title: Vitamin D deficiency exacerbates COPD-like characteristics in the lungs of cigarette smoke-exposed mice.
abstract: BACKGROUND
  Chronic obstructive pulmonary disease (COPD) is characterized by excessive inflammation and disturbed bacterial clearance in the airways. Although cigarette smoke (CS) exposure poses a major risk, vitamin D deficiency could potentially contribute to COPD progression. Many in vitro studies demonstrate important anti-inflammatory and antibacterial effects of vitamin D, but a direct contribution of vitamin D deficiency to COPD onset and disease progression has not been explored.
  
  
  METHODS
  In the current study, we used a murine experimental model to investigate the combined effect of vitamin D deficiency and CS exposure on the development of COPD-like characteristics. Therefore, vitamin D deficient or control mice were exposed to CS or ambient air for a period of 6 (subacute) or 12 weeks (chronic). Besides lung function and structure measurements, we performed an in depth analysis of the size and composition of the cellular infiltrate in the airways and lung parenchyma and tested the ex vivo phagocytic and oxidative burst capacity of alveolar macrophages.
  
  
  RESULTS
  Vitamin D deficient mice exhibited an accelerated lung function decline following CS exposure compared to control mice. Furthermore, early signs of emphysema were only observed in CS-exposed vitamin D deficient mice, which was accompanied by elevated levels of MMP-12 in the lung. Vitamin D deficient mice showed exacerbated infiltration of inflammatory cells in the airways and lung parenchyma after both subacute and chronic CS exposure compared to control mice. Furthermore, elevated levels of typical proinflammatory cytokines and chemokines could be detected in the bronchoalveolar lavage fluid (KC and TNF-α) and lung tissue (IP-10, MCP-1, IL-12) of CS-exposed vitamin D deficient mice compared to control mice. Finally, although CS greatly impaired the ex vivo phagocytic and oxidative burst function of alveolar macrophages, vitamin D deficient mice did not feature an additional defect.
  
  
  CONCLUSIONS
  Our data demonstrate that vitamin D deficiency both accelerates and aggravates the development of characteristic disease features of COPD. As vitamin D deficiency is highly prevalent, large randomized trials exploring effects of vitamin D supplementation on lung function decline and COPD onset are needed.
authors.affiliation: Laboratory of Respiratory Diseases, Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Herestraat 49, 3000, Leuven, Belgium. nele.heulens@med.kuleuven.be.
authors.forename: Nele
authors.initials: N
authors.lastname: Heulens
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Herestraat 49, 3000, Leuven, Belgium. hannelie.korf@med.kuleuven.be.
authors.forename: Hannelie
authors.initials: H
authors.lastname: Korf
authors.affiliation: Laboratory of Respiratory Diseases, Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Herestraat 49, 3000, Leuven, Belgium. nele.cielen@med.kuleuven.be.
authors.forename: Nele
authors.initials: N
authors.lastname: Cielen
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Herestraat 49, 3000, Leuven, Belgium. elien.desmidt@med.kuleuven.be.
authors.forename: Elien
authors.initials: E
authors.lastname: De Smidt
authors.affiliation: Laboratory of Respiratory Diseases, Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Herestraat 49, 3000, Leuven, Belgium. karen.maes@med.kuleuven.be.
authors.forename: Karen
authors.initials: K
authors.lastname: Maes
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Herestraat 49, 3000, Leuven, Belgium. conny.gysemans@med.kuleuven.be.
authors.forename: Conny
authors.initials: C
authors.lastname: Gysemans
authors.affiliation: Translational Cell and Tissue Research, Department of Imaging and Pathology, Katholieke Universiteit Leuven, Minderbroederstraat 12, 3000, Leuven, Belgium. eric.verbeken@uzleuven.be.
authors.forename: Erik
authors.initials: E
authors.lastname: Verbeken
authors.affiliation: Laboratory of Respiratory Diseases, Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Herestraat 49, 3000, Leuven, Belgium. ghislaine.gayan-ramirez@med.kuleuven.be.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Gayan-Ramirez
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Herestraat 49, 3000, Leuven, Belgium. chantal.mathieu@uzleuven.be.
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
authors.affiliation: Laboratory of Respiratory Diseases, Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Herestraat 49, 3000, Leuven, Belgium. wim.janssens@uzleuven.be.
authors.forename: Wim
authors.initials: W
authors.lastname: Janssens
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002118:Calcium / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008262:Macrophage Activation; D016676:Macrophages, Alveolar; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010587:Phagocytosis; D011014:Pneumonia / Q000209:etiology / Q000503:physiopathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D011656:Pulmonary Emphysema / Q000209:etiology / Q000503:physiopathology; D016897:Respiratory Burst; D012307:Risk Factors; D012906:Smoke; D012907:Smoking / Q000009:adverse effects*; D013997:Time Factors; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood; D014808:Vitamin D Deficiency / Q000150:complications* / Q000175:diagnosis / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D012906:Smoke; D014807:Vitamin D; C104450:25-hydroxyvitamin D; D053508:Matrix Metalloproteinase 12; C000602031:matrix metallopeptidase 12, mouse; D002118:Calcium