title: Vitamin C Attenuates Hemorrhagic Hypotension Induced Epithelial-Dendritic Cell Transformation in Rat Intestines by Maintaining GSK-3β Activity and E-Cadherin Expression.
abstract: OBJECTIVE
  To investigate the roles of epithelial-dendritic cell transformation (EDT) characterized by the expression of dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) in the occurrence of tissue inflammation induced by hemorrhagic hypotension (HH), the protective effect of vitamin C (VitC), and the potential mechanisms.
  
  
  METHODS
  We conducted an in vitro study using the rat intestinal epithelial cells (IEC-6). After hypoxic culture with or without VitC for 2, 6, 24, and 48 h (n = 3 per group), the expression levels of DC-SIGN, E-cadherin, and Glycogen synthase kinase-3β-S9 (GSK-3β-S9) in IEC-6 cells, IL-1β, and IL-6 concentrations in the cell culture medium were measured. To investigate the potential mechanism, we inhibited E-cadherin expression by siRNA and GSK-3β activity by TDZD-8, respectively. The in vivo study was conducted by establishing SD rat HH model. We observed the expression levels and location of DC-SIGN in the intestines. We also showed histological damage, TNF-α and IL-6 concentrations, and organ injury scores at 2, 6, and 24 h after HH (n = 6 per group), with or without VitC pretreatment.
  
  
  RESULTS
  Hypoxia-induced DC-SIGN expression in IEC-6 cells in a time-dependent manner and the inflammatory factors were also increased. VitC inhibited all these phenomena. Hypoxia inhibited GSK-3β activity and E-cadherin expression. VitC could ease these inhibitions. The inhibitory effect of VitC on DC-SIGN was diminished when E-cadherin expression was inhibited in advance. TDZD-8 diminished the protective effect of VitC on E-cadherin and abolished inhibitory effect of VitC on DC-SIGN expression. HH-induced DC-SIGN expression in rat intestine epithelial cells and the histological damage scores and pro-inflammatory cytokine levels were also increased.
  
  
  CONCLUSIONS
  HH induces EDT in rat intestine epithelial cells. VitC maintains GSK-3β activity, attenuates the suppression of E-cadherin caused by hypoxia, and ultimately decreases DC-SIGN expression.
authors.affiliation: *Department of Emergency †Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Song
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Bing
authors.initials: B
authors.lastname: Zhao
authors.forename: Zhitao
authors.initials: Z
authors.lastname: Yang
authors.forename: Huiqiu
authors.initials: H
authors.lastname: Sheng
authors.forename: Jian
authors.initials: J
authors.lastname: Fei
authors.forename: Erzhen
authors.initials: E
authors.lastname: Chen
authors.forename: En-Qiang
authors.initials: EQ
authors.lastname: Mao
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D015820:Cadherins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D054338:Cell Transdifferentiation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006439:Hemodynamics; D006470:Hemorrhage / Q000150:complications*; D007022:Hypotension / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D037181:Lectins, C-Type / Q000378:metabolism; D008297:Male; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism; D012151:Resuscitation; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000517:prevention & control; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D001205:Ascorbic Acid; D015820:Cadherins; D015815:Cell Adhesion Molecules; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D018836:Inflammation Mediators; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C000605508:Gsk3b protein, rat