Hostname: page-component-78c5997874-s2hrs Total loading time: 0 Render date: 2024-11-10T12:13:19.358Z Has data issue: false hasContentIssue false
  • English
  • Français

Fat-soluble vitamins and atopic disease: what is the evidence?

Published online by Cambridge University Press:  25 November 2011

Augusto A. Litonjua
Augusto A. Litonjua*
Affiliation:
Channing Laboratory and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA
*
Corresponding author: Dr Augusto A. Litonjua, fax +1 617 525 0958, email augusto.litonjua@channing.harvard.edu
Rights & Permissions [Opens in a new window]

Abstract

The prevalence of asthma and other atopic disorders continues to increase worldwide. Examination of the epidemiologic patterns has revealed that this rise has occurred primarily in western, industrialised countries and countries transitioning to this lifestyle. While many changes have occurred in human populations over the years, it has been hypothesised that some of the relevant changes that have led to the rise in asthma and atopic disorders have been the changes from a traditional diet to a more western diet consisting of decreased intake of fruits and vegetables (sources of antioxidant vitamins and carotenoids) leading to decreased intakes of vitamins E and A, and a decrease in sun exposure (e.g. greater time spent indoors and heavy use of sunscreen) leading to decreased circulating levels of vitamin D. This review will examine the evidence for an effect of fat-soluble vitamins (vitamins A, D and K) on the development and severity of assthma and allergies. While observational studies suggest that these vitamins may play a salutary role in asthma and allergies, large, well-designed clinical trials are lacking. Of the fat-soluble vitamins, vitamin D holds great promise as an agent for primary and secondary prevention of disease. Ongoing clinical trials will help determine whether results of observational studies can be applied to the clinical setting.

Keywords

Vitamin EVitamin AVitamin DAsthmaEczemaAllergic rhinitis
Type
70th Anniversary Conference on ‘Vitamins in early development and healthy aging: impact on infectious and chronic disease’
Information
Proceedings of the Nutrition Society , Volume 71 , Issue 1 , February 2012 , pp. 67 - 74
Copyright
Copyright © The Author 2011

Abbreviations:
Th

T-helper

VDR

vitamin D receptor

Epidemiology of asthma and allergies

Asthma and allergies are common chronic diseases in industrialised countries( 1 – Reference Devereux 4 ). In the US, recent reports from national surveys show that the prevalence of asthma continues to rise in both children and adults, and in all racial and ethnic groups( 5 , Reference Moorman, Zahran and Truman 6 ). Recently, analyses have shown that asthma incurs substantial health care costs( Reference Barnett and Nurmagambetov 7 , Reference Sullivan, Ghushchyan and Slejko 8 ), with estimates approaching $56 billion. While data are not as detailed as that for asthma, other allergic disorders have also shown increases. Recent National Health and Nutrition Examination Survey data showed that close to half (42·5%) of the US population are atopic( Reference Gergen, Arbes and Calatroni 9 ) and both atopic dermatitis (eczema) and allergic rhinitis also incur significant healthcare costs( Reference Ellis, Drake and Prendergast 10 , Reference Malone, Lawson and Smith 11 ).

Asthma and allergies have also increased worldwide( Reference Masoli, Fabian and Holt 12 , Reference Flohr 13 ). An examination of these trends shows that the increases have been the greatest in industrialised countries and in those countries transitioning to a more industrialised lifestyle. Among the cited reasons for this pattern is a difference in diet from a more traditional diet rich in fruits and vegetables to a more ‘Western’ affluent diet rich in refined grains, red meats and saturated fats( Reference Flohr 13 – Reference Litonjua 16 ). The evidence for the effect of diet on asthma and allergies is accumulating, but is far from definitive. The purpose of this paper is to review the evidence for an effect of fat-soluble vitamins on asthma and allergies. There are no studies on vitamin K and asthma and allergies; thus, this review is limited to vitamins A, D and E.

Vitamin A and atopic diseases

Vitamin A comprises a group of compounds that play important roles in vision, bone growth, reproduction, cell division, cell differentiation and immune function( 17 – Reference Semba 20 ). In the diet, vitamin A comes in two forms, either preformed vitamin A (retinol) or pro-vitamin A carotenoid( 17 ). Preformed vitamin A comes from animal sources such as liver and whole milk, and from fortified foods. Pro-vitamin A carotenoid comes from plant sources in the forms of β-carotene, α-carotene, and β-cryptoxanthine.

Potential mechanisms of vitamin A in atopic diseases

Vitamin A may affect the risk for atopic disorders in two ways. Firstly, oxidative stress plays an important role in the pathogenesis of asthma and allergies( Reference Riedl and Nel 21 ) and the pro-vitamin A carotenoids exhibit antioxidant properties in vitro ( Reference Paiva and Russell 22 ); however, there remains some controversy as to whether they have antioxidant properties in human subjects( 23 ). Nevertheless, carotenoids have been investigated in conjunction with antioxidants in many human dietary studies of asthma and lung disease. Secondly, vitamin A has multiple modulatory effects on cells of the immune system (reviewed in Mora et al.( Reference Mora, Iwata and von Andrian 24 )), some of which may have relevance to asthma and allergy pathogenesis. Vitamin A has been shown to enhance proliferation( Reference Ertesvag, Engedal and Naderi 25 ) and prolong survival( Reference Engedal, Ertesvag and Blomhoff 26 ) of human T-cells, enhance dendritic cell maturation and antigen-presenting capacity( Reference Feng, Cong and Qin 27 , Reference Geissmann, Revy and Brousse 28 ), and promote differentiation of T-regulatory cells( Reference Benson, Pino-Lagos and Rosemblatt 29 , Reference Sun, Hall and Blank 30 ) while inhibiting T-helper (Th) 17 cells( Reference Mucida, Park and Kim 31 ). On the other hand, vitamin A has also been shown to promote the Th2 cell responses( Reference Lovett-Racke and Racke 32 , Reference Schuster, Kenyon and Stephensen 33 ), which are central to asthma and allergy pathogenesis.

Observational studies of vitamin A in atopic diseases

Multiple epidemiologic studies have evaluated the relationship between vitamin A (either by blood levels of constituents or estimation of intakes from food frequency questionnaires) and atopy, wheezing and asthma. Nurmatov et al.( Reference Nurmatov, Devereux and Sheikh 34 ) recently performed a review and meta-analysis of these studies and found about equal numbers of studies reporting either no association or a potentially beneficial effect. Two studies have investigated maternal intakes of carotenoids in pregnancy and neither found effects on either wheezing( Reference Litonjua, Rifas-Shiman and Ly 35 , Reference Martindale, McNeill and Devereux 36 ), asthma( Reference Martindale, McNeill and Devereux 36 ) or atopic dermatitis( Reference Litonjua, Rifas-Shiman and Ly 35 ) in young children.

Clinical trials of vitamin A supplementation in atopic diseases

There are no primary trials of vitamin A supplementation to prevent or manage atopic diseases. However, there have been secondary analyses of large trials of β-carotene in conjunction with antioxidants, and no effects were seen on wheezing symptoms, dypnea, lung function or asthma exacerbations( Reference Rautalahti, Virtamo and Haukka 37 ).

