The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer

Respiratory Research

Robert Bals³  Rebecca Eschmann²  Meret Branscheidt²  Tetyana Zakharkina³  Silke Meyer¹  Rembert A Koczulla²  Timm Greulich²  Christian Herr³ 

[1] Department of Internal Medicine, Division of Endocrinology & Diabetology, Department of Internal Medicine, University Hospital Marburg, 35043 Marburg, Germany;Department of Internal Medicine, Division for Pulmonary Diseases, Philipps-Universtät Marburg, 35043 Marburg, Germany;Department of Pulmonology, University of the Saarland, 66421 Homburg Saar, Germany

关键词: immunity;    respiratory tract infection;    COPD;    asthma;    mortality;    Vitamin D;   

Others  :  796895
DOI  :  10.1186/1465-9921-12-31

 received in 2010-05-03, accepted in 2011-03-18,  发布年份 2011

【 摘 要 】

The role of vitamin D (VitD) in calcium and bone homeostasis is well described. In the last years, it has been recognized that in addition to this classical function, VitD modulates a variety of processes and regulatory systems including host defense, inflammation, immunity, and repair. VitD deficiency appears to be frequent in industrialized countries. Especially patients with lung diseases have often low VitD serum levels. Epidemiological data indicate that low levels of serum VitD is associated with impaired pulmonary function, increased incidence of inflammatory, infectious or neoplastic diseases. Several lung diseases, all inflammatory in nature, may be related to activities of VitD including asthma, COPD and cancer. The exact mechanisms underlying these data are unknown, however, VitD appears to impact on the function of inflammatory and structural cells, including dendritic cells, lymphocytes, monocytes, and epithelial cells. This review summarizes the knowledge on the classical and newly discovered functions of VitD, the molecular and cellular mechanism of action and the available data on the relationship between lung disease and VitD status.

【 授权许可】

   
2011 Herr et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Autier P, Gandini S: Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med 2007, 167:1730-1737.
• [2]Goldblatt H, Soames KM: The Supplementary Value of Light Rays to a Diet Graded in its Content of Fat-Soluble Organic Factor. Biochem J 1923, 17:622-629.
• [3]Steenbock H: The Induction of Growth Promoting and Calcifying Properties in a Ration by Exposure to Light. Science 1924, 60:224-225.
• [4]McCollum EV, Pitz W, Simmonds N, Becker JE, Shipley PG, Bunting RW: The effect of additions of fluorine to the diet of the rat on the quality of the teeth. 1925. Studies on experimental rickets. XXI. An experimental demonstration of the existence of a vitamin which promotes calcium deposition. 1922. The effect of additions of fluorine to the diet of the rat on the quality of the teeth. 1925. J Biol Chem 2002, 277:E8.
• [5]Holick MF: Evolution and function of vitamin D. Recent Results Cancer Res 2003, 164:3-28.
• [6]Baker AR, McDonnell DP, Hughes M, Crisp TM, Mangelsdorf DJ, Haussler MR, et al.: Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci USA 1988, 85:3294-3298.
• [7]Burmester JK, Wiese RJ, Maeda N, DeLuca HF: Structure and regulation of the rat 1,25-dihydroxyvitamin D3 receptor. Proc Natl Acad Sci USA 1988, 85:9499-9502.
• [8]Lu Z, Hanson K, DeLuca HF: Cloning and origin of the two forms of chicken vitamin D receptor. Arch Biochem Biophys 1997, 339:99-106.
• [9]Li YC, Bergwitz C, Juppner H, Demay MB: Cloning and characterization of the vitamin D receptor from Xenopus laevis. Endocrinology 1997, 138:2347-2353.
• [10]Laing CJ, Fraser DR: The vitamin D system in iguanian lizards. Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology 1999, 123:373-379.
• [11]Ciesielski F, Rochel N, Mitschler A, Kouzmenko A, Moras D: Structural investigation of the ligand binding domain of the zebrafish VDR in complexes with 1alpha,25(OH)2D3 and Gemini: purification, crystallization and preliminary X-ray diffraction analysis. J Steroid Biochem Mol Biol 2004, 89-90:55-59.
