key: cord-017428-euzvhtax
authors: Janssens, Wim; Lehouck, An; Decramer, Marc; Gayan-Ramirez, Ghislaine
title: Vitamin D and Chronic Obstructive Pulmonary Disease
date: 2012-02-17
journal: Vitamin D and the Lung
DOI: 10.1007/978-1-61779-888-7_11
sha: 
doc_id: 17428
cord_uid: euzvhtax

Vitamin D is an important regulator of calcium and bone homeostasis. It is also involved in the regulation of different genes and cellular functions, particularly in the context of inflammation, regeneration and immune control. Conversely, vitamin D deficiency which is often found in chronic, infectious and inflammatory diseases is thought to drive or enhance uncontrolled inflammation. Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation of the airways most often because of cigarette smoking. It has been recognized that repetitive airway infections and systemic consequences or co-morbidities also contribute to the progressive nature of COPD. Vitamin D deficiency is known to sneak in from the early stages of COPD, to become highly prevalent at the more severe stages, and may thereby catalyse airway infection, inflammation and systemic consequences. Undoubtedly, vitamin D deficiency enhances bone resorption and osteoporosis in COPD for which appropriate vitamin D supplementation is recommended. However, conflicting evidence has emerged on the extra-calcemic effects of vitamin D in COPD. A recent intervention trial with high-dose supplementation in COPD was only able to reduce exacerbation frequency in the subgroup of patients with lowest baseline vitamin D levels. It confirms that severe vitamin D deficiency is a health hazard but that more clinical and experimental studies are needed to explore how vitamin D deficiency may affect airway biology and systemic effects in the context of smoke-induced lung diseases.

Over the last years, there is an increasing interest in the role of vitamin D and vitamin D de fi ciency in various chronic diseases. Besides the well-known effect of vitamin D de fi ciency on bone loss in adults, accumulating evidence also links a low vitamin D nutritional status to highly prevalent chronic illnesses, including cancers, autoimmune diseases, infectious and cardiovascular diseases [1] [2] [3] . Vitamin D is now known to have an important in fl uence on immunoregulation and on the expression of antimicrobial peptides. Since patients with chronic obstructive pulmonary disease (COPD) often integrate all of these co-morbid diseases in one and given that most of COPD exacerbations are triggered by bacterial and viral infection, vitamin D could play a key role in the pathogenesis of this disease. This chapter aims to discuss the prevalence and determinants of vitamin D de fi ciency in COPD, the wellknown effect of vitamin D in the development and treatment of COPD-associated osteoporosis and its potential role in the uncontrolled in fl ammatory cascade and systemic consequences of the disease.

COPD is a chronic disease characterized by air fl ow limitation that is progressive, not fully reversible and associated with an abnormal in fl ammatory response of the lungs to noxious particles or gases. In Western countries, tobacco smoke is the major cause for COPD, accounting for 90-95% of the cases. Since only 20% of smokers develop severe COPD, other factors (biological, hereditary, environmental) must be involved [ 4 ] . Narrowing of the airways by in fl ammation, mucus production, irreversible remodelling and emphysema results in a limitation of expiratory air fl ow and disturbed gas exchange [ 5 ] . Currently, it is estimated that 210 million people suffer from COPD worldwide, a number that is still increasing. By 2020, the World Health Organization predicts that COPD will rise from the sixth to the third leading cause of death, next to only cardiovascular disease and cancer [ 6 ] . According to the Global Obstructive Lung Disease (GOLD) de fi nition, diagnosis of COPD should be based on spirometry measurements with a post-bronchodilator forced expiratory volume in 1 s over forced vital capacity ratio (FEV 1 /FVC) below 0.7. Subsequently, COPD can be categorized in different stages of severity (GOLD stages) going from mild, moderate and severe to very severe disease according to FEV 1 [ 7 ] . It should be noted, however, that the majority of COPD patients, especially in the early stages of the disease, report no complaints, do not perform spirometry and thus are unaware of their disease. Treatment for COPD focuses on minimizing symptoms and preventing exacerbations. With the exception of smoking cessation, so far, no treatment has clearly proven to signi fi cantly modify COPD disease progression. Recent data, however, indicate that pharmacological intervention with inhalation therapy may slow down the yearly decline of FEV 1 [8] [9] [10] .

The pathophysiology of COPD is characterized by an increased in fl ammatory response in the airways and parenchyma. Besides an increase in number of neutrophils, macrophages and T-lymphocytes, COPD is associated with elevated concentrations of various cytokines, including interleukins (IL-1, IL-6 and IL-8), tumour necrosis factor alpha (TNF-a ), oxidative stress and the release of proteolytic enzymes. Cigarette smoke is known to cause a direct injury of the airway epithelial cells leading to the release of endogenous intracellular molecules or danger-associated molecular patterns (DAMPs). These signals are recognized by Toll-like receptors on epithelial cells which initiate a non-speci fi c in fl ammatory response. As reaction on the release of early cytokines (TNF-a , IL-1, IL-8), macrophages, neutrophils and dendritic cells are recruited to the site of in fl ammation [ 11 ] . Proteolytic enzymes and reactive oxygen species are released which may cause further damage to the lung. Next, self-antigens and antigens coming from pathogens bound to dendritic cells can activate naive T cells into Th1 cells [ 12 ] and may lead to antibody producing B cells. This adaptive immune response may then further enhance the in fl ammatory cascade. In addition, the observed reduction of regulatory T cells (Treg) in COPD lungs against the rise of pro-in fl ammatory Th17 cells is pointing towards an impaired immune regulation in COPD [ 13 ] .

Macrophages are believed to play a central role in the pathophysiology of COPD [ 14 ] . They are important sources of pro-in fl ammatory mediators but may also protect against infection by phagocytosis. In COPD, alveolar macrophages appear to be resistant to the anti-in fl ammatory effects of corticosteroids by the reduced activity of histone deacetylase 2 (HDAC2), a nuclear enzyme that switches off in fl ammatory genes activated by the nuclear factor NF-k B [ 15 ] . Additionally, Taylor and colleagues recently demonstrated that the phagocytotic capacity of macrophages of COPD patients is impaired, which may lead to bacterial colonization and increased exacerbation frequency [ 16 ] . Overall, the complexity of the pathogenesis of COPD with different mechanisms and risk factors is re fl ected in the broad variation of clinical phenotypes.

