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

Sundar, Isaac K.; Hwang, Jae Woong; Wu, Shaoping; Sun, Jun; Rahman, Irfan

doi:10.1016/j.bbrc.2011.02.011

Cited by 94 publications

(83 citation statements)

References 34 publications

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“…In airway epithelial cells, VitD induces the expression of the antimicrobial peptide cathelicidin (16,17). VitD deficiency in mice causes alterations in the structure of the lung with decreased functional capacity (18), and deletion of the VDR leads to premature emphysema (19). Surprisingly, a recent paper showed that dietary VitD deficiency did not result in a frank change of the pulmonary response to lipopolysaccharide (LPS) in a mouse model (20).…”

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Vitamin D Deficiency Does Not Result in a Breach of Host Defense in Murine Models of Pneumonia

et al. 2016

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bVitamin D (VitD) has a role in the regulation of calcium and phosphate metabolism and in addition impacts the activity of the immune system. VitD deficiency might be linked to increased susceptibility to respiratory tract infection. The aim of the present study was to characterize the impact of VitD deficiency on the susceptibility to bacterial infection in murine models. C57BL/6N mice were fed a diet with or without VitD for 10 weeks. The VitD-deficient or -sufficient mice were infected with Pseudomonas aeruginosa or Streptococcus pneumoniae. The colonization and inflammatory response in the lung were analyzed at defined time points. The serum 25-hydroxy-VitD concentration was significantly lower in mice on the VitD-deficient diet. In infection experiments with Pseudomonas aeruginosa or Streptococcus pneumoniae, no differences could be observed in the numbers of viable bacteria or in differential cell counts in the bronchoalveolar lavage fluids. Measurements of inflammatory cytokines (KC and interleukin-1␤ [IL-1␤]) did not show significant differences between the groups. In conclusion, VitD-deficient animals did not show significantly increased susceptibility to infection or an altered course of infection. The immune systems of humans and mice likely respond differently to VitD. Murine models are likely not appropriate for drawing conclusions on the role of VitD in human pulmonary host defense.

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Vitamin D Deficiency Does Not Result in a Breach of Host Defense in Murine Models of Pneumonia

et al. 2016

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“…The zymography was performed to determine the activity of MMPs in mouse lungs as described previously (46,47). Briefly, the lung tissue was homogenized with 50 mM Tris·HCl (pH 7.4) on ice, and lung homogenates that contained 200 g of protein were mixed with an equal volume of sample buffer [80 mmol/l Tris·HCl (pH 6.8), 4% SDS, 10% glycerol, 0.01% bromophenol blue].…”

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confidence: 99%

SIRT1 redresses the imbalance of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-9 in the development of mouse emphysema and human COPD

Yao

Hwang

Sundar

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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I. SIRT1 redresses the imbalance of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-9 in the development of mouse emphysema and human COPD. Am J Physiol Lung Cell Mol Physiol 305: L615-L624, 2013. First published September 13, 2013 doi:10.1152/ajplung.00249.2012, a protein/ histone deacetylase, protects against the development of pulmonary emphysema. However, the molecular mechanisms underlying this observation remain elusive. The imbalance of tissue inhibitor of matrix metalloproteinases (TIMPs)/matrix metalloproteinases (MMPs) plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD)/emphysema. We hypothesized that SIRT1 protects against emphysema by redressing the imbalance between MMPs and TIMPs. To test this hypothesis, SIRT1-deficient and overexpressing/transgenic mice were exposed to cigarette smoke (CS). The protein level and activity of MMP-9 were increased in lungs of SIRT1-deficient mice exposed to CS compared with wild-type (WT) littermates, and these effects were attenuated by SIRT1 overexpression. SIRT1 deficiency decreased the level of TIMP-1, which was augmented in SIRT1 transgenic mice compared with WT littermates by CS. However, the level of MMP-2, MMP-12, TIMP-2, TIMP-3, or TIMP-4 was not altered by SIRT1 in response to CS exposure. SIRT1 reduction was associated with imbalance of TIMP-1 and MMP-9 in lungs of smokers and COPD patients. Mass spectrometry and immunoprecipitation analyses revealed that TIMP-1 acetylation on specific lysine residues was increased, whereas its interaction with SIRT1 and MMP-9 was reduced in mouse lungs with emphysema, as well as in lungs of smokers and COPD patients. SIRT1 deficiency increased CS-induced TIMP-1 acetylation, and these effects were attenuated by SIRT1 overexpression. These results suggest that SIRT1 protects against COPD/emphysema, in part, via redressing the TIMP-1/MMP-9 imbalance involving TIMP-1 deacetylation. Thus redressing the TIMP-1/MMP-9 imbalance by pharmacological activation of SIRT1 is an attractive approach in the intervention of COPD. SIRT1; cigarette smoke; MMPs; TIMPs; emphysema; COPD SIRTUIN1 (SIRT1), a type III histone/protein deacetylase, plays an important role in inflammation, stress resistance, and cellular senescence/aging through the deacetylation of histones, transcription factors, and signaling molecules. It is a redoxsensitive deacetylase that can be posttranslationally modified by oxidants and carbonyl stress, leading to proteasomal degradation (9,36,59). This may be one of the reasons for the reduction of SIRT1 level in peripheral lung tissues of smokers and patients with chronic obstructive pulmonary disease (COPD)/emphysema (36, 55). Recently, we have shown that SIRT1 protects against pulmonary emphysema in mice (55). However, the mechanisms of SIRT1 in preventing the progression of COPD/emphysema are not fully understood.The imbalance of tissue inhibitors of metalloproteinases (TIMPs)/matrix metalloproteinases (MMPs) in the lungs has been implicated in the d...

