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Obesity-induced Vitamin D Deficiency Contributes to Lung Fibrosis and Airway Hyperresponsiveness

Authors
 Heejae Han  ;  Sook In Chung  ;  Hye Jung Park  ;  Eun Yi Oh  ;  Sung-Ryeol Kim  ;  Kyung Hee Park  ;  Jae-Hyun Lee  ;  Jung-Won Park 
Citation
 AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol.64(3) : 357-367, 2021-03 
Journal Title
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
ISSN
 1044-1549 
Issue Date
2021-03
MeSH
Animals ; Biomarkers / metabolism ; Body Weight / drug effects ; Cells, Cultured ; Cytokines / metabolism ; Diet, High-Fat ; Dietary Supplements ; Epithelial-Mesenchymal Transition / drug effects ; Glucose Tolerance Test ; Inflammation / pathology ; Insulin / metabolism ; Leptin / blood ; Lung / metabolism ; Lung / pathology ; Male ; Methacholine Chloride ; Mice, Inbred C57BL ; Mice, Transgenic ; Obesity / blood ; Obesity / complications* ; Pulmonary Fibrosis / blood ; Pulmonary Fibrosis / etiology* ; Receptors, Calcitriol / metabolism ; Renin / blood ; Renin-Angiotensin System / drug effects ; Respiratory Hypersensitivity / blood ; Respiratory Hypersensitivity / etiology* ; Transforming Growth Factor beta1 / metabolism ; Vitamin D / analogs & derivatives ; Vitamin D / blood ; Vitamin D / pharmacology ; Vitamin D Deficiency / blood ; Vitamin D Deficiency / etiology*
Keywords
asthma ; lung fibrosis ; obesity ; transforming growth factor-β1 ; vitamin D
Abstract
Vitamin D (VitD) has pleiotropic effects. VitD deficiency is closely involved with obesity and may contribute to the development of lung fibrosis and aggravation of airway hyperresponsiveness (AHR). We evaluated the causal relationship between VitD deficiency and the lung pathologies associated with obesity. In vivo effects of VitD supplementation were analyzed using high-fat diet (HFD)-induced obese mice and TGF-β1 (transforming growth factor-β1) triple transgenic mice. Effects of VitD supplementation were also evaluated in both BEAS-2B and primary lung cells from the transgenic mice. Obese mice had decreased 25-OH VitD and VitD receptor expressions with increases of insulin resistance, renin and angiotensin-2 system (RAS) activity, and leptin. In addition, lung pathologies such as a modest increase in macrophages, enhanced TGF-β1, IL-1β, and IL-6 expression, lung fibrosis, and AHR were found. VitD supplementation to HFD-induced obese mice recovered these findings. TGF-β1-overexpressing transgenic mice enhanced macrophages in BAL fluid, lung expression of RAS, epithelial-mesenchymal transition markers, AHR, and lung fibrosis. VitD supplementation also attenuated these findings in addition to the attenuation of the expressions of TGF-β1, and phosphorylated Smad-2/3 in lung. Supplementing in vitro-stimulated BEAS-2B and primary lung cells with VitD inhibited TGF-β1 expression, supporting the suppressive effect of VitD for TGF-β1 expression. These results suggest that obesity leads to VitD deficiency and worsens insulin resistance while enhancing the expression of leptin, RAS, TGF-β1, and proinflammatory cytokines. These changes may contribute to the development of lung fibrosis and AHR. VitD supplementation rescues these changes and may have therapeutic potential for asthma with obesity.
Full Text
https://www.atsjournals.org/doi/10.1165/rcmb.2020-0086OC
DOI
10.1165/rcmb.2020-0086OC
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Sung Ryeol(김성렬) ORCID logo https://orcid.org/0000-0001-7418-0049
Park, Kyung Hee(박경희) ORCID logo https://orcid.org/0000-0003-3605-5364
Park, Jung Won(박중원) ORCID logo https://orcid.org/0000-0003-0249-8749
Park, Hye Jung(박혜정) ORCID logo https://orcid.org/0000-0002-1862-1003
Lee, Jae Hyun(이재현) ORCID logo https://orcid.org/0000-0002-0760-0071
Chung, Sook In(정숙인) ORCID logo https://orcid.org/0000-0002-7915-9203
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/186807
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