With progression of the disease, as marked by a decline of forced expiratory volume in 1 s (FEV 1 ), COPD patients become more prone to exacerbations. An exacerbation of COPD is an acute worsening of respiratory symptoms which is associated with increased symptoms and worsening of lung function. Recent studies have shown that quality of life and health status of patients are mainly determined by the presence and frequency of such exacerbations which, in turn, may lead to a faster decline in FEV 1 [ 17 ] . Although viral and bacterial infections are assumed to be the major cause of exacerbations, other factors including environmental pollution and allergens have also been identi fi ed [ 18 ] . The exact role of bacterial infection in COPD exacerbations is often biased by bacterial colonization of the airways during stable state with the same organisms as those isolated at exacerbations: Haemophilus in fl uenzae , Streptococcus pneumoniae , Moraxella catarrhalis , Staphylococcus aureus and Pseudomonas aeruginosa . Different studies have shown that prevalence and load of organisms increases during an exacerbation [ 19 ] , but recent evidence indicates that the acquisition of a new bacterial strain is likely the main trigger of an exacerbation [ 20, 21 ] . Besides bacterial infections, exacerbations may also be triggered by viral infections, including infections with rhinoviruses , coronavirus , respiratory syncytial virus , in fl uenza , parain fl uenza and adenoviru s. Moreover, recently, a frequent exacerbator phenotype has been identi fi ed suggesting that the innate and adaptive immune defence of the host also contributes to exacerbation susceptibility and that individualized therapy may become important in the nearby future [ 22 ] .

COPD is not restricted to the lungs but also associated with systemic in fl ammation and increased co-morbidities which are now considered as important targets in the therapeutic approach of COPD. Increased systemic levels of TNF-a , IL-6 and C-reactive protein (CRP) are commonly found in patients with COPD [ 23 ] . Common co-morbidities of COPD include lung cancer, cardiovascular disease, osteoporosis, diabetes and skeletal muscle dysfunction [ 24, 25 ] . Whether these co-morbidities are caused by the underlying disease or just co-exist because of common risk factors such as smoking, ageing and inactivity is far from understood. Most likely, both mechanisms play together and the attractive hypothesis of in fl ammation in the lung "spilling over" into the systemic circulation and affecting other organs is corroborating this idea [ 26 ] . Whatever the mechanism may be, the presence of these co-morbidities clearly contributes to the poor outcome in COPD [ 27, 28 ] .

Vitamin D is generally obtained by photosynthesis in the skin but can also be derived from nutrition (fatty fi sh, fi sh liver oils and dairy products). Ultraviolet light catalyses the fi rst step in the vitamin D biosynthesis, which is the conversion of 7-dehydrocholesterol into pre-vitamin D. The next step is a hydroxylation in the liver into 25-OHD, which then circulates in serum with a long half-life of 15 days. Next, 25-OHD is hydroxylated again into the active vitamin D metabolite 1,25(OH) 2 D by 1 ahydroxylase (CYP27B1) in the kidney which is controlled by serum levels of calcium and phosphate and regulating hormones such as parathyroid hormone (PTH), calcitonin and phosphatonins. 1,25(OH) 2 D also induces the expression of a 24-hydroxylase (CYP24A1) which catabolizes 25-OHD and 1,25(OH) 2 D into biologically inactive, water-soluble metabolites, thereby serving as its own negative feedback. The majority of 25-OHD and 1,25(OH) 2 D are bound to plasma proteins, of which more than 90% to the vitamin D binding protein (DBP), which carry out the delivery to their respective target organs [ 29 ] . 1,25(OH) 2 D may thus bind to the nuclear vitamin D receptor (VDR) in the intestine, bone, kidney and parathyroid gland cells, resulting in the maintenance of normal serum calcium and phosphorus levels and their related effects on mineralization and turnover of bone [ 30, 31 ] . Since 1 a -hydroxylase and the nuclear receptor VDR are widely present in cells of several extrarenal tissues such as skin, bone, prostate and immune cells, local 1,25(OH) 2 D concentrations can also exert different autocrine and paracrine functions. Although the enzyme found here is identical to the one that is expressed in the kidney, its expression is regulated by immune signals instead of mediators of bone and calcium homeostasis [ 32, 33 ] . 1,25(OH) 2 D mediates its effects by binding to the nuclear VDR The vitamin-VDR complex may then activate vitamin D response elements (VDRE) on genes involved in different cellular processes. It is estimated that about 3% of the mouse/human genome is regulated by vitamin D [ 34 ] . Directly or indirectly, vitamin D controls many genes that are involved in the regulation of cellular proliferation, differentiation and apoptosis of healthy and pathological cells.

Because of its long half-life, 25-OHD is typically used to determine vitamin D status. It re fl ects vitamin D synthesized in the skin as well as that acquired from the diet and vitamin D degradation by catabolizing enzymes. When focusing on the calcemic effects, vitamin D insuf fi ciency is best de fi ned as a 25-OHD level below 20 ng/ml (50 nmol/l) [ 2, 35 ] . A sensitive parameter to determine vitamin D de fi ciency is serum levels of PTH. Older data have clearly demonstrated that levels of 25-OHD below 20 ng/ml are associated with an increase in PTH expression [ 36 ] . Based on observational studies, several experts have suggested that, for non-calcemic effects, serum levels of at least 30 ng/ml (75 nmol/l) are required, but so far, intervention studies to support this are lacking.