Vitamin E and atopic diseases

Vitamin E is a collection of fat-soluble compounds, found in many foods, that has distinctive antioxidant activities( 38 ). Naturally occurring vitamin E exists in eight chemical forms (α-, β-, γ- and δ-tocopherol and α-, β-, γ- and δ-tocotrienol), of which α-tocopherol has the greatest bioavailability and is the best characterised( Reference Singh and Devaraj 39 ). Foods that contain vitamin E include nuts (e.g. peanuts, hazelnuts and almonds) and seeds (e.g. sunflower seeds), green vegetables (e.g. spinach and broccoli) and vegetable oils( 38 ).

Potential mechanisms of vitamin E in atopic diseases

Vitamin E exerts its effects on the immune system by its antioxidant and anti-inflammatory properties (reviewed in Mora et al. ( Reference Mora, Iwata and von Andrian 24 ) and Pekmezci( Reference Pekmezci 40 )). Vitamin E has been shown to inhibit NF-κB pathways( Reference Morante, Sandoval and Gomez-Cabrera 41 , Reference Suzuki and Packer 42 ) and to prevent release of reactive oxygen species( Reference Jialal, Devaraj and Kaul 43 ) and pro-inflammatory cytokines, such as IL-1, IL-6 and TNF( Reference Singh and Devaraj 39 , Reference Devaraj and Jialal 44 , Reference Munteanu and Zingg 45 ). Vitamin E has been shown to inhibit the secretion and gene expression of IL-4, a central cytokine in the Th2 allergic inflammatory pathway, in human peripheral blood T-cells( Reference Li-Weber, Giaisi and Treiber 46 ), and to prevent the suppression of NRF2 (nuclear factor (erythroid-derived-2)-like 2)( Reference Dworski, Han and Blackwell 47 ), the master transcription factor regulating expression of phase II antioxidant and detoxifying enzymes. There is some human evidence that lower intakes of vitamin E in pregnancy heightened responses of cord blood mononuclear cells to antigen stimulation( Reference Devereux, Barker and Seaton 48 ). This finding needs to be confirmed in other studies and the implications for the development of asthma and atopic disease need to be clarified.

Observational studies of vitamin E in atopic diseases

As oxidative stress was recognised as contributing to the pathogenesis of asthma and allergies, the effect of dietary vitamin E and other antioxidants have been studied for many years. There have been numerous studies of vitamin E and asthma and allergy symptoms and biomarkers (reviewed in Litonjua( Reference Litonjua 16 ) and Romieu and Trenga( Reference Romieu and Trenga 49 )). While there have been inconsistencies, most studies have shown lower prevalence of wheezing, cough and shortness of breath in those with higher vitamin E intakes. These studies have also shown a higher lung function in those with higher vitamin E intakes. Others have shown a decreased risk for allergic sensitisation( Reference Sausenthaler, Loebel and Linseisen 50 ). Gao et al.( Reference Gao, Gao, Li and Zhu 51 ) performed a meta-analysis on the cross-sectional effect of vitamin E on asthma and found five studies of good quality; there was no effect of vitamin E intake on the risk for having asthma. On the other hand, in their meta-analysis, Nurmatov et al.( Reference Nurmatov, Devereux and Sheikh 34 ) found a significant protective effect of maternal vitamin E intake and wheezing in 2-year-old children.

Clinical trials of vitamin E supplementation in atopic diseases

Several clinical trials of vitamin E supplementation, either alone or in combination with other antioxidants, have been conducted in asthma. Pearson et al.( Reference Pearson, Lewis and Britton 52 ) randomised seventy-two adult asthmatics to either 500 mg vitamin E or placebo for 6 weeks. They did not find any effect of vitamin E on symptom scores, lung function, bronchodilator use or serum IgE levels. However, two other trials suggest that the effect of vitamin E may be seen only in the proper environmental context. Sienra-Monge et al.( Reference Sienra-Monge, Ramirez-Aguilar and Moreno-Macias 53 ) randomised 117 asthmatic children to either 50 mg/d vitamin E plus 250 mg/d vitamin C or placebo, for 4 months. The increase in concentration of the inflammatory cytokine, IL-6, from nasal lavages in response to ozone exposure was abrogated in the intervention group compared with the placebo group. Romieu et al.( Reference Romieu, Sienra-Monge and Ramirez-Aguilar 54 ), using the same dose of daily antioxidant vitamins as Sienra-Monge in 158 asthmatic children, also showed that antioxidant supplementation eliminated the lung function decrements associated with ozone exposure. These latter studies suggest that antioxidant supplementation dampens the inflammatory response to oxidant exposure in asthmatics. Finally, vitamin E supplementation (800 mg/d, compared with placebo, was found to lower nasal symptom scores in patients with seasonal allergic rhinitis( Reference Shahar, Hassoun and Pollack 55 ).

While there are no published primary clinical trials of vitamin E for asthma or allergy prevention, Greenough et al.( Reference Greenough, Shaheen and Shennan 56 ) performed a secondary analysis on 772 2-year-old children whose mothers had participated in a trial of vitamins E and C supplementation to prevent pre-eclampsia. They did not find any difference in the rates of asthma or eczema among the children from mothers in the intervention group v. placebo.

Vitamin D and atopic diseases

Vitamin D is both a nutrient and a hormone( Reference Holick 57 ). Vitamin D is found in only few foods that human subjects eat( Reference Lamberg-Allardt 58 ), and most vitamin D in the human diet is obtained from fortified foods and from supplements. This is likely because human subjects have the capability of producing vitamin D. 7-Dehydrocholesterol is distributed in the skin. After exposure to sunlight, 7-dehydrocholesterol is converted to pre-vitamin D3, which is then transformed to vitamin D3 by a thermally induced isomerisation. Vitamin D3 then undergoes hydroxylation in the liver to 25-hydroxyvitamin D and then in the kidney to its biologically active form 1,25-dihydroxyvitamin D3 ( Reference Holick 57 ). Serum 25-hydroxyvitamin D is the major circulating metabolite of vitamin D, reflects input from cutaneous synthesis and dietary intake, and measurement of levels is the standard measure of vitamin D status( Reference Hollis, Wagner and Drezner 59 ). The determinants of vitamin D status include exposure to the sun and time spent outdoors( Reference van der Mei, Blizzard and Ponsonby 60 , Reference Sahota, Barnett and Lesosky 61 ), diet and supplement use( Reference Sahota, Barnett and Lesosky 61 ), latitude, season, age, skin colour and skin coverage (i.e. clothing and sunblock use)( Reference Webb 62 ). There is controversy surrounding what is the desirable (or sufficient) level of circulating 25-hydroxyvitamin D. The recent Institute of Medicine report recommended that a level of 20 ng/ml should be considered sufficient( Reference Ross, Taylor, Yaktine and Del Valle 63 ). However, since these recommendations were primarily based on bone health, with the committee concluding that there was insufficient evidence to date to make recommendations for other conditions, these recommendations were thought by some to be too low( Reference Heaney and Holick 64 ).

