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• W2092234732 abstract "Pulmonary disorders including asthma have been linked to the vitamin D axis.1Gupta A. Sjoukes A. Richards D. Banya W. Hawrylowicz C. Bush A. et al.Relationship between serum vitamin D, disease severity and airway remodeling in children with asthma.Am J Respir Crit Care Med. 2011; 184: 1342-1349Crossref PubMed Scopus (247) Google Scholar, 2Hollams E.M. Hart P.H. Holt B.J. Serralha M. Parsons F. de Klerk N.H. et al.Vitamin D and atopy and asthma phenotypes in children: a longitudinal cohort study.Eur Respir J. 2011; 38: 1320-1327Crossref PubMed Scopus (150) Google Scholar This axis includes vitamin D, vitamin D binding protein (VDBP), and the vitamin D receptor. VDBP is a serum protein that binds circulating vitamin D with high affinity and also possesses immunomodulatory functions that may be of particular relevance in pulmonary infections and inflammation.3Chishimba L. Thickett D.R. Stockley R.A. Wood A.M. The vitamin D axis in the lung: a key role for vitamin D-binding protein.Thorax. 2010; 65: 456-462Crossref PubMed Scopus (156) Google Scholar, 4Wood A.M. Bassford C. Webster D. Newby P. Rajesh P. Stockley R.A. et al.Vitamin D-binding protein contributes to COPD by activation of alveolar macrophages.Thorax. 2011; 66: 205-210Crossref PubMed Scopus (86) Google Scholar, 5Metcalf J.P. Thompson A.B. Gossman G.L. Nelson K.J. Koyama S. Rennard S.I. et al.Gcglobulin functions as a cochemotaxin in the lower respiratory tract: a potential mechanism for lung neutrophil recruitment in cigarette smokers.Am Rev Respir Dis. 1991; 143: 844-849Crossref PubMed Google ScholarA recent study identified that circulating VDBP levels inversely correlate with lung function in an adult cohort with chronic obstructive pulmonary disease and that sputum VDBP contributes to macrophage activation.4Wood A.M. Bassford C. Webster D. Newby P. Rajesh P. Stockley R.A. et al.Vitamin D-binding protein contributes to COPD by activation of alveolar macrophages.Thorax. 2011; 66: 205-210Crossref PubMed Scopus (86) Google Scholar Little is known about the role of VDBP in children with asthma. We hypothesized that children with severe therapy-resistant asthma (STRA) have higher levels of VDBP in the airway—measured in the bronchoalveolar lavage (BAL) fluid—than do nonasthmatic controls, which is associated with worse clinical parameters of asthma control including lung function, symptoms, and pathophysiology.Fifteen children with STRA, 7 with moderate asthma, and 6 nonasthmatic controls were recruited from the Royal Brompton Hospital, London. STRA was defined as previously.6Bush A. Saglani S. Management of severe asthma in children.Lancet. 2010; 376: 814-825Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar Briefly, children with STRA had persistent symptoms despite treatment with high-dose inhaled corticosteroids (ICS) (at least 800 μg/d of beclomethasone equivalent) and trials of add-on drugs (long-acting β2-agonists, leukotriene receptor antagonists, and oral theophylline in a low, anti-inflammatory dose), recurrent severe asthma exacerbations, and/or persistent airflow obstruction (post–oral steroid, postbronchodilator Z score < −1.96 for FEV1 despite above therapy); all children had been through a detailed protocol to optimize adherence and other aspects of basic management, as far as is possible. Approval for the study of pediatric patients was given by the Royal Brompton Hospital Ethics Committee, and written informed consent from parents and age-appropriate assent from children was obtained in each case. Children with moderate asthma were well controlled on a lower dose (<800 μg/d) of ICS. The nonasthmatic controls comprised children with no lower respiratory tract disease undergoing a clinically indicated bronchoscopy for upper airway problems such as stridor.The VDBP level in BAL, serum, and