• [12]Whitfield GK, Dang HT, Schluter SF, Bernstein RM, Bunag T, Manzon LA, et al.: Cloning of a functional vitamin D receptor from the lamprey (Petromyzon marinus), an ancient vertebrate lacking a calcified skeleton and teeth. Endocrinology 2003, 144:2704-2716.
• [13]Sergeev IN, Buffenstein R, Pettifor JM: Vitamin D receptors in a naturally vitamin D-deficient subterranean mammal, the naked mole rat (Heterocephalus glaber): biochemical characterization. Gen Comp Endocrinol 1993, 90:338-345.
• [14]Cavaleros M, Buffenstein R, Ross FP, Pettifor JM: Vitamin D metabolism in a frugivorous nocturnal mammal, the Egyptian fruit bat (Rousettus aegyptiacus). Gen Comp Endocrinol 2003, 133:109-117.
• [15]Copping AM: Origin of vitamin D in cod-liver oil: vitamin D content of zooplankton. Biochem J 1934, 28:1516-1520.
• [16]Sasaki J, Miyazaki A, Saito M, Adachi T, Mizoue K, Hanada K, et al.: Transformation of vitamin D3 to 1 alpha,25-dihydroxyvitamin D3 via 25-hydroxyvitamin D3 using Amycolata sp. strains. Appl Microbiol Biotechnol 1992, 38:152-157.
• [17]Yasutake Y, Fujii Y, Cheon WK, Arisawa A, Tamura T: Crystallization and preliminary X-ray diffraction studies of vitamin D3 hydroxylase, a novel cytochrome P450 isolated from Pseudonocardia autotrophica. Acta Crystallogr Sect F Struct Biol Cryst Commun 2009, 65:372-375.
• [18]Sasaki J, Mikami A, Mizoue K, Omura S: Transformation of 25- and 1 alpha-hydroxyvitamin D3 to 1 alpha, 25-dihydroxyvitamin D3 by using Streptomyces sp. strains. Appl Environ Microbiol 1991, 57:2841-2846.
• [19]Sawada N, Sakaki T, Yoneda S, Kusudo T, Shinkyo R, Ohta M, et al.: Conversion of vitamin D3 to 1alpha,25-dihydroxyvitamin D3 by Streptomyces griseolus cytochrome P450SU-1. Biochem Biophys Res Commun 2004, 320:156-164.
• [20]MacLaughlin JA, Anderson RR, Holick MF: Spectral character of sunlight modulates photosynthesis of previtamin D3 and its photoisomers in human skin. Science 1982, 216:1001-1003.
• [21]St-Arnaud R: The direct role of vitamin D on bone homeostasis. Arch Biochem Biophys 2008, 473:225-230.
• [22]Janssens W, Lehouck A, Carremans C, Bouillon R, Mathieu C, Decramer M: Vitamin D beyond bones in chronic obstructive pulmonary disease: time to act. Am J Respir Crit Care Med 2009, 179:630-636.
• [23]Sawada N, Sakaki T, Ohta M, Inouye K: Metabolism of vitamin D(3) by human CYP27A1. Biochem Biophys Res Commun 2000, 273:977-984.
• [24]Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW: Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci USA 2004, 101:7711-7715.
• [25]Negri AL: Proximal tubule endocytic apparatus as the specific renal uptake mechanism for vitamin D-binding protein/25-(OH)D3 complex. Nephrology (Carlton ) 2006, 11:510-515.
• [26]Cross HS, Kallay E, Lechner D, Gerdenitsch W, Adlercreutz H, Armbrecht HJ: Phytoestrogens and vitamin D metabolism: a new concept for the prevention and therapy of colorectal, prostate, and mammary carcinomas. J Nutr 2004, 134:1207S-1212S.
• [27]Penna G, Adorini L: 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol 2000, 164:2405-2411.
• [28]Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW: Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J Immunol 2008, 181:7090-7099.