Vitamin D deficiency has been documented in many populations worldwide( Reference Holick 65 , Reference Nesby-O'Dell, Scanlon and Cogswell 66 ). Vitamin D deficiency has occurred despite fortification of foods in some westernised countries and despite intake of multivitamins containing vitamin D, due to the fact that intake from foods and regular multivitamins are insufficient to overcome the lack of exposure to sunlight. Deficiency has also been documented in areas of the world that are considered sun-replete, and this suggests that as countries adopt a western lifestyle, there is shift from outdoor activities to more time spent indoors. For example, it is estimated that in the US alone, Americans spend an average of 93% of their time indoors( 67 ).

Potential mechanisms

The idea of a link between vitamin D and asthma is not new. In 1934, Rappaport et al. reported on 212 patients with either hay fever or both asthma and hay fever who had undergone treatment with viosterol which contains irradiated or activated ergosterol( Reference Rappaport, Reed and Hathaway 68 ) (ergosterol is a plant-derived sterol that is converted to ergocalciferol (vitamin D2) on irradiation). The goal was to increase serum Ca levels and no direct effect of vitamin D was thought to occur. While the authors reported relief of symptoms in those patients treated with viosterol, they did not detect differences in levels of serum Ca among the patients. More recently, as the physiology of vitamin D and its pleiotropic effects have been elucidated, and with the advent of the ability to measure 25-hydroxyvitamin D levels and other vitamin D metabolites, various mechanisms for how vitamin D may play a role in the development and treatment of asthma have been uncovered.

Genetics

The vitamin D receptor (VDR) is a member of the steroid receptor superfamily. The gene maps to chromosome 12. Published associations between polymorphisms in the VDR gene with asthma have resulted in inconsistent results( Reference Poon, Laprise and Lemire 69 – Reference Wjst 73 ), More recently, it was shown that genetic variation in genes, other than VDR, involved in vitamin D metabolic and signalling pathways were preferentially transmitted to asthmatic children( Reference Wjst, Altmuller and Faus-Kessler 74 ).

Genetic studies have also been performed in animal models and human tissues in vitro. Studies in mouse models from one research group have shown that VDR knockout mice do not develop experimental asthma( Reference Wittke, Weaver and Mahon 75 ) and that expression of VDR is necessary for induction of lung inflammation( Reference Wittke, Chang and Froicu 76 ). On the other hand, Bossé et al. recently reported that VDR is present in human bronchial smooth muscle cells( Reference Bosse, Maghni and Hudson 77 ), and vitamin D regulates the expression of many genes, including genes from pathways of smooth muscle cell contraction, inflammation, as well as glucocorticoid and prostaglandin regulation.

In addition to the vitamin D pathway genes, many genes contain vitamin D responsive elements that may either up-regulate or down-regulate the expression of these genes( Reference Haussler, Haussler and Bartik 78 , Reference Dusso, Brown and Slatopolsky 79 ). For example, a recent study using chromatin immunoprecipitation followed by massively parallel DNA sequencing identified 2776 genomic positions occupied by the VDR after calcitriol stimulation; there were 229 genes with significant changes in expression in response to vitamin D( Reference Ramagopalan, Heger and Berlanga 80 ). Thus, the genetics of vitamin D in asthma is likely to be highly complex and far-reaching.

Infections

The role of infections in the inception of asthma continues to be debated. Respiratory viruses have been associated with the development of asthma( Reference Jackson, Gangnon and Evans 81 ). However, while the attack rate of respiratory viruses in early childhood is high, only a proportion of children go on to develop asthma as a consequence of these early-life infections. We have hypothesised that vitamin D status may, in part, determine who goes on to develop asthma and allergies after early-life viral respiratory infections( Reference Litonjua 82 ). Vitamin D induces the production of the antimicrobial polypeptide, cathelicidin( Reference Liu, Stenger and Tang 83 ), which has both bacterial and anti-viral effects( Reference Grant 84 , Reference Herr, Shaykhiev and Bals 85 ). Because of the effects of vitamin D on the immune system (reviewed later), it is plausible that a vitamin D-deficient state predisposes children to develop asthma after viral infections. This hypothesis will need to be tested in clinical trials of vitamin D supplementation with a collection of appropriate specimens for adequate viral identification.

Immune system effects

VDR( Reference Dickson 86 , Reference Minghetti and Norman 87 ) and vitamin D metabolic enzymes( Reference Holick 65 , Reference Akeno, Saikatsu and Kawane 88 ) have been identified in cells of the immune system, such as T( Reference Mahon, Wittke and Weaver 89 ), activated B-cells( Reference Heine, Anton and Henz 90 ) and dendritic cells( Reference Adorini, Penna and Giarratana 91 ). Several reviews have summarised the effects of vitamin D on immune function( Reference Mora, Iwata and von Andrian 24 , Reference Hewison 92 – Reference Bikle 94 ). Vitamin D has far-ranging effects on immune cells, including modulation of Th1 and Th2 responses, induction of T-regulatory cells, suppression of Th17 cells, and regulation of maturation of dendritic cells. Directly relevant to asthma, there is evidence that vitamin D may have a therapeutic role in steroid-resistance by enhancing responsiveness to glucocorticoids for induction of IL-10( Reference Xystrakis, Kusumakar and Boswell 95 ), and modulating human airway smooth muscle secretion of pro-inflammatory chemokines( Reference Banerjee, Damera and Bhandare 96 ). An additional role of vitamin D in allergic asthma may be to potentiate the effects of allergen immunotherapy. In a mouse model of allergic asthma, co-administration of 1α,25-dihydroxyvitamin D3 with allergen immunotherapy inhibited airway hyper-responsiveness and potentiated the reduction of ovalbumin-specific IgE levels, airway eosinophilia and Th2 cytokines( Reference Taher, van Esch and Hofman 97 ).

Effects on lung development and lung function

Lung development begins in utero and continues through the first few years of life (reviewed in Burri( Reference Burri 98 )). At the end of fetal lung development, the alveolar epithelium undergoes abrupt differentiation as part of the preparation for gas exchange after birth. Fetal pulmonary maturation includes the differentiation of type II pneumocytes, with progressive disappearance of glycogen and the start of surfactant synthesis. In rat models, vitamin D is important in lung maturation and surfactant production( Reference Marin, Dufour and Nguyen 99 – Reference Nguyen, Guillozo and Garabedian 103 ), and in human subjects, the effect of vitamin D on surfactant production has been confirmed( Reference Rehan, Torday and Peleg 104 ), although the mechanisms appear to be more complex than those in the rat( Reference Phokela, Peleg and Moya 105 ).