cell culture supernatant was measured by using ELISA (Immunodiagnostik, Bensheim, Germany), and serum 25-hydroxyvitamin D3 level was measured by using a 2-dimensional high performance liquid chromatography system tandem mass spectrometry. Total filtered BAL cells (1 × 106 per mL in RPMI/10% FCS) were cultured for 72 hours at 37°C/5% CO2 in the presence of LPS (50 ng/mL, Sigma-Aldrich, Poole, United Kingdom) with or without dexamethasone (10−7 mol/L, Sigma-Aldrich).Children with STRA had significantly higher levels of VDBP in BAL but not in serum as compared with those in moderate asthma (P < .05) and control individuals (P < .01). There was a negative association between the concentration of VDBP in BAL, but not in serum, and asthma control (assessed by using the asthma control test; BAL VDBP Spearman r = −0.5, P = .01; serum VDBP Spearman r = 0.2, P = .3) as well as spirometry (FEV1% [BAL VDBP Spearman r = −0.4, P = .01; serum VDBP Spearman r = −0.3, P = .2]) and a positive association with ICS usage (BAL VDBP Spearman r = 0.6, P = .002; serum VDBP Spearman r = −0.3, P = .2). There was no correlation between BAL VDBP and serum VDBP (Spearman r = −0.199; P = .3) (Fig 1) . In vitro, the corticosteroid dexamethasone did not promote VDBP synthesis by total BAL cells (n = 7, paired t test P = .8; data not shown). There was no association between circulating 25(OH)vitamin D3 level and either BAL or serum VDBP concentration (BAL VDBP Spearman r = −0.3, P = .1; serum VDBP Spearman r = 0.1, P = .6) (Fig 2).Fig 2No association between serum 25-hydroxyvitamin D3 levels (25 [OH] D3) and BAL VDBP (A; r = −0.3; P = .1) and serum VDBP (B; r = 0.1; P = .6). Correlation was determined by using the Spearman rank correlation coefficient.View Large Image Figure ViewerDownload Hi-res image Download (PPT)In this cross-sectional study, we identify that BAL, but not serum, levels of VDBP are significantly higher in STRA and that BAL VDBP levels inversely correlate with asthma severity, as assessed by the asthma control test, spirometry, and ICS usage. Serum VDBP status did not influence any of these parameters of asthma control and did not correlate with BAL VDBP level. Dexamethasone is reported to increase the VDBP level in the airway in mice and in human hepatoma cells,7Guha C. Osawa M. Werner P.A. Galbraith R.M. Paddock G.V. Regulation of human Gc (vitamin D–binding) protein levels: hormonal and cytokine control of gene expression in vitro.Hepatology. 1995; 21: 1675-1681PubMed Google Scholar, 8Zhao J. Yeong L.H. Wong W.S.F. Dexamethasone alters bronchoalveolar lavage fluid proteome in a mouse asthma model.Int Arch Allergy Immunol. 2007; 142: 219-229Crossref PubMed Scopus (34) Google Scholar suggesting a potential iatrogenic cause for our observations; however, our findings indicate no modulation of VDBP expression by total BAL cells exposed to dexamethasone in vitro. These data highlight the potential importance of the vitamin D axis, beyond vitamin D itself, in children with asthma.The vast majority of circulating vitamin D, both 25(OH)D3 and 1,25(OH)D3, is bound to VDBP, which circulates at levels that far exceed those of its cargo. The cellular uptake of vitamin D can occur via both VDBP-independent and -dependent pathways, although we do not yet fully comprehend the implication of signaling via these different routes. In vitro addition of VDBP to monocyte cultures impairs vitamin D responsiveness9Chun R.F. Lauridsen A.L. Suon L. Zella L.A. Pike J.W. Modlin R.L. et al.Vitamin D-binding protein directs monocyte responses to 25-hydroxy- and 1,25-dihydroxyvitamin D.J Clin Endocrinol Metab. 