Dietary sources of vitamin D are limited, and food forti fi cation is mostly inadequate or nonexistent. Although sunlight is the most important source of vitamin D, several other factors can in fl uence the amount of vitamin D that can be synthesized: season, latitude, clothing, the use of sunscreen, darker skin pigmentation and age. For example, ageing is associated with decreased concentrations of 7-dehydrocholesterol in the skin, thereby reducing the capacity to synthesize vitamin D. Even if regularly exposed to sunlight, elderly people produce 75% less cutaneous vitamin D than compared to young adults [ 36 ] . Due to cultural habits and clothing, even those who live in sunny climates are commonly found to be de fi cient in vitamin D. Data from the Third National Health and Nutrition Examination Survey (NHANES III) revealed that in US adults, only 30% of the white population and 5% of the African Americans had levels of vitamin D of at least 30 ng/ml [ 37 ] . According to the current de fi nitions, it is estimated that more than one billion people worldwide have impaired serum levels of vitamin D. As current supplementation regimens with a daily dose of 800-1,000 IU of vitamin D restore de fi cient serum 25-OHD levels in a general adult population to concentrations above 20 ng/ml, higher doses are probably required to increase 25-OHD levels to even higher levels that may be needed for non-calcemic diseases in a population at risk [ 38, 39 ] . At present, we can only speculate on what such ideal target range of 25-OHD levels is to maximally exploit these extra-calcemic effects [ 40 ] . We should also acknowledge that an extensive expert analysis of the potential effects of vitamin D supplementation on the health outcome of North-American subjects concluded that there is presently insuf fi cient evidence for extraskeletal bene fi ts of vitamin D therapy and that only new randomized controlled trials will be able to de fi ne such effect [ 41 ] .

COPD patients should be considered at high risk to become vitamin D de fi cient for a variety of reasons: lower food intake, reduced capacity for vitamin D synthesis of the skin by ageing and smoking, the absence of outdoor activity and sun exposure, impaired activation by renal dysfunction and a lower storage capacity in muscles or fat by wasting may all contribute to a defective vitamin D status in COPD [ 2 ] .

In 2005, Black and colleagues who examined spirometric data from the Third National Health and Nutrition Examination Survey, a cross-sectional survey on 14,091 US civilians over 20 years of age, discovered an important link between vitamin D and spirometric data [ 42 ] . After adjustment for potential confounders, a strong relationship between serum levels of 25-OHD and pulmonary function, as assessed by FEV 1 and FVC, was found. Although a signi fi cant correlation with airway obstruction could not be found, the observed dose-response relationship suggested a causal link [ 43 ] . The observation that smoking African-Americans more rapidly develop severe air fl ow obstruction as compared to Caucasians is also in agreement with the idea that a presumed lower vitamin D status in African-Americans correlates with an increased susceptibility to COPD [ 44 ] . Furthermore, different genetic variants involved in the vitamin D signalling pathway are shown to determine 25-OHD levels [ 45 ] , and some of these variants have repeatedly been associated with COPD. For instance, variants of the DBP gene ( GC ) have been shown to be protective or risk factors for COPD [ 46 ] , and a more recent robust candidate gene study in two large data sets identi fi ed the GC genes as susceptibility loci for COPD [ 47 ] . In a study of Forli and colleagues, vitamin D de fi ciency (<20 ng/ml) was found in more than 50% of a cohort waiting for lung transplantation [ 48 ] , but they failed to compare vitamin D serum levels with a matched control group. However, we recently demonstrated in a group of 414 smoking individuals that patients with COPD were more likely to suffer from vitamin D de fi ciency than aged and gender-matched healthy control smokers without COPD [ 49 ] . In COPD patients, we found a signi fi cant association between vitamin D serum levels and severity of disease assessed by FEV 1 . The prevalence of vitamin D de fi ciency de fi ned by 25-OHD levels below 20 ng/ml increased to, respectively, 60% and 75% in severe (GOLD 3) and very severe COPD patients (GOLD 4) (Fig. 11.1 ) . Interestingly, we also showed that 25-OHD levels were determined by genetic variants in the vitamin D binding gene ( GC) after correcting for age, gender, smoking history and disease severity and that homozygous carriers of the rs7041 T allele with lowest vitamin D levels exhibited an increased risk for COPD. Although the risk effect of certain GC alleles may relate to a lower bioavailability of vitamin D, other authors have suggested that protein variants of DBP may directly affect in fl ammation in the airways [ 50 ] . Wood and colleagues, for instance, demonstrated that local DBP expression in sputum of COPD patients correlates with macrophage phagocytosis capacity [ 49 ] suggesting that the risk effect of DBP may be found in a different activation of macrophages [ 51 ] .

A recent population based study in 2,943 individuals living in Hertfordshire (UK) found reduced vitamin D intake in the COPD subgroup of 521 individuals compared to the non-COPD subjects but was not able to con fi rm the positive association between 25-OHD serum levels and FEV 1 or FVC [ 52 ] . Surprisingly, Shaheen et al. found that patients with highest vitamin D levels were more likely to have COPD. They concluded that in contrast to a prudent dietary pattern with the intake of high amounts of antioxidants [ 53 ] , vitamin D was not an important determinant for adult pulmonary function and risk of COPD. Unfortunately, more than 50% of their population was taking dietary vitamin D supplements for unspeci fi ed reasons, which may have affected their analysis and biased their conclusions. Finally, in a small sub-study of the Lung Health Study III conducted in 198 selected individuals, mean 25-OHD levels of COPD patients with a rapid FEV 1 decline were found to be similar to mean 25-OHD levels of patients with a slow decline, suggesting again that vitamin D de fi ciency does not contribute to COPD progression [ 54 ] . Together, from these con fl icting data, it is clear that more prospective studies are needed to determine causal relationships between vitamin D de fi ciency and pulmonary function in COPD. But even if causality cannot be found for pulmonary function variables, vitamin D de fi ciency may still alter the disease course by affecting other outcomes such as respiratory tract infections or co-morbidities.