Apart from effects on type II pneumocytes and surfactant production, vitamin D also appears to have effects on lung growth and development, as shown in studies that have measured lung mechanics in both rats ( Reference Gaultier, Harf and Balmain 106 ) and mice( Reference Zosky, Berry and Elliot 107 ). In human subjects, vitamin D also has been shown to play a role in the developing lung. Lunghi et al.( Reference Lunghi, Meacci and Stio 108 ) obtained normal human fetal (16 weeks gestation) lung fibroblasts and reported that in the presence of vitamin D, pyruvate kinase activity and lactate production of the cells increased. Other findings included a decrease in cell number and DNA synthesis in the vitamin D exposed cells compared with control cells. Subsequently, they showed that the VDR was present in these human fetal fibroblasts( Reference Stio, Celli and Lunghi 109 ). Several large, general population-based studies have shown a positive relationship between vitamin D levels and lung function( Reference Black and Scragg 110 – Reference Tolppanen, Williams and Henderson 112 ). These findings have also been seen in asthmatic populations( Reference Li, Peng and Jiang 113 ). Other studies have found either associations with vitamin D intake but not circulating levels( Reference Shaheen, Jameson and Robinson 114 ) or no associations( Reference Cremers, Thijs and Penders 115 ).

Airway smooth muscle effects

Airway smooth muscle function is central in asthma pathogenesis. Vitamin D has been found to modulate inflammatory chemokines secreted by these airway smooth muscles( Reference Banerjee, Damera and Bhandare 96 ), and has been found to inhibit airway smooth muscle proliferation in asthmatic cells( Reference Damera, Fogle and Lim 116 ). Taken together, these findings suggest that vitamin D has salutary effects on airway obstruction by diminishing inflammation and decreasing airway remodelling that can lead to chronic, fixed airway obstruction.

Observational studies

Vitamin D and asthma development

Based on the effects of vitamin D on the developing immune system and the lung, it is possible that an adequate vitamin D status in pregnant mothers might prevent the development of asthma in children. Our group has reported protective effects of higher maternal dietary vitamin D intakes in pregnancy on wheezing phenotypes in young children in two separate cohorts( Reference Camargo, Rifas-Shiman and Litonjua 117 , Reference Devereux, Litonjua and Turner 118 ). These studies showed a 62 and 67% reduction in recurrent wheeze in young children born to mothers with the highest intakes of vitamin D. A third study from Finland on 1669 mother–child pairs has also shown a protective effect of higher maternal vitamin D intake on asthma in 5-year-old children( Reference Erkkola, Kaila and Nwaru 119 ). Additionally, this last study also found a protective effect of higher maternal vitamin D on allergic rhinitis. A fourth study from Japan has found similar effects( Reference Miyake, Sasaki and Tanaka 120 ). These studies are limited by the fact that vitamin D intake was calculated from FFQ (thus, no direct measure of vitamin D status in the mothers) and may be confounded by diet quality. However, all studies adjusted for total energy intake and for other nutrients associated with healthy diets.

Two other studies showed an adverse effect of vitamin D on asthma and allergies. A birth cohort from Northern Finland has shown that vitamin D supplementation in the first year of life increased the risk for atopy at 31 years of age( Reference Hypponen, Sovio and Wjst 121 ). However, this study did not assess maternal prenatal vitamin D status, did not assess childhood asthma or atopy, and did not have intervening measures of vitamin D status. A second study measured circulating vitamin D levels in pregnant women and reported that higher levels in pregnant women were associated with increased risks for eczema at 9 months and asthma at 9 years( Reference Gale, Robinson and Harvey 122 ). However, results were reported without adjustment for potential confounders, and there was significant loss to follow-up (61·8%) in the cohort at 9 years. A third study showed a protective effect of higher cord blood vitamin D levels and wheezing, but did not find an effect on incident asthma by 5 years of age( Reference Camargo, Ingham and Wickens 123 ). Thus, the question of whether adequate vitamin D status can prevent asthma remains controversial and two randomised clinical trials are under way to address the issue of primary prevention (http://www.ClinicalTrials.gov: NCT00920621 and NCT00856947).

While an adequate vitamin D status in pregnant mothers may protect against the development of asthma and allergies in the offspring, there are new data suggesting that there may be opportunities to intervene after birth. Hollams et al.( Reference Hill, Micklewright and Lewis 124 ) in a cohort of over 600 Australian children, showed that higher vitamin D levels at age 6 years were protective against the development of asthma, rhinoconjunctivitis and atopy at age 14 years.

Vitamin D, asthma exacerbations and severity of disease

Since vitamin D affects the risk of viral infections and these infections are a cause of asthma exacerbations, the question remains as to whether improving vitamin D status can decrease the risk of exacerbations. Our group showed that higher vitamin D levels were associated with decreased risks for severe asthma exacerbations in two asthma cohorts( Reference Brehm, Celedon and Soto-Quiros 125 , Reference Brehm, Schuemann and Fuhlbrigge 126 ). Furthermore, in asthmatics, vitamin D deficiency has also been associated with higher serum IgE( Reference Brehm, Celedon and Soto-Quiros 125 ), greater degrees of airway hyper-responsiveness( Reference Brehm, Celedon and Soto-Quiros 125 , Reference Sutherland, Goleva and Jackson 127 ), lower lung function( Reference Li, Peng and Jiang 113 , Reference Sutherland, Goleva and Jackson 127 ) and decreased responsiveness to glucocorticoids( Reference Brehm, Schuemann and Fuhlbrigge 126 – Reference Searing, Zhang and Murphy 128 ).

Clinical trials

Clinical trials of vitamin D supplementation as primary prevention for asthma and allergies are ongoing. A trial of vitamin D supplementation in Japanese school children showed a decrease in influenza A infections over a period of 6 months, although there was no difference in influenza B infections( Reference Urashima, Segawa and Okazaki 129 ). In the subset of children with asthma, secondary analyses found a reduction in the number of exacerbations among the children supplemented with vitamin D compared with placebo. In a small (n 48), 6-month clinical trial of children with newly diagnosed asthma( Reference Majak, Olszowiec-Chlebna and Smejda 130 ), asthma exacerbations were decreased in children supplemented with vitamin D compared with placebo, despite the fact that there were no significant differences in the overall levels of circulating vitamin D achieved in either group. Verification of these preliminary results will need to be seen in larger, well-designed clinical trials of asthmatics.

Conclusion

Multiple epidemiologic studies have suggested that fat-soluble vitamins may play a role in the pathogenesis of asthma and other allergic disorders. However, large, well-designed clinical trials are lacking. Of the fat-soluble vitamins, vitamin D holds great promise as an agent for primary and secondary prevention of disease. Ongoing clinical trials will help determine whether results of observational studies can be applied to the clinical setting.

Acknowledgements

The author declares no financial conflict of interest. The author is funded by a grant from the US National Institutes of Health (UO1 HL091528).