• [29]Yim S, Dhawan P, Ragunath C, Christakos S, Diamond G: Induction of cathelicidin in normal and CF bronchial epithelial cells by 1,25-dihydroxyvitamin D(3). J Cyst Fibros 2007, 6:403-410.
• [30]Holick MF: Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol 2009, 19:73-78.
• [31]Kochupillai N: The physiology of vitamin D: current concepts. Indian J Med Res 2008, 127:256-262.
• [32]Lauridsen AL, Vestergaard P, Hermann AP, Brot C, Heickendorff L, Mosekilde L, et al.: Plasma concentrations of 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D are related to the phenotype of Gc (vitamin D-binding protein): a cross-sectional study on 595 early postmenopausal women. Calcif Tissue Int 2005, 77:15-22.
• [33]Kann P: [Vitamin D and osteoporosis. Pathogenesis--therapy]. Dtsch Med Wochenschr 1994, 119:1479-1485.
• [34]Zhong Y, Armbrecht HJ, Christakos S: Calcitonin, a regulator of the 25-hydroxyvitamin D3 1alpha-hydroxylase gene. J Biol Chem 2009, 284:11059-11069.
• [35]Anderson PH, O'Loughlin PD, May BK, Morris HA: Quantification of mRNA for the vitamin D metabolizing enzymes CYP27B1 and CYP24 and vitamin D receptor in kidney using real-time reverse transcriptase- polymerase chain reaction. J Mol Endocrinol 2003, 31:123-132.
• [36]Hofbauer LC, Heufelder AE: Role of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in bone cell biology. J Mol Med 2001, 79:243-253.
• [37]Kochupillai N: The physiology of vitamin D: current concepts. Indian J Med Res 2008, 127:256-262.
• [38]Holick MF, Chen TC: Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr 2008, 87:1080S-1086S.
• [39]Lips P: Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev 2001, 22:477-501.
• [40]Uitterlinden AG, Fang Y, van Meurs JB, Pols HA, van Leeuwen JP: Genetics and biology of vitamin D receptor polymorphisms. Gene 2004, 338:143-156.
• [41]Williams CJB: Cod-liver Oil in Phthisis. Lond J Med 1849, 1:1-18.
• [42]Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC: 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science 1983, 221:1181-1183.
• [43]Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC: 1 alpha,25-Dihydroxyvitamin D3-binding macromolecules in human B lymphocytes: effects on immunoglobulin production. J Immunol 1986, 136:2734-2740.
• [44]Stroder J, Kasal P: Evaluation of phagocytosis in rickets. Acta Paediatr Scand 1970, 59:288-292.
• [45]Bar-Shavit Z, Noff D, Edelstein S, Meyer M, Shibolet S, Goldman R: 1,25-dihydroxyvitamin D3 and the regulation of macrophage function. Calcif Tissue Int 1981, 33:673-676.
• [46]Stenger S, Modlin RL: Control of Mycobacterium tuberculosis through mammalian Toll-like receptors. Curr Opin Immunol 2002, 14:452-457.
• [47]Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al.: Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006, 311:1770-1773.
• [48]Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE: Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 2007, 179:1634-1647.
• [49]Adams JS, Liu PT, Chun R, Modlin RL, Hewison M: Vitamin D in defense of the human immune response. Ann N Y Acad Sci 2007, 1117:94-105.
• [50]Adorini L, Penna G: Control of autoimmune diseases by the vitamin D endocrine system. Nat Clin Pract Rheumatol 2008, 4:404-412.
• [51]Lemire JM, Adams JS, Kermani-Arab V, Bakke AC, Sakai R, Jordan SC: 1,25-Dihydroxyvitamin D3 suppresses human T helper/inducer lymphocyte activity in vitro. J Immunol 1985, 134:3032-3035.
• [52]Lemire JM, Archer DC, Beck L, Spiegelberg HL: Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions. J Nutr 1995, 125:1704S-1708S.
• [53]Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HF, O'Garra A: 1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol 2001, 167:4974-4980.
• [54]Smolders J, Thewissen M, Peelen E, Menheere P, Cohen JW, Damoiseaux J, et al.: Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis. PLoS ONE 2009, 4:e6635.
