Vitamin D3 and Lung

Vitamin D plays an important role in the maintenance of normal health. It preventsoccurrence ofrickets and osteomalacia and maintains skeletal homeostasis. Itsdeficiency contributes to osteopenia, osteoporosis and increased risk of fractures. Its role in non-skeletal conditions is gaining importance in recent years. Thishas been made possible by the discovery of activating and inactivating enzymes ofvitamin D and Vitamin D receptors (VDRs) in the mammalian cells. Vitamin Dmodulates different processes and regulatory systems including host defense,inflammation, immunity and repair. Deficiency of vitamin D appears to have a role inthe risk of development of many chronic diseases such as diabetes, cancers,infections, cardiovascular diseases and autoimmune diseases.1 The influence ofvitamin D on other physiological and pathological processes has been recognizedrecently.

Vitamin D is a lipid soluble ketosteroid. There are two major forms of vitamin D, ergocalciferol (Vitamin D2) and cholecalciferol (Vitamin D3), representing its dualorigin. D2 can be obtained by diet of fortified milk products and fish. D3 is producedin the skin phytochemically where 7-dihydrocholesterol (7-DHC) is found in greatabundance. On exposure to ultraviolet light of sun at wavelengths between 270 and300 nm, 7-DHC gets converted to vitamin D3.2

In the early 1920s, it was found that certain foods on exposure to ultravioletlight become anti-rachitic.3 Elmer McCollum identified in 1922, anti-rachitic substancein cod liver oil and called it vitamin D (now called D3). Thus, light or sunshine hasbecome synonymous with vitamin D. Isomerized vitamin D3 enters the circulationbound either to vitamin D binding protein or to albumin to be transported to the liver. Then it is metabolized by enzymes belonging to a group of cytochromes P450 hydroxylase. In the liver, the first hydroxylation of vitamin D on C-25 is performedby mitochondrial 25-hydroxylase enzyme (CYP27A1).4 The inactive 25-(OH) D3metabolite or calcidiol, enters the systemic circulation and it has a half-life of 12-19 days. The serum level of 25-(OH) D3 reflects vitamin D status in the body.5 Onreaching the proximal renal tubule, it is further hydroxylated at position 1-alpha by themitochondrial cytochrome P450 enzyme, CYP27B1 and gets converted into clinicallybioactive1-alpha-25- dihydroxy vitamin D {1,25-(OH)2 D3} or calcitriol.6 Theeffects of the active metabolite are modified by binding to the vitamin D receptor(VDR).7 Vitamin D receptor protein is a 457-amino acid peptide that has a DNA binding domain, a ligand-binding domain and activating domain. The serum half-lifeof calcitriol is 15 hours. Many other cell types including lung epithelial cells arecapable to perform the conversion of calcidiol to calcitriol.8 Vitamin D isinactivated by the action of a catabolizing enzyme, 24 alpha hydroxylase, CYP24A1.

Epidemiologic studies have shown that low levels of serum vitamin D areassociated with impaired pulmonary functions, increased occurrence of inflammatory, infectious or neoplastic diseases. The examples include respiratory disorders whichare inflammatory in nature, such as asthma and chronic obstructive pulmonary disease (COPD) or infections such as tuberculosis or lung cancer. The exact mechanismunderlying such a development is undetermined. However, vitamin D appears toinfluence the inflammatory and structural cells such as dendritic cells, lymphocytes,monocytes and epithelial cells. 1,25-hydroxyvitamin D3 could influence tissue remodeling as it has thecapacity to inhibit the formation of matrix metalloproteinases, and facilitate fibroblast formation and influence collagen synthesis.9,10

Serum concentrations of vitamin D3 may influence pulmonary functions. In across-sectional survey of 14,076 young adults, it was found that there is a strongrelationship between serum concentrations of 25-hydroxyvitamin D3, forced expiratory volume (FEV) and forced expiratory volume in 1 second (FEV1).11

Cod liver oil rich in vitamin D was advocated in the treatment of tuberculosisbefore the discovery of streptomycin and its use. It was an earliest example of nontherapeutic use of vitamin D.Williams found that among 234 patients withtuberculosis, 206 showed marked and unequivocal improvement following treatmentwith cod liver oil.12 As vitamin D regulates many cellular processes, it acts like animmunomodulator. Antimicrobial activity of macrophages against Mycobacteriumtuberculosis is increased in presence of vitamin D following stimulation ofmycobacterial ligands.13 Mycobacterial activation of toll-like receptor-2 leads to anincreased expression of VDR and CYP27B, that causes an increased conversion of calcidiol to calcitriol.14