References

1. Global Initiative for Asthma Management and Prevention (1995) NHLBI/WHO Workshop Report. Publication No. 95-3659. Bethesda, MD: US Department of Health and Human Services, National Institutes of Health.Google Scholar
2. Masoli, M, Fabian, D, Holt, S et al. (2004). The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 59, 469–478.CrossRefGoogle Scholar
3. Mannino, DM, Homa, DM, Akinbami, LJ et al. (2002) Surveillance for asthma – United States, 1980–1999. MMWR Surveill Summ 51, 1–13.Google ScholarPubMed
4. Devereux, G (2003) The increase in allergic disease: environment and susceptibility. Proceedings of a symposium held at the Royal Society of Edinburgh, 4th June 2002. Clin Exp Allergy 33, 394–406.Google Scholar
5. Centers for Disease Control and Prevention (2011) Vital signs: asthma prevalence, disease characteristics, and self-management education: United States, 2001–2009. MMWR Morb Mortal Wkly Rep 60, 547–552.Google Scholar
6. Moorman, JE, Zahran, H, Truman, BI et al. (2011) Current asthma prevalence – United States, 2006–2008. MMWR Surveill Summ 60, 84–86.Google ScholarPubMed
7. Barnett, SB & Nurmagambetov, TA (2011) Costs of asthma in the United States: 2002–2007. J Allergy Clin Immunol 127, 145–152.CrossRefGoogle ScholarPubMed
8. Sullivan, PW, Ghushchyan, VH, Slejko, JF et al. (2011) The burden of adult asthma in the United States: evidence from the Medical Expenditure Panel Survey. J Allergy Clin Immunol 127, 363–369 e1–3.CrossRefGoogle ScholarPubMed
9. Gergen, PJ, Arbes, SJ Jr., Calatroni, A et al. (2009) Total IgE levels and asthma prevalence in the US population: results from the National Health and Nutrition Examination Survey 2005–2006. J Allergy Clin Immunol 124, 447–453.CrossRefGoogle ScholarPubMed
10. Ellis, CN, Drake, LA, Prendergast, MM et al. (2002) Cost of atopic dermatitis and eczema in the United States. J Am Acad Dermatol 46, 361–370.CrossRefGoogle ScholarPubMed
11. Malone, DC, Lawson, KA, Smith, DH et al. (1997) A cost of illness study of allergic rhinitis in the United States. J Allergy Clin Immunol 99, 22–27.Google ScholarPubMed
12. Masoli, M, Fabian, D, Holt, S et al. (2004) The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 59, 469–478.CrossRefGoogle ScholarPubMed
13. Flohr, C (2011) Recent perspectives on the global epidemiology of childhood eczema. Allergol Immunopathol (Madr) 39, 174–182.CrossRefGoogle ScholarPubMed
14. Devereux, G (2006) The increase in the prevalence of asthma and allergy: food for thought. Nat Rev Immunol 6, 869–874.CrossRefGoogle ScholarPubMed
15. Devereux, G & Seaton, A (2005) Diet as a risk factor for atopy and asthma. J Allergy Clin Immunol 115, 1109–1117.CrossRefGoogle ScholarPubMed
16. Litonjua, AA (2008) Dietary factors and the development of asthma. Immunol Allergy Clin North Am 28, 603–629, ix.CrossRefGoogle ScholarPubMed
17. Office of Dietary Supplements at the National Institutes of Health (2006) Dietary Supplement Fact Sheet: Vitamin A and Carotenoids. http://ods.od.nih.gov/factsheets/vitamina/ (updated 23 April 2006; cited 20 August 2011).Google Scholar
18. Gerster, H (1997) Vitamin A – functions, dietary requirements and safety in humans. Int J Vitam Nutr Res 67, 71–90.Google ScholarPubMed
19. Hinds, TS, West, WL & Knight, EM (1997) Carotenoids and retinoids: a review of research, clinical, and public health applications. J Clin Pharmacol 37, 551–558.CrossRefGoogle ScholarPubMed
20. Semba, RD (1998) The role of vitamin A and related retinoids in immune function. Nutr Rev 56, S38–S48.CrossRefGoogle ScholarPubMed
21. Riedl, MA & Nel, AE (2008) Importance of oxidative stress in the pathogenesis and treatment of asthma. Curr Opin Allergy Clin Immunol 8, 49–56.CrossRefGoogle ScholarPubMed
22. Paiva, SA & Russell, RM (1999) Beta-carotene and other carotenoids as antioxidants. J Am Coll Nutr 18, 426–433.CrossRefGoogle ScholarPubMed
23.Institute of Medicine (2000) Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids [National Academy of Sciences, Institute of Medicine, Food and Nutrition Board, editor]. Washington, DC: National Academy Press.Google Scholar
24. Mora, JR, Iwata, M & von Andrian, UH (2008) Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol 8, 685–698.CrossRefGoogle Scholar
25. Ertesvag, A, Engedal, N, Naderi, S et al. (2002) Retinoic acid stimulates the cell cycle machinery in normal T cells: involvement of retinoic acid receptor-mediated IL-2 secretion. J Immunol 169, 5555–5563.CrossRefGoogle ScholarPubMed
26. Engedal, N, Ertesvag, A & Blomhoff, HK (2004) Survival of activated human T lymphocytes is promoted by retinoic acid via induction of IL-2. Int Immunol 16, 443–453.CrossRefGoogle Scholar
27. Feng, T, Cong, Y, Qin, H et al. (2010) Generation of mucosal dendritic cells from bone marrow reveals a critical role of retinoic acid. J Immunol 185, 5915–5925.CrossRefGoogle ScholarPubMed
28. Geissmann, F, Revy, P, Brousse, N et al. (2003) Retinoids regulate survival and antigen presentation by immature dendritic cells. J Exp Med 198, 623–634.CrossRefGoogle ScholarPubMed
29. Benson, MJ, Pino-Lagos, K, Rosemblatt, M et al. (2007) All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med 204, 1765–1774.CrossRefGoogle ScholarPubMed
30. Sun, CM, Hall, JA, Blank, RB et al. (2007) Small intestine lamina propria dendritic cells promote de novo generation of Foxp3T reg cells via retinoic acid. J Exp Med 204, 1775–1785.CrossRefGoogle Scholar
31. Mucida, D, Park, Y, Kim, G et al. (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260.CrossRefGoogle ScholarPubMed
32. Lovett-Racke, AE & Racke, MK (2002) Retinoic acid promotes the development of Th2-like human myelin basic protein-reactive T cells. Cell Immunol 215, 54–60.CrossRefGoogle ScholarPubMed
33. Schuster, GU, Kenyon, NJ & Stephensen, CB (2008) Vitamin A deficiency decreases and high dietary vitamin A increases disease severity in the mouse model of asthma. J Immunol 180, 1834–1842.CrossRefGoogle ScholarPubMed
34. Nurmatov, U, Devereux, G & Sheikh, A (2011) Nutrients and foods for the primary prevention of asthma and allergy: systematic review and meta-analysis. J Allergy Clin Immunol 127, 724–733 e1–30.CrossRefGoogle ScholarPubMed