2010; 95: 3368-3376Crossref PubMed Scopus (185) Google Scholar presumably by limiting the free diffusion of unbound vitamin into the cells. This may represent one mechanism by which excessive VDBP in the airway may limit vitamin D bioactivity with potential immunological consequences.An alternative explanation may relate to the effects of VDBP on innate cell function. VDBP augments the chemotactic functions of monocytes and neutrophils and together with the macrophage activating factor drives macrophage activation in vitro toward a highly phagocytic phenotype with increased superoxide generation.3Chishimba L. Thickett D.R. Stockley R.A. Wood A.M. The vitamin D axis in the lung: a key role for vitamin D-binding protein.Thorax. 2010; 65: 456-462Crossref PubMed Scopus (156) Google Scholar, 4Wood A.M. Bassford C. Webster D. Newby P. Rajesh P. Stockley R.A. et al.Vitamin D-binding protein contributes to COPD by activation of alveolar macrophages.Thorax. 2011; 66: 205-210Crossref PubMed Scopus (86) Google Scholar Alveolar macrophages are the most abundant cell type in the airway and exhibit phenotypic changes in asthma. In health, local signals are likely to restrain these cells, making them relatively unresponsive to inflammatory stimuli, which is believed to be important for the prevention of airway hyperreactivity.10Holt P.G. Strickland D.H. Wikstrom M.E. Jahnsen F.L. Regulation of immunological homeostasis in the respiratory tract.Nat Rev Immunol. 2008; 8: 142-152Crossref PubMed Scopus (388) Google Scholar It is plausible that in asthma, excessive airway VDBP drives alveolar macrophages into a more inflammatory state, diverting them from their tolerogenic role.The final possible interpretation of these data could simply be that raised airway VDBP level is reflective of a chronic state of inflammation in the airway. Inflammatory cytokines are known to stimulate hepatic transcription of VDBP,7Guha C. Osawa M. Werner P.A. Galbraith R.M. Paddock G.V. Regulation of human Gc (vitamin D–binding) protein levels: hormonal and cytokine control of gene expression in vitro.Hepatology. 1995; 21: 1675-1681PubMed Google Scholar and this may also occur locally in the lung. This cross-sectional study cannot imply causality, but it strongly suggests that further study of VDBP as a potential biological mechanism or disease marker in asthma is warranted. Pulmonary disorders including asthma have been linked to the vitamin D axis.1Gupta A. Sjoukes A. Richards D. Banya W. Hawrylowicz C. Bush A. et al.Relationship between serum vitamin D, disease severity and airway remodeling in children with asthma.Am J Respir Crit Care Med. 2011; 184: 1342-1349Crossref PubMed Scopus (247) Google Scholar, 2Hollams E.M. Hart P.H. Holt B.J. Serralha M. Parsons F. de Klerk N.H. et al.Vitamin D and atopy and asthma phenotypes in children: a longitudinal cohort study.Eur Respir J. 2011; 38: 1320-1327Crossref PubMed Scopus (150) Google Scholar This axis includes vitamin D, vitamin D binding protein (VDBP), and the vitamin D receptor. VDBP is a serum protein that binds circulating vitamin D with high affinity and also possesses immunomodulatory functions that may be of particular relevance in pulmonary infections and inflammation.3Chishimba L. Thickett D.R. Stockley R.A. Wood A.M. The vitamin D axis in the lung: a key role for vitamin D-binding protein.Thorax. 2010; 65: 456-462Crossref PubMed Scopus (156) Google Scholar, 4Wood A.M. Bassford C. Webster D. Newby P. Rajesh P. Stockley R.A. et al.Vitamin D-binding protein contributes to COPD by activation of alveolar macrophages.Thorax. 2011; 66: 205-210Crossref PubMed Scopus (86) Google Scholar, 5Metcalf J.P. Thompson A.B. Gossman G.L. Nelson K.J. Koyama S. Rennard S.I. et al.Gcglobulin functions as a cochemotaxin in the lower respiratory tract: a potential mechanism for lung neutrophil recruitment in cigarette smokers.Am Rev Respir Dis. 1991; 143: 844-849Crossref PubMed Google Scholar A recent study identified that circulating VDBP levels inversely correlate with lung function in an adult cohort with chronic obstructive pulmonary disease and that sputum VDBP contributes to macrophage activation.4Wood A.M. Bassford C. Webster D. Newby P. Rajesh P. Stockley R.A. et al.Vitamin D-binding protein contributes to COPD by activation of alveolar macrophages.Thorax. 