Low levels of vitamin D result in low bioavailability of calcium which stimulates parathyroid glands to increase secretion of PTH. In the kidneys, PTH reduces the reabsorption of phosphate from the proximal tubule and increases calcium reabsorption in the distal tubule, resulting in a net increase in calcium/phosphate ratio. PTH also induces renal 1 a -hydroxylase expression which then leads to an increased production of active 1,25(OH) 2 D. 1,25(OH) 2 D enhances intestinal calcium absorption and acts on the immature osteoblastic cells to stimulate osteoclastogenesis through the RANKL/RANK regulatory system, with enhanced bone resorption and mobilization of calcium from the bone compartment, causing osteopenia, osteoporosis and increased risk for bone fractures [ 55 ] . This results in higher levels of calcium and 1,25(OH) 2 D with a negative feedback on PTH and a subsequent limitation of bone resorption. Osteoporosis is a skeletal disorder which is characterized by compromised bone strength resulting in a higher susceptibility to fractures. Bone strength is determined by the structural quality of the bone and by bone mineral density, the latter measured by dual X-ray absorptiometry (DXA) and used to de fi ne osteoporosis. Osteoporosis is a major health problem as osteoporotic fractures are a frequent cause of signi fi cant and long-lasting morbidity in older individuals. Hip fractures and other types of nonvertebral fractures account for most of the burden of osteoporosis, with increased mortality, functional decline, loss of quality of life and need for institutionalization [ 56 ] . Female gender, advancing age, a history of fragility fractures, current or former smoking, low body weight or weight loss and the use of systemic glucocorticoids are well-established risk factors for osteoporosis and osteoporotic fractures. As many of these risk factors are present in COPD patients, especially at the more severe stages, it should be no surprise that osteoporosis and COPD are strongly linked. A recent review of Graat-verboom et al. con fi rmed low body mass, disease severity, use of corticosteroids, age and female gender to be independent risk factors for osteoporosis in COPD [ 57 ] . The majority of studies have reported an increased risk for osteoporosis with decreasing FEV 1 (Fig. 11 .2 ) [59] [60] [61] .

The prevalence of osteoporosis in COPD varies between 9% and 59% depending on the diagnostic methods used, the population studied and the severity of the underlying respiratory disease [ 57 ] . Sin and colleagues used the NHANES III data to demonstrate that air fl ow obstruction is independently associated with reduced bone mineral density [ 59 ] . In their population-based cohort of 9,502 non-Hispanic White participants, 33% of all women with severe COPD had osteoporosis whereas almost all women with mild airway obstruction had osteopenia. In comparison, men were at lower risk than women but still, in men with severe COPD, the prevalence of osteoporosis and osteopenia was 11% and 60%, respectively, which was approximately three times higher than expected. Most studies looking at prevalence of osteoporosis have used DEXA scans which measure bone mineral density but do not evaluate micro-architectural changes of the bone. It is known that these microarchitectural changes may equally cause fragility fractures, even with normal bone density, and should therefore be considered to be osteoporotic as well. When taking DEXA measures and vertebral fragility fractures into account, Graat-Verboom et al. found that prevalence of osteoporosis almost doubled in 250 COPD outpatients [ 62 ] . It indicates that prevalence of osteoporosis in COPD might be much higher than the current prevalence data suggest [ 63 ] .

Interesting relationships are also found with emphysema which is associated with reduced bone mineral density and lower body mass index and which may represent a clinical phenotype at risk for osteoporosis [ 64, 65 ] . Visual emphysema as assessed by CT scan was found to be an independent risk factor for osteopenia/osteoporosis [ 66 ] , and different bone turnover markers are increased in COPD. Recent data also show that osteoprotegerin, which is critically involved in bone turnover by blocking RANK-RANKL interaction, may become a useful marker for parenchymal lung destruction in COPD [ 67, 68 ] . It is currently not known whether the vitamin D pathway is involved in the speci fi c development of emphysema, but studies in laboratory animals certainly corroborate this idea [ 69, 70 ] .

The consequences of osteoporotic fragility fractures in a COPD population may be detrimental. In hip-fracture patients, mortality is close to 20% within 1 year, and of those who do survive the fracture, again, some 20% will have to be institutionalized because of its functional consequences [ 71 ] . The exact prevalence of hip fractures in COPD patients has not been studied in detail, but it is probable that the impact of such events in disabled COPD patients will be even worse. Additionally, vertebral compression fractures can lead to back pain, functional impairments, increased kyphosis with reduced rib cage mobility and decline of pulmonary function [72] [73] [74] . The impact of loss of vertebral height on pulmonary deterioration in COPD has been demonstrated by Leech and colleagues who found that vital capacity and total lung capacity incrementally declined as the number of thoracic vertebral fractures increased [ 72 ] . In the EOLO study, a large COPD cohort of up to 3,000 participants, more than 40%, had one or more vertebral fractures and the prevalence signi fi cantly correlated with severity of disease [ 75 ] . Kyphosis related to osteoporosis may also cause limitation in rib mobility and inspiratory muscle dysfunction and was also correlated with loss of FEV 1 and FVC [ 76 ] .

There is no doubt that vitamin D protects against osteoporosis and osteoporotic fractures, and therefore, suf fi cient vitamin D supplementation should be encouraged. The fact that the majority of COPD patients are of older age, have many common risk factors for osteoporosis and are more likely to be de fi cient in vitamin D supports standard supplementation, especially at the more severe stages of disease. A daily dose of 700-800 IU of vitamin D together with an adequate daily calcium intake (1,000 mg) is probably the best strategy to prevent fractures in older subjects. Such supplementation is known to restore low serum 25-OHD levels in a general adult population to concentrations above the 20 ng/ml (50 nmol/l) threshold. Patients with COPD, particularly those on systemic corticosteroids, should also be considered for a DEXA scan and if needed, osteoporosis medication [ 58 ] . Even though causality and therapeutic bene fi ts of vitamin D remain to be established for pulmonary in fl ammation and other co-morbidities, prevention of vertebral fractures will positively affect pulmonary function [ 75 ] .

