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

Christian Herr 0 1 3 Timm Greulich 0 3 Rembert A Koczulla 0 3 Silke Meyer 2 Tetyana Zakharkina 0 1 3 Meret Branscheidt 0 3 Rebecca Eschmann 0 3 Robert Bals 0 1 3 0 Department of Internal Medicine, Division for Pulmonary Diseases , Philipps- Universtat Marburg, 35043 Marburg , Germany 1 Department of Pulmonology, University of the Saarland , 66421 Homburg Saar , Germany 2 Department of Internal Medicine, Division of Endocrinology & Diabetology, Department of Internal Medicine, University Hospital Marburg , 35043 Marburg , Germany 3 Department of Internal Medicine, Division for Pulmonary Diseases , Philipps- Universtat Marburg, 35043 Marburg , Germany 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. - Evolutionary aspects VitD and its receptors are found throughout the animal kingdom and are often linked to bone and calcium metabolisms. The fact that precursors of VitD are found in ancient organisms like krill and phytoplankton that existed unchanged for at least 750 million years [5] highlights its importance in physiologic and homeostatic processes. Variants of VitD and its receptors have been identified in higher terrestrial vertebrates like humans [6], rodents [7], birds [8], amphibia [9], reptiles [10], as well as in zebrafish [11]. These animals possess a calcified skeleton and depend on a functional VitD hormone system for calcium and phosphorus homeostasis. Surprisingly, functional VitD receptors (VDRs) have also been found in lampreys, an ancient vertebrate that lacks a calcified skeleton [12]. VDRs were also identified in animals with a naturally impoverished VitD status like the subterranean mole rat [13] and a frugivorous nocturnal mammal, the Egyptian fruit bat Cavaleros [14]. VitD precursors have been found in ancient organisms like phytoplankton and zooplankton, some of which exist unchanged for at least 750 million years [5,15]. Functional VitD hydroxylases have also been characterized in bacteria like strains of actinomyces [16,17] and streptomyces [18,19]. The precursors of VitD in those organisms may function as a natural sunscreen to protect the host against UV-radiation, since the absorption spectra of pro-vitamin D and their photoproducts overlap with the absorption maxima of DNA, RNA, and proteins [20]. Role of VitD in bone metabolism VitD, which is photosynthesized in the skin or has been derived from nutrition, is metabolized two times, before it mediates its calcemic effects by binding to the nuclear VitD receptor (VDR) [21,22](Figure 1). The metabolizing enzymes belong to a group of cytochrome P450 hydroxylases, which can be found in eukaryotes, bacteria, fungi and plants. In the human liver, the first hydroxylation of VitD on C-25 is performed by mitochondrial 25hydroxylase enzymes (gene names: CYP27A1 [23] and/ or CYP2R1 [24]) that both belong to the cytochrome P450 family. The inactive 25-(OH)-vitamin D3 (25-(OH) D3) metabolite is further hydroxylated at position 1a by the mitochondrial cytochrome P450 enzyme 25-hydroxyvitamin-D-1a-hydroxylase (gene name: CYP27B1) and converted to the bioactive 1a,25-dihydroxyvitamin D (1,25-(OH)2D3). This latter step is mainly localized to the proximal kidney tubule [25], however, many other cell types, including lung epithelial cells, are capable to perform this reaction [26-29]. The serum concentration of 25-(OH)D3 reflects the organisms VitD supply [30]. In the blood, VitD and the inactive, relatively stable 25(OH)D3 metabolite are bound in 99% to the vitamin D binding protein (DBP) [31]. DBP polymorphisms (Gc phenotype) are related to the DBP concentration and VitD status [32]. The 1a-hydroxylation of 25-(OH)D3 is upregulated by parathyroid hormone (PTH), calcitonin, low calcium- and phosphate levels as well as by estrogen, prolactin and growth hormone [33]. Calcitonin, cortisol, high phosphate levels and 25-(OH)D3 suppress the 25-hydroxyvitamin D-1a-hydroxylase activity [34]. 1,25-(OH)2D3 itself works as its own negative feedback regulator by induction of the expression of a 24-hydydroxylase (CYP24A1). Further, 1,25-(OH)2D3 decreases the production and secretion of PTH. PTH synthesis and secretion is induced by decreased serum calcium levels, which are detected by the calcium sensing receptor of the parathyroid gland. PTH effects renal tubular reabsorption of calcium, renal production of 1,25-(OH) 2D3 and promotes osteoclastogenesis [35]. 1,25-(OH)2D3 is essential for the development and maintenance of the growth plate, chondrocyte growth, and the mineralised bone [21]. 1,25-(OH)2D3 modulates the osteoclastogenesis by regulation of the receptor activator of nuclear factor kappa B (RANK), RANK ligand (RANKL) and the soluble receptor osteoprotegerin Figure 1 Metabolism and effects of VitD. VitD can be obtained from food or from synthesis in the skin under exposure to light. The precursor is hydroxylated cytochrome P450 25-hydroxylase enzymes CYP27A1 and/or CYP2R1 and subsequently by the cytochrome P450 enzyme 25hydroxyvitamin D-1a-hydroxylase (CYP27B1) and converted to the bioactive 1,25-(OH)2D3, which has role in Ca and bone metabolism and, in addition, in several other biological processes. Of note, bioactive 1,25-(OH)2D3 can also be generated in lung epithelia cells and monocytes/ macrophages. (OPG) [36]. It increases the expression of RANKL on the osteoblast surface, which supports maturation of progenitor and mature osteoclasts, and it inhibits OPG expression, which binds RANKL and prevents RANK mediated osteoclastogenesis [37]. VitD deficiency causes the development of an imbalanced calcium- and phosphate-homeostasis and the occurrence of the bone diseases osteopenia, osteoporosis, rickets, and osteomalacia with a subsequently increased fracture risk [38]. The 25-(OH)D3 serum concentration is directly associated with bone mineral densitys. VitD deficiency has several causes including inadeq (...truncated)