• [55]Ginde AA, Sutherland ER: Vitamin D in asthma: panacea or true promise? J Allergy Clin Immunol 2010, 126:59-60.
• [56]Penna G, Amuchastegui S, Giarratana N, Daniel KC, Vulcano M, Sozzani S, et al.: 1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells. J Immunol 2007, 178:145-153.
• [57]Penna G, Adorini L: 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol 2000, 164:2405-2411.
• [58]Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW: Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J Immunol 2008, 181:7090-7099.
• [59]Hansdottir S, Monick MM, Lovan N, Powers L, Gerke A, Hunninghake GW: Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state. J Immunol 2010, 184:965-974.
• [60]Litonjua AA, Weiss ST: Is vitamin D deficiency to blame for the asthma epidemic? J Allergy Clin Immunol 2007, 120:1031-1035.
• [61]Poon AH, Laprise C, Lemire M, Montpetit A, Sinnett D, Schurr E, et al.: Association of vitamin D receptor genetic variants with susceptibility to asthma and atopy. Am J Respir Crit Care Med 2004, 170:967-973.
• [62]Sutherland ER, Goleva E, Jackson LP, Stevens AD, Leung DY: Vitamin D Levels, Lung Function and Steroid Response in Adult Asthma. Am J Respir Crit Care Med 2010, 181:699-704.
• [63]Brehm JM, Celedon JC, Soto-Quiros ME, Avila L, Hunninghake GM, Forno E, et al.: Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica. Am J Respir Crit Care Med 2009, 179:765-771.
• [64]Brehm JM, Schuemann B, Fuhlbrigge AL, Hollis BW, Strunk RC, Zeiger RS, et al.: Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. J Allergy Clin Immunol 2010, 126:52-58.
• [65]Camargo CA Jr, Rifas-Shiman SL, Litonjua AA, Rich-Edwards JW, Weiss ST, Gold DR, et al.: Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age. Am J Clin Nutr 2007, 85:788-795.
• [66]Devereux G, Litonjua AA, Turner SW, Craig LC, McNeill G, Martindale S, et al.: Maternal vitamin D intake during pregnancy and early childhood wheezing. Am J Clin Nutr 2007, 85:853-859.
• [67]Gale CR, Robinson SM, Harvey NC, Javaid MK, Jiang B, Martyn CN, et al.: Maternal vitamin D status during pregnancy and child outcomes. Eur J Clin Nutr 2008, 62:68-77.
• [68]Wittke A, Weaver V, Mahon BD, August A, Cantorna MT: Vitamin D receptor-deficient mice fail to develop experimental allergic asthma. J Immunol 2004, 173:3432-3436.
• [69]Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H: Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr 2010, 91:1255-1260.
• [70]Xystrakis E, Kusumakar S, Boswell S, Peek E, Urry Z, Richards DF, et al.: Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest 2006, 116:146-155.
• [71]Black PN, Scragg R: Relationship between serum 25-hydroxyvitamin d and pulmonary function in the third national health and nutrition examination survey. Chest 2005, 128:3792-3798.
• [72]Wright RJ: Make no bones about it: increasing epidemiologic evidence links vitamin D to pulmonary function and COPD. Chest 2005, 128:3781-3783.
• [73]Forli L, Halse J, Haug E, Bjortuft O, Vatn M, Kofstad J, et al.: Vitamin D deficiency, bone mineral density and weight in patients with advanced pulmonary disease. J Intern Med 2004, 256:56-62.
• [74]Jorgensen NR, Schwarz P, Holme I, Henriksen BM, Petersen LJ, Backer V: The prevalence of osteoporosis in patients with chronic obstructive pulmonary disease: a cross sectional study. Respir Med 2007, 101:177-185.
• [75]Janssens W, Bouillon R, Claes B, Carremans C, Lehouck A, Buysschaert I, et al.: Vitamin D Deficiency is Highly Prevalent in COPD and Correlates with Variants in the Vitamin D Binding Gene. Thorax 2010, 65:215-20.
• [76]Holick MF: Vitamin D deficiency. N Engl J Med 2007, 357:266-281.