Along with a progressive loss of pulmonary function, COPD patients become more prone to acute COPD exacerbations which are an important cause of hospitalization, impaired quality of life and mortality [ 77 ] . Appropriate antimicrobial treatment is essential in the treatment of acute bacterial exacerbations whereas in case of colonization, repetitive and long-term antibiotic treatments are still avoided as they contribute to the multi-resistance of colonizing strains. Anti-in fl ammatory treatments different from inhaled and systemic corticosteroids are currently validated in COPD to reduce exacerbations on top of bronchodilator therapy. PDE4 inhibitors and neo-macrolides are the most promising agents from this perspective and seem to be bene fi cial for a subgroup of patients with repetitive exacerbations [78] [79] [80] . An attractive alternative approach might be the up-regulation of the innate immune defence system with vitamin D, particularly with regard to antimicrobial polypeptides [ 81 ] . Wang and colleagues demonstrated that in different cell types such as epithelial cells and white blood cells, the genes encoding for antimicrobial polypeptides such as cathelicidin (LL-37) and b -defensin are driven by VDR elements containing promoters [ 82 ] . In human monocytes, TLR activation up-regulates expression of the VDR and the 1-a -hydroxylase genes, leading to induction of LL-37 and killing of intracellular Mycobacterium tuberculosis [ 83 ] . LL-37 is also found to be very effective in the killing of a number of antibiotic-resistant strains such as Pseudomonas and S. aureus , different viruses and Chlamydia [ 84, 85 ] . As LL-37 is diffusely expressed in the surface epithelia of human airways, in the submucosal glands and in macrophages and neutrophils [ 86 ] , substitution of local vitamin D insuf fi ciency may reduce bacterial load and concomitant airway in fl ammation [ 87 ] . Apart from its potential bene fi t on bacterial eradication, vitamin D may also down-regulate the complex in fl ammatory cascade at several levels. In vitro vitamin D can reduce the expression of TLRs which are critical in the induction of the early immune response [ 88 ] . High levels of vitamin D also inhibit dendritic cell maturation with lower expression of MHC class II molecules, down-regulation of co-stimulatory molecules and lower production of pro-in fl ammatory cytokines such as IL-2, IL-12, IFN-g and IL-23 [ 33, 89 ] . In several mouse models, vitamin D also leads to a switch from a Th1/Th17 responses towards a Th2 and regulatory T cell answer [ 1, [90] [91] [92] . Low serum levels of vitamin D have also been correlated with a decreased phagocytic activity of macrophages in patients with rickets [ 93 ] whereas antimicrobial activity of macrophages against M. tuberculosis could be increased by vitamin D supplementation [ 94 ] . Overall, the potential of vitamin D in reducing proin fl ammatory processes of the innate and adaptive immune system, together with an increased bacterial eradication by self antimicrobial peptides and enhanced macrophage phagocytosis, may offer great potential in the treatment of exacerbations.

Indirect clinical evidence for such hypothesis may be found in the observation that exacerbations of COPD are most common in winter, when 25-OHD levels are lowest. In addition, data from NHANES III showed that upper respiratory tract infections were most frequent in patients with lowest vitamin D levels. To further investigate such intriguing hypothesis, a randomized placebo-controlled intervention trial was performed to evaluate the effect of vitamin D supplementation in COPD patients, prone to exacerbations [ 95 ] . One hundred and eighty-two patients with moderate to very severe COPD and a history of recent exacerbations were supplemented with 100,000 IU vitamin D or placebo every 4 weeks over one year. Because of high-dose supplementation mean, 25-OHD serum levels increased signi fi cantly in the intervention arm and reached stable mean serum levels of 50 ng/ml, which is in the therapeutic range of the hypothesized extra-calcemic effects [ 2 ] . However, despite effective supplementation, no signi fi cant difference in time to fi rst exacerbation, time to fi rst hospitalization and exacerbation rate could be observed between the intervention and the control group. The absence of a therapeutic effect of vitamin D may relate to the fact that most of the patients presented with severe disease and were on maximal inhalation therapy. As all these treatments are known to reduce exacerbations [ 96, 97 ] , it is likely that any additional effect of vitamin D on top of regular treatment is more dif fi cult to obtain. Intervention within the more early COPD stages taking less medications might therefore be more effective which is in line with the idea that such milder stages are also more sensitive to disease modi fi cation [ 98 ] .

Interestingly, a signi fi cant baseline vitamin level by treatment interaction was observed for exacerbation rates. When performing a post hoc analysis in the subgroup of patients with very de fi cient vitamin D levels at baseline (<10 ng/ml), a signi fi cant 43% reduction of the number of exacerbations was observed in the intervention group. As one out of six COPD patients in the trial presented with such asymptomatic low baseline 25-OHD levels which persisted during the entire course of the study, further focus and future studies on this important subgroup may be warranted, eventually resulting in better patient-tailored interventions. Recently, a frequent exacerbator phenotype has been indenti fi ed suggesting that individualized therapy-including appropriate vitamin D substitution-may become important [ 22 ] .

We also assessed for the presence and load of pathogenic bacteria in cultures of morning sputa during the trial but found no difference in eradication between both study arms. However, monocyte phagocytosis capacity in peripheral blood monocytes of patients receiving vitamin D was signi fi cantly increased compared to the placebo group, an effect which was more pronounced in the subgroup with lowest baseline levels. It is therefore tempting to speculate that the signi fi cant reduction of exacerbations in the vitamin D de fi cient subgroup is explained by an important upregulation of impaired phagocytosis capacity [ 51 ] . So far, hard evidence for this mechanism is lacking. Finally, it should be noted that the lack of an overall effect could also relate to local vitamin D insensitivity because of epigenetic modi fi cations. In line with the known corticosteroid resistance in COPD [ 99 ] , recent studies in cancer have shown that epigenetic silencing of key enzymes of the vitamin D pathway may occur leaving tumour cells insensitive to vitamin D therapy [ 100, 101 ] . At least, epigenetic modi fi cations especially in the context of smoking or poor diet may explain why many observations suggest causal relationships between vitamin D de fi ciency and in fl ammatory diseases whilst supplementation later on in the disease cannot reverse this process [ 102 ] .