A high vitamin D levels are associated with improved pulmonary functions,decreased airway hyper-respon siveness and improved glucocorticoid response.15 There is an increased requirement of inhaled corticosteroid in children with lowerlevels of vitamin D.16 There is decreased vitamin D level in children exhibitingmildto-moderate persistent asthma and the chances for exacerbation are great.17 There appears to be a connection between vitamin D status and chronicobstructive pulmonary disease (COPD). Vitamin D deficiency is highly prevalent inCOPD.18 Many factors may be responsible for vitamin D deficiency in COPD.They include poor diet, a decreased capacity of aging skin for vitamin D synthesis,decreased outdoor activity with decreased exposure to sun, increased catabolism byglucocorticoids, impaired activation of vitamin D due to renal dysfunction andlowered storage capacity in muscles or fat due to wasting. Thus, there is a disturbancein intake, synthesis, storage and metabolism of vitamin D in COPD patients. VitaminD is capable of regulating extracellular matrix turnover and growth factor releasethrough matrix metalloproteinases that has a role in COPD development. Vitamin Ddeficiency may lead to an increased degradation of lung parenchyma.1

Respiratory tract infections are more common in winter than during summer.Deficient food intake and lack of sunlight exposure determine the vitamin D status.There is a seasonal difference in vitamin D levels in human beings. During winter,there is insufficient ultraviolet B exposure to produce sufficient amounts of vitaminD. Vitamin D insufficiency may lead to seasonal influenza and other viral respiratorytract infections.19 In the Third National Health and Nutritional ExaminationSurvey, it was found that lower vitamin D levels are independently associated with recentupper respiratory tract infections.20 This association with vitamin D was evenstronger when the patients had asthma and COPD.

Calcitriol has shown to inhibit the proliferation of human cells and apoptosis.Vitamin D regulates cytoplasmic signaling pathways that have effect on cellulardifferentiation and growth through proteins.21 Malignant cells found in thecancerous growth of the lung cause destruction of vitamin D. High levels of vitamin D3 helps the body make protein that work against cancer cells. A Finnish prospectivestudy that analyzed the data on serum vitamin D levels and 6937 cases of lung cancer,found an association between the serum level of 1,25-(OH)2 D3 and lung cancer.22 High levels of vitamin D are concerned with the production of proteins that actagainst cancer cells. Zhou and colleagues found an improved survival in early stage oflung cancer in presence of higher circulating levels of 1,25-(OH)2 D3.23 Theynoted a 26% improved survival for patients whose 1,25-(OH)2 D3 levels were greaterthan 21.6 ng/mL compared with those whose levels were less than 10.2 ng/mL.

Malignant cells of lung cancer produce an enzyme CYP24.Higashimoto and colleagues have reported that 1,25-(OH)2 D3 inhibited thegrowth of lung cancer cell lines.24 The efficacy was mediated by VDR and affectedcell cycle regulation in small cell carcinoma.25 Nithya Ramnath and colleaguesdetermined the level of CYP24A1 that encodes an enzyme that is over-expressed inmany cancers.26 The enzyme breaks down calcitriol that has an anti-proliferative effect. The level of CYP24A1 was estimated in 836 patients with adenocarcinoma ofthe lung. Its expression was 8 to 50 times higher in cancerous patients compared topatients with healthy lung tissue. This enzyme is elevated in lung cancer that reducesthe active form of vitamin D.13 It is associated with greater aggressiveness of thetumour and worse survival. Those having higher levels of CYP24A1 had a 42%chance of survival after 5 years compared with an 81% chance for those with lowCYP24A1 levels.

Vitamin D acts on malignant cells and causes their differentiation and decreaseproliferation. Low levels of Vitamin D have a greater chance of developing lungcancer. Vitamin D by affecting a broad range of cellular pathways possesses atherapeutic role for secondary prevention of cancer either by itself or in combinationwith a CYP24A1 inhibitor. There is need to prevent breakdown of calcitriol intumours by blocking CYP24A1. In patients who exhibit a high expression ofCYP24A1, there is likelihood of the necessity to use a specific CYP24A1 inhibitor incombination with 1,25-(OH)2 D3 therapy.

Vitamin D is involved in many activities in addition to its effect on calciumand bone homeostasis. It appears to play a role in immune regulation, host defense,cell proliferation and inflammation. Vitamin D deficiency has been recognized in anumber of pulmonary diseases. The benefits of Vitamin D supplementation in theseconditions are to be substantiated. The addition of vitamin D may help in prevention ofmany of the lung diseases.