35. Litonjua, AA, Rifas-Shiman, SL, Ly, NP et al. (2006) Maternal antioxidant intake in pregnancy and wheezing illnesses at 2 years of age. Am J Clin Nutr 84, 903–911.CrossRefGoogle Scholar
36. Martindale, S, McNeill, G, Devereux, G et al. (2005) Antioxidant intake in pregnancy in relation to wheeze and eczema in the first two years of life. Am J Respir Crit Care Med 171, 121–128.CrossRefGoogle ScholarPubMed
37. Rautalahti, M, Virtamo, J, Haukka, J et al. (1997) The effect of alpha-tocopherol and beta-carotene supplementation on COPD symptoms. Am J Respir Crit Care Med 156, 1447–1452.CrossRefGoogle ScholarPubMed
38. Office of Dietary Supplements at the National Institutes of Health (2011) Dietary Supplement Fact Sheet: Vitamin E. http://ods.od.nih.gov/factsheets/VitaminE (updated 24 June 2011; cited 20 August 2011).Google Scholar
39. Singh, U & Devaraj, S (2007) Vitamin E: inflammation and atherosclerosis. Vitam Horm 76, 519–549.CrossRefGoogle ScholarPubMed
40. Pekmezci, D (2011) Vitamin E and immunity. Vitam Horm 86, 179–215.CrossRefGoogle ScholarPubMed
41. Morante, M, Sandoval, J, Gomez-Cabrera, MC et al. (2005) Vitamin E deficiency induces liver nuclear factor-kappaB DNA-binding activity and changes in related genes. Free Radic Res 39, 1127–1138.CrossRefGoogle ScholarPubMed
42. Suzuki, YJ & Packer, L (1993) Inhibition of NF-kappa B activation by vitamin E derivatives. Biochem Biophys Res Commun 193, 277–283.CrossRefGoogle ScholarPubMed
43. Jialal, I, Devaraj, S & Kaul, N (2001) The effect of alpha-tocopherol on monocyte proatherogenic activity. J Nutr 1, 389S–394S.CrossRefGoogle Scholar
44. Devaraj, S & Jialal, I (1999) Alpha-tocopherol decreases interleukin-1 beta release from activated human monocytes by inhibition of 5-lipoxygenase. Arterioscl Thromb Vasc Biol 19, 1125–1133.CrossRefGoogle ScholarPubMed
45. Munteanu, A & Zingg, JM (2007) Cellular, molecular and clinical aspects of vitamin E on atherosclerosis prevention. Mol Asp Med 28, 538–590.CrossRefGoogle ScholarPubMed
46. Li-Weber, M, Giaisi, M, Treiber, MK et al. (2002) Vitamin E inhibits IL-4 gene expression in peripheral blood T cells. Eur J Immunol 32, 2401–2408.3.0.CO;2-S>CrossRefGoogle ScholarPubMed
47. Dworski, R, Han, W, Blackwell, TS et al. (2011) Vitamin E prevents NRF2 suppression by allergens in asthmatic alveolar macrophages in vivo . Free Radic Biol Med 51, 516–521.CrossRefGoogle ScholarPubMed
48. Devereux, G, Barker, RN & Seaton, A (2002) Antenatal determinants of neonatal responses to allergens. Clin Exp Allergy 32, 43–50.CrossRefGoogle ScholarPubMed
49. Romieu, I & Trenga, C (2001) Diet and obstructive lung diseases. Epidemiol Rev 23, 268–287.CrossRefGoogle ScholarPubMed
50. Sausenthaler, S, Loebel, T, Linseisen, J et al. (2009) Vitamin E intake in relation to allergic sensitization and IgE serum concentration. Cent Eur J Public Health 17, 79–85.CrossRefGoogle ScholarPubMed
51. Gao, J, Gao, X, Li, W, Zhu, Y et al. (2008) Observational studies on the effect of dietary antioxidants on asthma: a meta-analysis. Respirology 13, 528–536.CrossRefGoogle ScholarPubMed
52. Pearson, PJ, Lewis, SA, Britton, J et al. (2004) Vitamin E supplements in asthma: a parallel group randomised placebo controlled trial. Thorax 59, 652–656.CrossRefGoogle ScholarPubMed
53. Sienra-Monge, JJ, Ramirez-Aguilar, M, Moreno-Macias, H et al. (2004) Antioxidant supplementation and nasal inflammatory responses among young asthmatics exposed to high levels of ozone. Clin Exp Immunol 138, 317–322.CrossRefGoogle ScholarPubMed
54. Romieu, I, Sienra-Monge, JJ, Ramirez-Aguilar, M et al. (2002) Antioxidant supplementation and lung functions among children with asthma exposed to high levels of air pollutants. Am J Respir Crit Care Med 166, 703–709.CrossRefGoogle ScholarPubMed
55. Shahar, E, Hassoun, G & Pollack, S (2004) Effect of vitamin E supplementation on the regular treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol 92, 654–658.CrossRefGoogle ScholarPubMed
56. Greenough, A, Shaheen, SO, Shennan, A et al. (2010) Respiratory outcomes in early childhood following antenatal vitamin C and E supplementation. Thorax 65, 998–1003.CrossRefGoogle ScholarPubMed
57. Holick, MF (2007) Vitamin D deficiency. N Engl J Med 357, 266–281.CrossRefGoogle ScholarPubMed
58. Lamberg-Allardt, C (2006) Vitamin D in foods and as supplements. Prog Biophys Mol Biol 92, 33–38.CrossRefGoogle ScholarPubMed
59. Hollis, BW, Wagner, CL, Drezner, MK et al. (2007) Circulating vitamin D(3) and 25-hydroxyvitamin D in humans: An important tool to define adequate nutritional vitamin D status. J Steroid Biochem Mol Biol 103, 631–634.CrossRefGoogle ScholarPubMed
60. van der Mei, IA, Blizzard, L, Ponsonby, AL et al. (2006) Validity and reliability of adult recall of past sun exposure in a case-control study of multiple sclerosis. Cancer Epidemiol Biomarkers Prev 15, 1538–1544.CrossRefGoogle Scholar
61. Sahota, H, Barnett, H, Lesosky, M et al. (2008) Association of vitamin D related information from a telephone interview with 25-hydroxyvitamin D. Cancer Epidemiol Biomarkers Prev 17, 232–238.CrossRefGoogle Scholar
62. Webb, AR (2006) Who, what, where and when-influences on cutaneous vitamin D synthesis. Prog Biophys Mol Biol 92, 17–25.CrossRefGoogle ScholarPubMed
63. Institute of Medicine (2010) Dietary Reference Intakes for Calcium and Vitamin D [Ross, AC, Taylor, CL, Yaktine, AL and Del Valle, HB, editors]. Washington, DC: National Academies Press.Google ScholarPubMed
64. Heaney, RP & Holick, MF (2011) Why the IOM recommendations for vitamin D are deficient. J Bone Miner Res 26, 455–457.CrossRefGoogle ScholarPubMed
65. Holick, MF (2006) High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 81, 353–373.CrossRefGoogle ScholarPubMed
66. Nesby-O'Dell, S, Scanlon, KS, Cogswell, ME et al. (2002) Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988–1994. Am J Clin Nutr 76, 187–192.CrossRefGoogle ScholarPubMed
67. US Environmental Protection Agency (1989) Report to Congress on Indoor Air Quality, Volume II: Assessment and Control of Indoor Air Pollution, Report No. EPA 400-1-89-001C. Washington, DC: EPA.Google Scholar