Skeletal muscle weakness is common in moderate to severe COPD and is an independent predictor of respiratory failure and death [ 103 ] . Although the underlying mechanisms of skeletal muscle dysfunction in COPD are not entirely understood, it is generally accepted that the combination of disuse because of respiratory limitation, with elevated oxidative stress, systemic in fl ammation, hypoxia and frequent steroid intake, is the main cause of deterioration [ 25 ] . Rehabilitation programmes in COPD are proven successful, but there is still a large variability in training effectivity [ 104, 105 ] . Since muscle weakness is a prominent feature in rickets and chronic renal failure, and epidemiological studies found a positive association between 25-OHD levels and lower extremity function in older persons, vitamin D could be an important factor in muscle health [ 106 ] . In elderly individuals, vitamin D status predicts physical performance and consequent decline during long-term follow-up [ 107 ] . Several double-blind randomized controlled trials demonstrated that vitamin D supplementation increased muscle strength and balance and reduced the risk of falling in elderly [ 108 ] . Although a recent meta-analysis looking at the effect of vitamin D supplementation on muscle strength was negative, positive effects were still found in very de fi cient patients [ 109 ] . Moreover, the cross-sectional analysis from NHANES indicated that muscle strength continued to increase throughout 25-OHD serum levels of 9-37 ng/ml, indicating that for obtaining bene fi cial effects on the muscle, higher dose supplementation might be necessary [ 106 ] .

On the pathological level, adults with vitamin D de fi ciency show predominantly type II muscle fi bre atrophy [ 110 ] with several muscle abnormalities such as enlarged inter fi brillar spaces, in fi ltration of fat, fi brosis and glycogen granules [ 111 ] . Conversely, increase in relative fi bre composition and type II fi bre dimensions has been reported in elderly after treatment with vitamin D [ 112 ] . These type II fi bres are also the fi rst to be recruited to prevent falling [ 113 ] , which may explain why vitamin D supplementation is shown to reduce falling [ 114 ] . In COPD, limb muscle adaptation leads to a decrease of the proportion of slow oxidative type I fi bres with a relative increase towards glycolytic type II fi bres [ 115, 116 ] , those fi bres that are preferentially affected by vitamin D de fi ciency. Therefore, vitamin D de fi ciency may be of particular concern in COPD patients with muscle weakness and dysfunction.

The exact mechanisms by which vitamin D affect muscle function are not fully understood. However, 1,25(OH) 2 D may impair muscle function by altering calcium regulation. In particular, 1,25(OH) 2 D is responsible for the active calcium transportation into the sarcoplasmic reticulum by Ca-ATPase. It is known to regulate Ca-ATPase by phosphorylation of proteins in the sarcoplasmic reticulum membrane; it can increase phosphate transport across the membrane and interacts with calmodulin [ 110, 117 ] . Interestingly, calmodulin is highly sensitive to oxidative stress [ 118 ] , a typical feature of COPD, and 1,25(OH) 2 D may yield antioxidant properties. Thus, both vitamin D de fi ciency and increased oxidative stress through, e.g. smoking may act synergistically impairing calmodulin function, muscle structure and contractility. 1,25(OH) 2 D has also an important role in protein synthesis in the muscle cell, mediated through nuclear receptor-mediated gene transcription [ 113 ] . For example, it can affect actin and troponin C content, two major contractile proteins in skeletal muscle [ 119 ] , or may up-regulate gene expression of muscular growth factors, for instance, IGF-I [ 120 ] .

Although it is tempting to extrapolate these vitamin D-mediated actions in skeletal muscles of healthy or elderly subjects [ 108, 121 ] to a speci fi c population of COPD patients, it is still to be shown that vitamin D de fi ciency contributes to the observed muscle weakness in COPD. At present, there is no direct evidence for such causal relationship but the observation that VDR genotypes may in fl uence quadriceps strength in COPD patients is in line with this assumption [ 122 ] . Recent data also show that vitamin D de fi cient COPD patients referred for rehabilitation have a higher risk for dropout and reduced bene fi t on walking endurance [ 123 ] . In a post hoc analysis in moderate to severe COPD, we also found a signi fi cant effect of high-dose vitamin D supplementation on top of 3 months of rehabilitation in terms of improved exercise capacity [ 124 ] . Therefore, randomized controlled trials investigating if supplementation of vitamin D de fi ciency may positively affect muscle force, muscle function and general COPD outcomes are urgently needed.

In the last years, many clinical studies have associated low vitamin D levels to prevalence and incidence of cancer, including lung cancer [ 125, 126 ] . Several studies associate vitamin D de fi ciency with autoimmune diseases like type I diabetes, multiple sclerosis and rheumatoid arthritis [127] [128] [129] . De fi cient vitamin D levels have been linked to chronic infections such as tuberculosis and acute viral infections like in fl uenza or upper tract respiratory infections [130] [131] [132] [133] . Similar data are also available which link vitamin D de fi ciency to cardiovascular diseases, arterial hypertension and even all cause mortality [ 134 ] . It is beyond the scope of this book chapter to review all evidence on vitamin D in these different chronic diseases, but it is striking that many of them are currently considered to be co-morbid conditions of COPD and accepted as important determinants of COPD outcome and prognosis [ 23, 25 ] . Tackling vitamin D-mediated effects in these co-morbid conditions may therefore indirectly improve COPD status [ 135 ] . It should be stressed, however, that the above mentioned relationships between vitamin D de fi ciency and different chronic diseases are speculative and most often rely on cross-sectional and retrospective observations or on evidence of in vitro and animal research. In humans, placebo-controlled intervention studies and observational studies with prospective long-term follow-up speci fi cally designed to demonstrate causal relationships are often lacking. Moreover, recent intervention studies with vitamin D supplementation in multiple sclerosis, diabetes, in fl uenza and tuberculosis have reported disappointing results, most often by their limitation of statistical power or insuf fi cient supplementation [136] [137] [138] [139] . Recent expert analysis therefore concluded that there is yet insuf fi cient evidence for extra-calcemic bene fi ts of vitamin D therapy and that more randomized placebo-controlled interventions trials are needed to de fi ne such effects [ 41 ] . For COPD in particular, intervention studies targeting co-morbid conditions to improve COPD-speci fi c outcomes will be needed and in analogy with the ongoing trial on statins in COPD patients ( www.clinicaltrials.gov ), one may think about a large intervention study with vitamin D supplements.

