title: VDR attenuates acute lung injury by blocking Ang-2-Tie-2 pathway and renin-angiotensin system.
abstract: Acute lung injury (ALI) is a hallmark of systemic inflammation associated with high mortality. Although the vitamin D receptor (VDR) is highly expressed in the lung, its role in lung physiology remains unclear. We investigated the effect of VDR deletion on ALI using a lipopolysaccharide (LPS)-induced sepsis model. After LPS challenge VDR-null mice exhibited more severe ALI and higher mortality compared with wild-type (WT) counterparts, manifested by increased pulmonary vascular leakiness, pulmonary edema, apoptosis, neutrophil infiltration, and pulmonary inflammation, which was accompanied by excessive induction of angiopoietin (Ang)-2 and myosin light chain (MLC) phosphorylation in the lung. 1,25-Dihydroxyvitamin D blocked LPS-induced Ang-2 expression by blocking nuclear factor-κB activation in human pulmonary artery endothelial cells. The severity of lung injury seen in VDR-null mice was ameliorated by pretreatment with L1-10, an antagonist of Ang-2, suggesting that VDR signaling protects the pulmonary vascular barrier by targeting the Ang-2-Tie-2-MLC kinase cascade. Severe ALI in VDR-null mice was also accompanied by an increase in pulmonary renin and angiotensin II levels, and pretreatment of VDR-null mice with angiotensin II type 1 receptor blocker losartan partially ameliorated the severity of LPS-induced lung injury. Taken together, these observations provide evidence that the vitamin D-VDR signaling prevents lung injury by blocking the Ang-2-Tie-2-MLC kinase cascade and the renin-angiotensin system.
authors.affiliation: Laboratory of Metabolic Disease Research and Drug Development and Shengjing Hospital, China Medical University, Shenyang, 110000, China; kong_juan@hotmail.com; Ravi Thadhani, M.P.H., Renal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114. E-mail: thadhani.ravi@mgh.harvard.edu; and Yan Chun Li, Department of Medicine, The University of Chicago, 900 East 57th Street, KCBD 9110, Chicago, Illinois 60637. E-mail: cyan@medicine.bsd.uchicago.edu.
authors.forename: Juan
authors.initials: J
authors.lastname: Kong
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Zhu
authors.forename: Yongyan
authors.initials: Y
authors.lastname: Shi
authors.forename: Tianjing
authors.initials: T
authors.lastname: Liu
authors.forename: Yunzi
authors.initials: Y
authors.lastname: Chen
authors.forename: Ishir
authors.initials: I
authors.lastname: Bhan
authors.forename: Qun
authors.initials: Q
authors.lastname: Zhao
authors.forename: Ravi
authors.initials: R
authors.lastname: Thadhani
authors.forename: Yan Chun
authors.initials: YC
authors.lastname: Li
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D042702:Angiopoietin-2 / Q000378:metabolism*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002117:Calcitriol / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D042783:Endothelial Cells / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D042787:Receptor, TIE-2 / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D042702:Angiopoietin-2; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D018167:Receptors, Calcitriol; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D002117:Calcitriol