• [77]Schellenberg D, Pare PD, Weir TD, Spinelli JJ, Walker BA, Sandford AJ: Vitamin D binding protein variants and the risk of COPD. Am J Respir Crit Care Med 1998, 157:957-961.
• [78]Taes YE, Goemaere S, Huang G, Van PI, De BD, Verhasselt B, et al.: Vitamin D binding protein, bone status and body composition in community-dwelling elderly men. Bone 2006, 38:701-707.
• [79]Janssens W, Lehouck A, Carremans C, Bouillon R, Mathieu C, Decramer M: Vitamin D Beyond Bones in Chronic Obstructive Pulmonary Disease: Time to Act. Am J Respir Crit Care Med 2009, 179:630-636.
• [80]Leech JA, Dulberg C, Kellie S, Pattee L, Gay J: Relationship of lung function to severity of osteoporosis in women. Am Rev Respir dis 1990, 141:68-71.
• [81]Nuti R, Siviero P, Maggi S, Guglielmi G, Caffarelli C, Crepaldi G, et al.: Vertebral fractures in patients with chronic obstructive pulmonary disease: the EOLO Study. Osteoporos Int 2009, 20:989-998.
• [82]Schlaich C, Minne HW, Bruckner T, Wagner G, Gebest HJ, Grunze M, et al.: Reduced pulmonary function in patients with spinal osteoporotic fractures. Osteoporos Int 1998, 8:261-267.
• [83]Niewoehner DE: The impact of severe exacerbations on quality of life and the clinical course of chronic obstructive pulmonary disease. Am J Med 2006, 119:38-45.
• [84]Camargo CA Jr, Ginde AA, Clark S, Cartwright CP, Falsey AR, Niewoehner DE: Viral pathogens in acute exacerbations of chronic obstructive pulmonary disease. Intern Emerg Med 2008, 3:355-359.
• [85]Mogulkoc N, Karakurt S, Isalska B, Bayindir U, Celikel T, Korten V, et al.: Acute purulent exacerbation of chronic obstructive pulmonary disease and Chlamydia pneumoniae infection. Am J Respir Crit Care Med 1999, 160:349-353.
• [86]Lieberman D, Lieberman D, Printz S, Ben-Yaakov M, Lazarovich Z, Ohana B, et al.: Atypical pathogen infection in adults with acute exacerbation of bronchial asthma. Am J Respir Crit Care Med 2003, 167:406-410.
• [87]Papi A, Luppi F, Franco F, Fabbri LM: Pathophysiology of exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2006, 3:245-251.
• [88]Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, et al.: Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004, 173:2909-2912.
• [89]Boyan BD, Wong KL, Fang M, Schwartz Z: 1alpha,25(OH)2D3 is an autocrine regulator of extracellular matrix turnover and growth factor release via ERp60 activated matrix vesicle metalloproteinases. J Steroid Biochem Mol Biol 2007, 103:467-472.
• [90]Culpitt SV, Rogers DF, Traves SL, Barnes PJ, Donnelly LE: Sputum matrix metalloproteases: comparison between chronic obstructive pulmonary disease and asthma. Respir Med 2005, 99:703-710.
• [91]Bahar-Shany K, Ravid A, Koren R: Upregulation of MMP-9 production by TNFalpha in keratinocytes and its attenuation by vitamin D. J Cell Physiol 2010, 222:729-737.
• [92]Sin DD, Man SF: Systemic inflammation and mortality in chronic obstructive pulmonary disease. Can J Physiol Pharmacol 2007, 85:141-147.
• [93]Walter RE, Wilk JB, Larson MG, Vasan RS, Keaney JF Jr, Lipinska I, et al.: Systemic inflammation and COPD: the Framingham Heart Study. Chest 2008, 133:19-25.
• [94]Gosselink R, Troosters T, Decramer M: Peripheral muscle weakness contributes to exercise limitation in COPD. Am J Respir Crit Care Med 1996, 153:976-980.
• [95]Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, Staehelin HB, Bazemore MG, Zee RY, et al.: Effect of Vitamin D on falls: a meta-analysis. Jama 2004, 291:1999-2006.