Indirectly or directly, vitamin D is also believed to regulate extracellular matrix homeostasis in other tissues than bone, within particular lung and skin tissue via the control of transforming growth factor-b , matrix metalloproteinase and plasminogen activator systems [140] [141] [142] [143] . There is compelling evidence that vitamin D plays a key role in foetal lung growth, development and maturation [ 144, 145 ] . Although 1.25 (OH) 2 D toxicity in Klotho-null mice results in a phenotype of skin atrophy, osteoporosis and emphysema [ 146 ] , recent data in mice show that severe vitamin D de fi ciency from early life also results in a impaired lung function by differences in lung volume and growth [ 69 ] . Evidence from human epidemiological studies also suggests that higher prenatal uptake of vitamin D protects against childhood wheezing [ 147 ] . As impaired lung growth and childhood asthma are known risk factors for COPD at later age [ 148, 149 ] , the causal link between vitamin D de fi ciency and COPD may therefore already exist from early childhood on. Again, recent evidence from animal studies corroborates this idea. VDR knockout mice develop emphysematous airspace enlargement which is associated with the up-regulation of matrix metalloproteinases in the lung, an increased in fl ux of in fl ammatory cells and the development of typical lymphoid aggregates around the peripheral airways [ 70 ] .

The evidence that the vitamin D pathway plays a pivotal role in the biology of healthy and diseased lungs is compelling. As with many chronic diseases, vitamin D de fi ciency is highly prevalent in COPD and occurs more frequently with increasing disease severity. Such de fi ciency may not only enhance local airway in fl ammation but may also induce or accelerate ongoing co-morbid diseases and subsequently impair the general prognosis of the disease (Fig. 11.3 ). So far, there is only hard evidence for a causal role of vitamin D de fi ciency in the pathogenesis of COPDrelated osteoporosis. For extra-calcemic effects, a recent randomized controlled trial demonstrated no overall effect of high-dose supplementation on exacerbations but was supportive for an important effect in a limited subgroup of patients highly de fi cient for vitamin D. Before embarking on new intervention trials with vitamin D in COPD targeting subgroups, more fundamental research is needed to learn how vitamin D and its de fi ciency interact with smoking in the development of COPD. Only then we will be able to understand why so far most intervention trials with vitamin D have failed to yield important health bene fi ts in chronic diseases including COPD.

Vitamin D and health: perspectives from mice and man

Vitamin D de fi ciency

Vitamin D and human health: lessons from vitamin D receptor null mice

Gene-environment interactions in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease

Projections of global mortality and burden of disease from 2002 to 2030

Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary

Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study

Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespeci fi ed subgroup analysis of a randomised controlled trial

Tiotropium as a fi rst maintenance drug in COPD: secondary analysis of the UPLIFT trial

Chronic obstructive pulmonary disease: molecular and cellular mechanisms

Antielastin autoimmunity in tobacco smoking-induced emphysema

Phenotypic characterisation of T-lymphocytes in COPD: abnormal CD4+CD25+ regulatory T-lymphocyte response to tobacco smoking

Alveolar macrophages as orchestrators of COPD

Role of HDAC2 in the pathophysiology of COPD

Schematic representation of potential relationship between vitamin D and COPD

Defective macrophage phagocytosis of bacteria in COPD

Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease

COPD exacerbations: de fi ning their cause and prevention

Effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of COPD

New strains of bacteria and exacerbations of chronic obstructive pulmonary disease

Airway bacterial concentrations and exacerbations of chronic obstructive pulmonary disease

Susceptibility to exacerbation in chronic obstructive pulmonary disease

COPD as a systemic disease

Systemic effects of COPD

COPD as a lung disease with systemic consequences-clinical impact, mechanisms, and potential for early intervention

From COPD to chronic systemic in fl ammatory syndrome?

Mortality in COPD: role of comorbidities

Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD

Biological and clinical aspects of the vitamin D binding protein (Gc-globulin) and its polymorphism

Vitamin D physiology

Overview of general physiologic features and functions of vitamin D

Identi fi cation and immune regulation of 25-hydroxyvitamin D-1-alpha-hydroxylase in murine macrophages

Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts

Genetics and biology of vitamin D receptor polymorphisms

13th workshop consensus for vitamin D nutritional guidelines

Vitamin D de fi ciency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications

Demographic differences and trends of vitamin D insuf fi ciency in the US population

Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes

Vitamin D toxicity, policy, and science

Vitamin D beyond bones in chronic obstructive pulmonary disease: time to act

IOM report sets new dietary intake levels for calcium and vitamin D to maintain health and avoid risks associated with excess

Relationship between serum 25-hydroxyvitamin d and pulmonary function in the Third National Health and Nutrition Examination Survey

Make no bones about it: increasing epidemiologic evidence links vitamin D to pulmonary function and COPD

Smoking patterns in African Americans and whites with advanced COPD

Common genetic determinants of vitamin D insuf fi ciency: a genome-wide association study

Vitamin D binding protein variants and the risk of COPD

Candidate genes for COPD in two large data sets

Vitamin D de fi ciency, bone mineral density and weight in patients with advanced pulmonary disease

Vitamin D de fi ciency is highly prevalent in COPD and correlates with variants in the vitamin D binding gene

The vitamin D axis in the lung: a key role for vitamin D-binding protein

Vitamin D-binding protein contributes to COPD by activation of alveolar macrophages

Relationship of vitamin D status to adult lung function and COPD

The relationship of dietary patterns with adult lung function and COPD

Vitamin D status and longitudinal lung function decline in the lung health study

Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families

Meta-analysis: excess mortality after hip fracture among older women and men

Current status of research on osteoporosis in COPD: a systematic review

The risk of osteoporosis in Caucasian men and women with obstructive airways disease

Low bone mineral density in COPD patients related to worse lung function, low weight and decreased fat-free mass

Low bone mineral density is related to severity of chronic obstructive pulmonary disease

Osteoporosis in COPD outpatients based on bone mineral density and vertebral fractures