2011; 66: 205-210Crossref PubMed Scopus (86) Google Scholar Little is known about the role of VDBP in children with asthma. We hypothesized that children with severe therapy-resistant asthma (STRA) have higher levels of VDBP in the airway—measured in the bronchoalveolar lavage (BAL) fluid—than do nonasthmatic controls, which is associated with worse clinical parameters of asthma control including lung function, symptoms, and pathophysiology. Fifteen children with STRA, 7 with moderate asthma, and 6 nonasthmatic controls were recruited from the Royal Brompton Hospital, London. STRA was defined as previously.6Bush A. Saglani S. Management of severe asthma in children.Lancet. 2010; 376: 814-825Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar Briefly, children with STRA had persistent symptoms despite treatment with high-dose inhaled corticosteroids (ICS) (at least 800 μg/d of beclomethasone equivalent) and trials of add-on drugs (long-acting β2-agonists, leukotriene receptor antagonists, and oral theophylline in a low, anti-inflammatory dose), recurrent severe asthma exacerbations, and/or persistent airflow obstruction (post–oral steroid, postbronchodilator Z score < −1.96 for FEV1 despite above therapy); all children had been through a detailed protocol to optimize adherence and other aspects of basic management, as far as is possible. Approval for the study of pediatric patients was given by the Royal Brompton Hospital Ethics Committee, and written informed consent from parents and age-appropriate assent from children was obtained in each case. Children with moderate asthma were well controlled on a lower dose (<800 μg/d) of ICS. The nonasthmatic controls comprised children with no lower respiratory tract disease undergoing a clinically indicated bronchoscopy for upper airway problems such as stridor. The VDBP level in BAL, serum, and cell culture supernatant was measured by using ELISA (Immunodiagnostik, Bensheim, Germany), and serum 25-hydroxyvitamin D3 level was measured by using a 2-dimensional high performance liquid chromatography system tandem mass spectrometry. Total filtered BAL cells (1 × 106 per mL in RPMI/10% FCS) were cultured for 72 hours at 37°C/5% CO2 in the presence of LPS (50 ng/mL, Sigma-Aldrich, Poole, United Kingdom) with or without dexamethasone (10−7 mol/L, Sigma-Aldrich). Children with STRA had significantly higher levels of VDBP in BAL but not in serum as compared with those in moderate asthma (P < .05) and control individuals (P < .01). There was a negative association between the concentration of VDBP in BAL, but not in serum, and asthma control (assessed by using the asthma control test; BAL VDBP Spearman r = −0.5, P = .01; serum VDBP Spearman r = 0.2, P = .3) as well as spirometry (FEV1% [BAL VDBP Spearman r = −0.4, P = .01; serum VDBP Spearman r = −0.3, P = .2]) and a positive association with ICS usage (BAL VDBP Spearman r = 0.6, P = .002; serum VDBP Spearman r = −0.3, P = .2). There was no correlation between BAL VDBP and serum VDBP (Spearman r = −0.199; P = .3) (Fig 1) . In vitro, the corticosteroid dexamethasone did not promote VDBP synthesis by total BAL cells (n = 7, paired t test P = .8; data not shown). There was no association between circulating 25(OH)vitamin D3 level and either BAL or serum VDBP concentration (BAL VDBP Spearman r = −0.3, P = .1; serum VDBP Spearman r = 0.1, P = .6) (Fig 2). In this cross-sectional study, we identify that BAL, but not serum, levels of VDBP are significantly higher in STRA and that BAL VDBP levels inversely correlate with asthma severity, as assessed by the asthma control test, spirometry, and ICS usage. Serum VDBP status did not influence any of these parameters of asthma control and did not correlate with BAL VDBP level. Dexamethasone is reported to increase the VDBP level in the airway in mice and in human hepatoma cells,7Guha C. Osawa M. Werner P.A. Galbraith R.M. Paddock G.V. Regulation of human Gc (vitamin D–binding) protein levels: hormonal and cytokine control of gene expression in vitro.Hepatology. 