68. Rappaport, BZ, Reed, CI, Hathaway, ML et al. (1934) The treatment of hay fever and asthma with viosterol of high potency. J Allergy 5, 541–553.CrossRefGoogle Scholar
69. Poon, AH, Laprise, C, Lemire, M et al. (2004) Association of vitamin D receptor genetic variants with susceptibility to asthma and atopy. Am J Respir Crit Care Med 170, 967–973.CrossRefGoogle ScholarPubMed
70. Raby, BA, Lazarus, R, Silverman, EK et al. (2004) Association of vitamin D receptor gene polymorphisms with childhood and adult asthma. Am J Respir Crit Care Med 170, 1057–1065.CrossRefGoogle ScholarPubMed
71. Saadi, A, Gao, G, Li, H et al. (2009) Association study between vitamin D receptor gene polymorphisms and asthma in the Chinese Han population: a case-control study. BMC Med Genet 10, 71.CrossRefGoogle ScholarPubMed
72. Vollmert, C, Illig, T, Altmuller, J et al. (2004) Single nucleotide polymorphism screening and association analysis–exclusion of integrin beta 7 and vitamin D receptor (chromosome 12q) as candidate genes for asthma. Clin Exp Allergy 34, 1841–1850.CrossRefGoogle ScholarPubMed
73. Wjst, M (2005) Variants in the vitamin D receptor gene and asthma. BMC Genet 6, 2.CrossRefGoogle ScholarPubMed
74. Wjst, M, Altmuller, J, Faus-Kessler, T et al. (2006) Asthma families show transmission disequilibrium of gene variants in the vitamin D metabolism and signalling pathway. Respir Res 7, 60.CrossRefGoogle ScholarPubMed
75. Wittke, A, Weaver, V, Mahon, BD et al. (2004) Vitamin D receptor-deficient mice fail to develop experimental allergic asthma. J Immunol 173, 3432–3436.CrossRefGoogle ScholarPubMed
76. Wittke, A, Chang, A, Froicu, M et al. (2007) Vitamin D receptor expression by the lung micro-environment is required for maximal induction of lung inflammation. Arch Biochem Biophys 460, 306–313.CrossRefGoogle ScholarPubMed
77. Bosse, Y, Maghni, K & Hudson, TJ (2007) 1alpha,25-dihydroxy-vitamin D3 stimulation of bronchial smooth muscle cells induces autocrine, contractility, and remodeling processes. Physiol Genomics 29, 161–168.CrossRefGoogle Scholar
78. Haussler, MR, Haussler, CA, Bartik, L et al. (2008) Vitamin D receptor: molecular signaling and actions of nutritional ligands in disease prevention. Nutr Rev 66, S98–112.CrossRefGoogle ScholarPubMed
79. Dusso, AS, Brown, AJ & Slatopolsky, E (2005) Vitamin D. Am J Physiol Renal Physiol 289, F8–28.CrossRefGoogle ScholarPubMed
80. Ramagopalan, SV, Heger, A, Berlanga, AJ et al. ( 2010)A ChIP-seq defined genome-wide map of vitamin D receptor binding: Associations with disease and evolution. Genome Res 20, 1352–1360.CrossRefGoogle ScholarPubMed
81. Jackson, DJ, Gangnon, RE, Evans, MD et al. (2008) Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am J Respir Crit Care Med 178, 667–672.CrossRefGoogle ScholarPubMed
82. Litonjua, AA (2009) Childhood asthma may be a consequence of vitamin D deficiency. Curr Opin Allergy Clin Immunol 9, 202–207.CrossRefGoogle ScholarPubMed
83. Liu, PT, Stenger, S, Tang, DH et al. (2007) Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J Immunol 179, 2060–2063.CrossRefGoogle ScholarPubMed
84. Grant, WB (2008) Hypothesis–ultraviolet-B irradiance and vitamin D reduce the risk of viral infections and thus their sequelae, including autoimmune diseases and some cancers. Photochem Photobiol 84, 356–365.CrossRefGoogle ScholarPubMed
85. Herr, C, Shaykhiev, R & Bals, R (2007) The role of cathelicidin and defensins in pulmonary inflammatory diseases. Expert Opin Biol Ther 7, 1449–1461.CrossRefGoogle ScholarPubMed
86. Dickson, I (1987) New approaches to vitamin D. Nature 325, 18.CrossRefGoogle ScholarPubMed
87. Minghetti, PP & Norman, AW (1988) 1,25(OH)2-vitamin D3 receptors: gene regulation and genetic circuitry. FASEB J 2, 3043–3053.CrossRefGoogle Scholar
88. Akeno, N, Saikatsu, S, Kawane, T et al. (1997) Mouse vitamin D-24-hydroxylase: molecular cloning, tissue distribution, and transcriptional regulation by 1alpha,25-dihydroxyvitamin D3 . Endocrinology 138, 2233–2240.CrossRefGoogle Scholar
89. Mahon, BD, Wittke, A, Weaver, V et al. (2003) The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells. J Cell Biochem 89, 922–932.CrossRefGoogle ScholarPubMed
90. Heine, G, Anton, K, Henz, BM et al. (2002) 1alpha,25-dihydroxyvitamin D3 inhibits anti-CD40 plus IL-4-mediated IgE production in vitro . Eur J Immunol 32, 3395–3404.Google Scholar
91. Adorini, L, Penna, G, Giarratana, N et al. (2004) Dendritic cells as key targets for immunomodulation by Vitamin D receptor ligands. J Steroid Biochem Mol Biol 89–90, 437–441.CrossRefGoogle ScholarPubMed
92. Hewison, M (2011)Vitamin D and immune function: an overview. Proc Nutr Soc 18, 1–12.Google Scholar
93. Hewison, M (2011) Vitamin D and innate and adaptive immunity. Vitam Horm 86, 23–62.CrossRefGoogle ScholarPubMed
94. Bikle, DD (2011) Vitamin D regulation of immune function. Vitam Horm 86, 1–21.CrossRefGoogle ScholarPubMed
95. Xystrakis, E, Kusumakar, S, Boswell, S et al. (2006) Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest 116, 146–155.CrossRefGoogle ScholarPubMed
96. Banerjee, A, Damera, G, Bhandare, R et al. (2008) Vitamin D and glucocorticoids differentially modulate chemokine expression in human airway smooth muscle cells. Br J Pharmacol 155, 84–92.CrossRefGoogle ScholarPubMed
97. Taher, YA, van Esch, BC, Hofman, GA et al. (2008) 1alpha,25-dihydroxyvitamin D3 potentiates the beneficial effects of allergen immunotherapy in a mouse model of allergic asthma: role for IL-10 and TGF-beta. J Immunol 180, 5211–5221.CrossRefGoogle Scholar
98. Burri, PH (1984) Fetal and postnatal development of the lung. Annu Rev Physiol 46, 617–628.CrossRefGoogle ScholarPubMed
99. Marin, L, Dufour, ME, Nguyen, TM et al. (1993) Maturational changes induced by 1 alpha,25-dihydroxyvitamin D3 in type II cells from fetal rat lung explants. Am J Physiol 265, L45–L52.Google ScholarPubMed
100. Marin, L, Dufour, ME, Tordet, C et al. 1,25(OH)2D3 stimulates phospholipid biosynthesis and surfactant release in fetal rat lung explants. Biol Neonate 57, 257–260.CrossRefGoogle Scholar