Correlates of osteoporosis in chronic obstructive pulmonary disease: an underestimated systemic component

Characterisation of phenotypes based on severity of emphysema in chronic obstructive pulmonary disease

Relationship between pulmonary emphysema and osteoporosis assessed by CT in patients with COPD

Radiographic emphysema predicts low bone mineral density in a tobacco-exposed cohort

Relationship between osteoporosis and adipose tissue leptin and osteoprotegerin in patients with chronic obstructive pulmonary disease

Osteoprotegerin in sputum is a potential biomarker in COPD

Vitamin D de fi ciency causes de fi cits in lung function and alters lung structure

Deletion of vitamin D receptor leads to premature emphysema/COPD by increased matrix metalloproteinases and lymphoid aggregates formation

A prospective study on socioeconomic aspects of fracture of the proximal femur

Relationship of lung function to severity of osteoporosis in women

Association of osteoporotic vertebral compression fractures with impaired functional status

The association of radiographically detected vertebral fractures with back pain and function: a prospective study

Vertebral fractures in patients with chronic obstructive pulmonary disease: the EOLO study

Reduced pulmonary function in patients with spinal osteoporotic fractures

The impact of severe exacerbations on quality of life and the clinical course of chronic obstructive pulmonary disease

Reduction of exacerbations by the PDE4 inhibitor ro fl umilast-the importance of de fi ning different subsets of patients with COPD

Azithromycin for prevention of exacerbations of COPD

Ro fl umilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials

Antimicrobial peptides of multicellular organisms

Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression

Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response

Human cathelicidin (LL-37), a multifunctional peptide, is expressed by ocular surface epithelia and has potent antibacterial and antiviral activity

Activities of LL-37, a cathelin-associated antimicrobial peptide of human neutrophils

The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface

Fighting infections with vitamin D

Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns

Vitamin D signaling in immunemediated disorders: evolving insights and therapeutic opportunities

Prevention of autoimmune diabetes in NOD mice by 1,25 dihydroxyvitamin D3

The coming of age of 1,25-dihydroxyvitamin D(3) analogs as immunomodulatory agents

Immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a T helper (Th) 1/Th17 to a Th2 and regulatory T cell pro fi le

Evaluation of phagocytosis in rickets

Control of Mycobacterium tuberculosis through mammalian Toll-like receptors

High doses of vitamin D to reduce exacerbations in COPD: a randomized trial

A 4-year trial of tiotropium in chronic obstructive pulmonary disease

Combined salmeterol and fl uticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial

Treatment of COPD: the sooner the better?

Decreased histone deacetylase activity in chronic obstructive pulmonary disease

VDR microRNA expression and epigenetic silencing of vitamin D signaling in melanoma cells

DNA methylation-related vitamin D receptor insensitivity in breast cancer

Vitamin D and susceptibility of chronic lung diseases: role of epigenetics

Peripheral muscle weakness contributes to exercise limitation in COPD

Pulmonary rehabilitation in chronic obstructive pulmonary disease

Exercise training in COPD: how to distinguish responders from nonresponders

Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged > or =60

Vitamin D status predicts physical performance and its decline in older persons

Effect of vitamin D on falls: a metaanalysis

Effect of vitamin D supplementation on muscle strength: a systematic review and meta-analysis

Role of vitamin D in skeletal muscle function

Osteomalacic myopathy

Low-dose vitamin D prevents muscular atrophy and reduces falls and hip fractures in women after stroke: a randomized controlled trial

Vitamin D and its role in skeletal muscle

Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials

Oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in normal subjects and in patients with COPD

Muscle fi ber type IIX atrophy is involved in the loss of fat-free mass in chronic obstructive pulmonary disease

Induction of speci fi c proteins in cultured skeletal muscle cells by 1,25-dihydroxyvitamin D-3

Analysis of the oxidative damage-induced conformational changes of apo-and holocalmodulin by dose-dependent protein oxidative surface mapping

The effect of cholecalciferol in vivo on proteins and lipids of skeletal muscle from rachitic chicks

Vitamin D and human skeletal muscle

The effects of whole-body vibration training and vitamin D supplementation on muscle strength, muscle mass, and bone density in institutionalized elderly women: a 6-month randomized, controlled trial

Vitamin D receptor genotypes in fl uence quadriceps strength in chronic obstructive pulmonary disease

Vitamin d status in patients with chronic obstructive pulmonary disease who participate in pulmonary rehabilitation

Vitamin D supplementation during rehabilitation in patients with chronic obstructive pulmonary disease: an intervention study

Prospective study of predictors of vitamin D status and cancer incidence and mortality in men

Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial

Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study

Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis

Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey

Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey

Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis

Epidemic in fl uenza and vitamin D

Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults

Vitamin D de fi ciency an important, common, and easily treatable cardiovascular risk factor?

Treating the systemic effects of chronic obstructive pulmonary disease

A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis

Randomized trial of vitamin D supplementation to prevent seasonal in fl uenza A in schoolchildren

Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D de fi cient-a randomised, placebo-controlled trial

Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial

25-Dihydroxyvitamin D3 and its analogues down-regulate cell invasion-associated proteases in cultured malignant cells

25(OH)2D3 is an autocrine regulator of extracellular matrix turnover and growth factor release via ERp60 activated matrix vesicle metalloproteinases

Sputum matrix metalloproteases: comparison between chronic obstructive pulmonary disease and asthma

Upregulation of MMP-9 production by TNFalpha in keratinocytes and its attenuation by vitamin D

Childhood asthma may be a consequence of vitamin D de fi ciency

The in utero effects of maternal vitamin D de fi ciency: how it results in asthma and other chronic diseases

Premature aging-like phenotype in fi broblast growth factor 23 null mice is a vitamin D-mediated process

Maternal vitamin D intake during pregnancy and early childhood wheezing

Early life origins of chronic obstructive pulmonary disease

Risk factors for chronic obstructive pulmonary disease in a European cohort of young adults

Vitamin D de fi ciency and chronic obstructive pulmonary disease: a vicious circle