1995; 21: 1675-1681PubMed Google Scholar, 8Zhao J. Yeong L.H. Wong W.S.F. Dexamethasone alters bronchoalveolar lavage fluid proteome in a mouse asthma model.Int Arch Allergy Immunol. 2007; 142: 219-229Crossref PubMed Scopus (34) Google Scholar suggesting a potential iatrogenic cause for our observations; however, our findings indicate no modulation of VDBP expression by total BAL cells exposed to dexamethasone in vitro. These data highlight the potential importance of the vitamin D axis, beyond vitamin D itself, in children with asthma. The vast majority of circulating vitamin D, both 25(OH)D3 and 1,25(OH)D3, is bound to VDBP, which circulates at levels that far exceed those of its cargo. The cellular uptake of vitamin D can occur via both VDBP-independent and -dependent pathways, although we do not yet fully comprehend the implication of signaling via these different routes. In vitro addition of VDBP to monocyte cultures impairs vitamin D responsiveness9Chun R.F. Lauridsen A.L. Suon L. Zella L.A. Pike J.W. Modlin R.L. et al.Vitamin D-binding protein directs monocyte responses to 25-hydroxy- and 1,25-dihydroxyvitamin D.J Clin Endocrinol Metab. 2010; 95: 3368-3376Crossref PubMed Scopus (185) Google Scholar presumably by limiting the free diffusion of unbound vitamin into the cells. This may represent one mechanism by which excessive VDBP in the airway may limit vitamin D bioactivity with potential immunological consequences. An alternative explanation may relate to the effects of VDBP on innate cell function. VDBP augments the chemotactic functions of monocytes and neutrophils and together with the macrophage activating factor drives macrophage activation in vitro toward a highly phagocytic phenotype with increased superoxide generation.3Chishimba L. Thickett D.R. Stockley R.A. Wood A.M. The vitamin D axis in the lung: a key role for vitamin D-binding protein.Thorax. 2010; 65: 456-462Crossref PubMed Scopus (156) Google Scholar, 4Wood A.M. Bassford C. Webster D. Newby P. Rajesh P. Stockley R.A. et al.Vitamin D-binding protein contributes to COPD by activation of alveolar macrophages.Thorax. 2011; 66: 205-210Crossref PubMed Scopus (86) Google Scholar Alveolar macrophages are the most abundant cell type in the airway and exhibit phenotypic changes in asthma. In health, local signals are likely to restrain these cells, making them relatively unresponsive to inflammatory stimuli, which is believed to be important for the prevention of airway hyperreactivity.10Holt P.G. Strickland D.H. Wikstrom M.E. Jahnsen F.L. Regulation of immunological homeostasis in the respiratory tract.Nat Rev Immunol. 2008; 8: 142-152Crossref PubMed Scopus (388) Google Scholar It is plausible that in asthma, excessive airway VDBP drives alveolar macrophages into a more inflammatory state, diverting them from their tolerogenic role. The final possible interpretation of these data could simply be that raised airway VDBP level is reflective of a chronic state of inflammation in the airway. Inflammatory cytokines are known to stimulate hepatic transcription of VDBP,7Guha C. Osawa M. Werner P.A. Galbraith R.M. Paddock G.V. Regulation of human Gc (vitamin D–binding) protein levels: hormonal and cytokine control of gene expression in vitro.Hepatology. 1995; 21: 1675-1681PubMed Google Scholar and this may also occur locally in the lung. This cross-sectional study cannot imply causality, but it strongly suggests that further study of VDBP as a potential biological mechanism or disease marker in asthma is warranted." @default.
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