101. Nguyen, M, Trubert, CL, Rizk-Rabin, M et al. (2004) 1,25-Dihydroxyvitamin D3 and fetal lung maturation: immunogold detection of VDR expression in pneumocytes type II cells and effect on fructose 1,6 bisphosphatase. J Steroid Biochem Mol Biol 89–90, 93–97.CrossRefGoogle ScholarPubMed
102. Nguyen, TM, Guillozo, H, Marin, L et al. (1996) Evidence for a vitamin D paracrine system regulating maturation of developing rat lung epithelium. Am J Physiol 271, L392–L399.Google ScholarPubMed
103. Nguyen, M, Guillozo, H, Garabedian, M et al. ( 1987) Lung as a possible additional target organ for vitamin D during fetal life in the rat. Biol Neonate 52, 232–240.CrossRefGoogle ScholarPubMed
104. Rehan, VK, Torday, JS, Peleg, S et al. (2002) 1Alpha,25-dihydroxy-3-epi-vitamin D3, a natural metabolite of 1alpha,25-dihydroxy vitamin D3: production and biological activity studies in pulmonary alveolar type II cells. Mol Genet Metab 76, 46–56.CrossRefGoogle Scholar
105. Phokela, SS, Peleg, S, Moya, FR et al. (2005) Regulation of human pulmonary surfactant protein gene expression by 1alpha,25-dihydroxyvitamin D3 . Am J Physiol Lung Cell Mol Physiol 289, L617–L626.CrossRefGoogle Scholar
106. Gaultier, C, Harf, A, Balmain, N et al. (1984) Lung mechanics in rachitic rats. Am Rev Respir Dis 130, 1108–1110.Google ScholarPubMed
107. Zosky, GR, Berry, LJ, Elliot, JG et al. (2011) Vitamin D deficiency causes deficits in lung function and alters lung structure. Am J Respir Crit Care Med 183, 1336–1343.CrossRefGoogle ScholarPubMed
108. Lunghi, B, Meacci, E, Stio, M et al. (1995) 1,25-dihydroxyvitamin D3 inhibits proliferation of IMR-90 human fibroblasts and stimulates pyruvate kinase activity in confluent-phase cells. Mol Cell Endocrinol 115, 141–148.CrossRefGoogle ScholarPubMed
109. Stio, M, Celli, A, Lunghi, B et al. (1997) Vitamin D receptor in IMR-90 human fibroblasts and antiproliferative effect of 1,25-dihydroxyvitamin D3 . Biochem Mol Biol Int 43, 1173–1181.Google Scholar
110. Black, PN & Scragg, R (2005) Relationship between serum 25-hydroxyvitamin D and pulmonary function in the third national health and nutrition examination survey. Chest 128, 3792–3798.CrossRefGoogle ScholarPubMed
111. Berry, DJ, Hesketh, K, Power, C et al. (2011) Vitamin D status has a linear association with seasonal infections and lung function in British adults. Br J Nutr 1–8.Google Scholar
112. Tolppanen, AM, Williams, D, Henderson, J et al. (2011) Serum 25-hydroxy-vitamin D and ionised calcium in relation to lung function and allergen skin tests. Eur J Clin Nutr 65, 493–500.CrossRefGoogle ScholarPubMed
113. Li, F, Peng, M, Jiang, L et al. (2011) Vitamin D deficiency is associated with decreased lung function in Chinese adults with asthma. Respiration 81, 469–475.CrossRefGoogle ScholarPubMed
114. Shaheen, SO, Jameson, KA, Robinson, SM et al. (2011) Relationship of vitamin D status to adult lung function and COPD. Thorax 66, 692–698.CrossRefGoogle ScholarPubMed
115. Cremers, E, Thijs, C, Penders, J et al. (2011) Mommers M. Maternal and child's vitamin D supplement use and vitamin D level in relation to childhood lung function: the KOALA Birth Cohort Study. Thorax 66, 474–480.CrossRefGoogle ScholarPubMed
116. Damera, G, Fogle, H, Lim, P et al. (2009) Vitamin D inhibits growth of human airway smooth muscle cells through growth factor-induced phosphorylation of retinoblastoma protein and checkpoint kinase 1. Br J Pharmacol 158, 1429–1441.CrossRefGoogle ScholarPubMed
117. Camargo, JCA, Rifas-Shiman, SL, Litonjua, AA et al. (2007) Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at age 3 years. Am J Clin Nutr 85, 788–795.CrossRefGoogle Scholar
118. Devereux, G, Litonjua, AA, Turner, S et al. (2007) Maternal vitamin D intake during pregnancy and early childhood wheezing. Am J Clin Nutr 85, 853–859.CrossRefGoogle ScholarPubMed
119. Erkkola, M, Kaila, M, Nwaru, BI et al. (2009) Maternal vitamin D intake during pregnancy is inversely associated with asthma and allergic rhinitis in 5-year-old children. Clin Exp Allergy 39, 875–882.CrossRefGoogle Scholar
120. Miyake, Y, Sasaki, S, Tanaka, K et al. (2010) Dairy food, calcium and vitamin D intake in pregnancy, and wheeze and eczema in infants. Eur Respir J 35, 1228–1234.CrossRefGoogle ScholarPubMed
121. Hypponen, E, Sovio, U, Wjst, M et al. (2004) Infant vitamin D supplementation and allergic conditions in adulthood: northern Finland birth cohort 1966. Ann NY Acad Sci 1037, 84–95.CrossRefGoogle ScholarPubMed
122. Gale, CR, Robinson, SM, Harvey, NC et al. (2007) Maternal vitamin D status during pregnancy and child outcomes. Eur J Clin Nutr 62, 68–77.CrossRefGoogle ScholarPubMed
123. Camargo, CA Jr, Ingham, T, Wickens, K et al. (2011) Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma. Pediatrics 127, e180–e187.CrossRefGoogle ScholarPubMed
124. Hill, J, Micklewright, A, Lewis, S et al. (1997) Investigation of the effect of short-term change in dietary magnesium intake in asthma. Eur Respir J 10, 2225–2229.CrossRefGoogle ScholarPubMed
125. Brehm, JM, Celedon, JC, Soto-Quiros, ME et al. (2009) Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica. Am J Respir Crit Care Med 179, 765–771.CrossRefGoogle ScholarPubMed
126. Brehm, JM, Schuemann, B, Fuhlbrigge, AL et al. (2010) Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. J Allergy Clin Immunol 126, 52–58 e5.CrossRefGoogle ScholarPubMed
127. Sutherland, ER, Goleva, E, Jackson, LP et al. (2010) Vitamin D levels, lung function, and steroid response in adult asthma. Am J Respir Crit Care Med 181, 699–704.CrossRefGoogle ScholarPubMed
128. Searing, DA, Zhang, Y, Murphy, JR et al. (2010) Decreased serum vitamin D levels in children with asthma are associated with increased corticosteroid use. J Allergy Clin Immunol 125, 995–1000.CrossRefGoogle ScholarPubMed
129. Urashima, M, Segawa, T, Okazaki, M et al. (2010) Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr 91, 1255–1260.CrossRefGoogle ScholarPubMed
130. Majak, P, Olszowiec-Chlebna, M, Smejda, K et al. (2011) Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. J Allergy Clin Immunol 127, 1294–1296.CrossRefGoogle ScholarPubMed