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“…In combination with transcription factors and coregulatory proteins, the 1,25(OH) 2 D 3 -VDR complex promotes or suppresses the transcription of a wide range of genes (76). VDR knockout in mice results in early-onset emphysema and decline in lung function, with lymphoid aggregate formation secondary to inflammatory changes (94). More subtle mutations or polymorphisms in the VDR gene, which may affect gene promotion, RNA transcription efficacy, or protein structure, have been associated with a variety of diseases, such as such as multiple sclerosis, type I diabetes mellitus, osteoporosis, and colon, breast, and prostate cancer (49,74,97).…”

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The impact of vitamin D on fetal and neonatal lung maturation. A systematic review

Lykkedegn

Sørensen

Beck-Nielsen

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

108

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-Respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) are major complications to preterm birth. Hypovitaminosis D is prevalent in pregnancy. We systematically reviewed the evidence of the impact of vitamin D on lung development, surfactant synthesis, RDS, and BPD searching PubMed, Embase, and Cochrane databases with the terms vitamin D AND (surfactant OR lung maturation OR lung development OR respiratory distress syndrome OR fetal lung OR prematurity OR bronchopulmonary dysplasia). Three human studies, ten animal studies, two laboratory studies, and one combined animal and laboratory study were included. Human evidence was sparse, allowing no conclusions. BPD was not associated with vitamin D receptor polymorphism in a fully adjusted analysis. Animal and laboratory studies showed substantial positive effects of vitamin D on the alveolar type II cell, fibroblast proliferation, surfactant synthesis, and alveolarization. These data support the hypothesis of hypovitaminosis D as a frequent, modifiable risk factor of RDS and BPD, which should be tested in randomized controlled trials on pregnant women, those with threatening preterm delivery, or in the preterm neonates. Future experimental and human studies should aim to identify optimal time windows, vitamin D doses, and cut-off levels for 25-hydroxyvitamin D in interventions against RDS, BPD, and later adverse respiratory outcomes. vitamin D; fetus; lung; surfactant; preterm; neonate THE IMPORTANCE OF VITAMIN D in nonskeletal fetal and childhood health has become increasingly recognized in the last decades (19,65). The impact of vitamin D on early lung development and maturation and lung diseases of early life is an emerging field of research. Hypovitaminosis D during pregnancy is associated with reduced placental development and weight, leading to a presumed risk of preterm birth (24,25), which per se may lead to respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD). Moreover, vitamin D is suggested to play a role in the embryogenesis and in cellular growth and differentiation, including lung development and regulation of lung maturation in the fetus (23,29,38,70,71,108), whereby hypovitaminosis D could be hypothesized to aggravate premature neonatal lung diseases.Vitamin D is involved in the development of the innate and adaptive immune system, and, because of its unique capacity to bind to the vitamin D receptor (VDR) and thereby to serve as a transcriptional factor, vitamin D can regulate gene expression and exert widespread immunomodulatory effects including proliferation, differentiation, and complex regulation (19, 56, 58 -61, 64, 65, 68, 69, 105). Evidence suggests that vitamin D may stimulate regulatory T cell development and T cell function to suppress inappropriate Th1 and Th2 responses to environmental exposure (i.e., allergens, infection load), leading to a more balanced immune response inhibiting autoimmune diseases (with Th1 dominance) and allergic diseases (Th2 dominance) (55). Vitamin D could therefore be inv...

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

Cited by 94 publications

References 34 publications

Vitamin D Deficiency Does Not Result in a Breach of Host Defense in Murine Models of Pneumonia

Vitamin D Deficiency Does Not Result in a Breach of Host Defense in Murine Models of Pneumonia

SIRT1 redresses the imbalance of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-9 in the development of mouse emphysema and human COPD

The impact of vitamin D on fetal and neonatal lung maturation. A systematic review

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