supports an important immunomodulatory function for the biologically active metabolite of vitamin D,1,25-dihydroxyvitamin D (1,25[OH]2D). Respiratory epithelial cells and leucocytes express both the vitamin D receptor and CYP27B1, the enzyme which converts 25-hydroxyvitamin D to 1,25(OH)2D. Observational and ecological studies report associations between inadequate vitamin D status and susceptibility to ARTI, and vitamin D deficiency has been proposed as the seasonal stimulus for influenza epidemics. In children, associations between profound vitamin D deficiency and susceptibility to lower respiratory tract infection have been reported in a variety of settings. In adults, particularly amongst those with asthma and COPD, inadequate vitamin D status has been reported to be associated with susceptibility to upper respiratory tract infection. Vitamin D supplementation trials for the prevention of ARTI report conflicting results. This may reflect variation in study populations and methodology, or factors such as genetic heterogeneity within the vitamin D metabolic or signalling pathways. Further trials of vitamin D supplementation in different settings, with measurement of participants' vitamin D status and evaluation of genetic factors which might modify the effect of vitamin D supplementation are needed.

Tuberculosis is a major global health problem: the World Health Organisation estimates that there were 9.4 million incident cases and 1.8 million deaths from the disease in 2008. The development of new agents to prevent acquisition or reactivation of latent Mycobacterium tuberculosis infection and to allow shortening of antimicrobial therapy regimens for active tuberculosis without loss of efficacy is a research priority. In this article we describe the immunomodulatory actions of vitamin D metabolites in mycobacterial infection and review the growing body of evidence from observational and intervention studies suggesting that vitamin D might have a role in the prevention and treatment of TB.

Lung cancer is one of the most common cancers but treatment has limited success and survival rates remain low. The active metabolite of vitamin D, 1,25-dihydroxyvitamin D, has anti-proliferative and pro-apoptotic actions in lung carcinoma cell lines in vitro. Vitamin D deficiency is associated with poor prognosis in lung cancer, and lung cancer survival varies according to vitamin D receptor genotype. Randomized controlled trials should be performed to determine whether vitamin D supplementation might have a role as an adjunct to conventional treatments for lung cancer.

The non-classical role for vitamin D in maintaining immune homeostasis has been recognised for 30 years. A definitive link between vitamin D status and the immune response has now been established by a multitude of association studies which link both vitamin D deficiency and genetic polymorphisms in vitamin D-related genes to susceptibility to respiratory diseases including tuberculosis, upper respiratory tract infection, chronic obstructive pulmonary disease (COPD), asthma and lung cancer. This review considers the mechanisms by which immune cells and lung epithelial cells respond to infection or injury by inducing intracellular metabolism of vitamin D. The effects of vitamin D metabolites on induction of phagocyte antimicrobial responses, modulation of DC maturation and T cell priming, skewing of the cytokine milieu towards a type 2 inflammatory response and promotion of regulatory T (Treg) cell development will also be described.

Cheyne-Stokes breathing/central sleep apnea (CSB/CSA) commonly occurs in patients with congestive heart failure. Although the clinical significance of this primarily nocturnal breathing disorder is not certain, several studies have reported an association with increased mortality, as well as physiologic and biochemical changes that may lead to further deterioration of cardiac function. Suppression of CSB/CSA can be difficult to achieve and a consistently effective therapeutic strategy has not been identified. Optimizing medical management of the underlying heart failure is a logical initial intervention. In addition, positional therapy, oxygen, carbon dioxide, acetazolamide and theophylline have been associated with improvement of CSB/CSA in some patients. For patients with persistent CSB/CSA, nocturnal application of intrathoracic positive pressure via CPAP and BIPAP has sometimes been successful in attenuating CSB/CSA, but may not improve long-term survival. A newer technique, adaptive servo-ventilation that applies dynamic positive inspiratory pressure support in coordination with the patient's breathing pattern is promising, but more experience is needed to define the efficacy for attenuating CSB/CSA and long-term beneficial effects.

Strenuous exercise can cause significant changes in the concentration of several pro- and anti-inflammatory cytokines in healthy people, with wide ranging effects, but research evidence addressing this is limited in COPD. A systematic review was therefore undertaken to clarify whether acute exercise affects circulating inflammatory proteins in stable COPD. Computerised searches were conducted of The Cochrane Database of Systematic Reviews, EMBASE, CINAHL, OVID MEDLINE and NLM gateway to identify relevant articles up to July 2010. Ten published studies using various exercise modes to ascertain the impact of acute exercise tests on systemic inflammation in COPD were retained for the review. Six studies reported significant increases in inflammatory markers, of varying magnitude; four out of five maximal cycling studies reported increased IL-6/TNF-α. There was considerable variance in pre-test conditions/patient characterization, exercise protocols, and assay techniques. The findings indicate that exercise intensity and duration, body composition, individual immunity, hypoxaemia and blood sampling method possibly explain most variations between studies.