• [96]Leandro AC, Rocha MA, Cardoso CS, Bonecini-Almeida MG: Genetic polymorphisms in vitamin D receptor, vitamin D-binding protein, Toll-like receptor 2, nitric oxide synthase 2, and interferon-gamma genes and its association with susceptibility to tuberculosis. Braz J Med Biol Res 2009, 42:312-322.
• [97]Lewis SJ, Baker I, Davey SG: Meta-analysis of vitamin D receptor polymorphisms and pulmonary tuberculosis risk. Int J Tuberc Lung Dis 2005, 9:1174-1177.
• [98]Nnoaham KE, Clarke A: Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis. Int J Epidemiol 2008, 37:113-119.
• [99]Nursyam EW, Amin Z, Rumende CM: The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion. Acta Med Indones 2006, 38:3-5.
• [100]Martineau AR, Wilkinson RJ, Wilkinson KA, Newton SM, Kampmann B, Hall BM, et al.: A single dose of vitamin D enhances immunity to mycobacteria. Am J Respir Crit Care Med 2007, 176:208-213.
• [101]Wejse C, Gomes VF, Rabna P, Gustafson P, Aaby P, Lisse IM, et al.: Vitamin D as Supplementary Treatment for Tuberculosis - A Double-blind Randomized Placebo-controlled Trial. Am J Respir Crit Care Med 2009, 179:843-50.
• [102]Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, et al.: Epidemic influenza and vitamin D. Epidemiol Infect 2006, 134:1129-1140.
• [103]Ginde AA, Mansbach JM, Camargo CA Jr: Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med 2009, 169:384-390.
• [104]Avenell A, Cook JA, Maclennan GS, Macpherson GC: Vitamin D supplementation to prevent infections: a sub-study of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438). Age Ageing 2007, 36:574-577.
• [105]Laaksi I, Ruohola JP, Tuohimaa P, Auvinen A, Haataja R, Pihlajamaki H, et al.: An association of serum vitamin D concentrations < 40 nmol/L with acute respiratory tract infection in young Finnish men. Am J Clin Nutr 2007, 86:714-717.
• [106]Wayse V, Yousafzai A, Mogale K, Filteau S: Association of subclinical vitamin D deficiency with severe acute lower respiratory infection in Indian children under 5 y. Eur J Clin Nutr 2004, 58:563-567.
• [107]Li-Ng M, Aloia JF, Pollack S, Cunha BA, Mikhail M, Yeh J, et al.: A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections. Epidemiol Infect 2009, 137:1-9.
• [108]Garland CF, Gorham ED, Mohr SB, Garland FC: Vitamin D for cancer prevention: global perspective. Ann Epidemiol 2009, 19:468-483.
• [109]Jenab M, Bueno-de-Mesquita HB, Ferrari P, van Duijnhoven FJ, Norat T, Pischon T, et al.: Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations:a nested case-control study. Bmj 2010, 340:b5500.
• [110]Dogan I, Onen HI, Yurdakul AS, Konac E, Ozturk C, Varol A, et al.: Polymorphisms in the vitamin D receptor gene and risk of lung cancer. Med Sci Monit 2009, 15:BR232-BR242.
• [111]Kilkkinen A, Knekt P, Heliovaara M, Rissanen H, Marniemi J, Hakulinen T, et al.: Vitamin D status and the risk of lung cancer: a cohort study in Finland. Cancer Epidemiol Biomarkers Prev 2008, 17:3274-3278.
• [112]Heist RS, Zhou W, Wang Z, Liu G, Neuberg D, Su L, et al.: Circulating 25-hydroxyvitamin D, VDR polymorphisms, and survival in advanced non-small-cell lung cancer. J Clin Oncol 2008, 26:5596-5602.
• [113]Mernitz H, Smith DE, Wood RJ, Russell RM, Wang XD: Inhibition of lung carcinogenesis by 1alpha,25-dihydroxyvitamin D3 and 9-cis retinoic acid in the A/J mouse model: evidence of retinoid mitigation of vitamin D toxicity. Int J Cancer 2007, 120:1402-1409.