title: Carbon Monoxide-Releasing Molecule-2 Reduces Intestinal Epithelial Tight-Junction Damage and Mortality in Septic Rats.
abstract: OBJECTIVE
  Damage to intestinal epithelial tight junctions plays an important role in sepsis. Recently we found that Carbon Monoxide-Releasing Molecule-2 (CORM-2) is able to protect LPS-induced intestinal epithelial tight junction damage and in this study we will investigate if CORM-2 could protect intestinal epithelial tight junctions in the rat cecal ligation and puncture (CLP) model.
  
  
  METHODS
  The CLP model was generated using male Sprague-Dawley (SD) rats according to standard procedure and treated with CORM-2 or inactive CORM-2 (iCORM-2), 8 mg/kg, i.v. immediately after CLP induction and euthanized after 24h or 72h (for mortality rate only). Morphological changes were investigated using both transmission electron and confocal microscopy. The levels of important TJ proteins and phosphorylation of myosin light chain (MLC) were examined using Western blotting. Cytokines, IL-1β and TNF-α were measured using ELISA kits. The overall intestinal epithelial permeability was evaluated using FD-4 as a marker.
  
  
  RESULTS
  CORM-2, but not iCORM-2, significantly reduced sepsis-induced damage of intestinal mucosa (including TJ disruption), TJ protein reduction (including zonula occludens-l (ZO-1), claudin-1 and occludin), MLC phosphorylation and proinflammatory cytokine release. The overall outcomes showed that CORM-2 suppressed sepsis-induced intestinal epithelial permeability changes and reduced mortality rate of those septic rats.
  
  
  CONCLUSIONS
  Our data strongly suggest that CORM-2 could be a potential therapeutic reagent for sepsis by suppressing inflammation, restoring intestinal epithelial barrier and reducing mortality.
authors.affiliation: Department of General Surgery, Zhongda Hospital, Southeast University Medical School, Nanjing, Jiangsu 210009, China.
authors.forename: Shulong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Critical Care Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China.
authors.forename: Shuyun
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of General Surgery, Zhongda Hospital, Southeast University Medical School, Nanjing, Jiangsu 210009, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Critical Care Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China.
authors.forename: Qiankun
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Critical Care Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Critical Care Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China.
authors.forename: Shoutao
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, L69 7BE, United Kingdom.
authors.forename: Guozheng
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Zhongda Hospital, Southeast University Medical School, Nanjing, Jiangsu 210009, China.
authors.forename: Zhenling
authors.initials: Z
authors.lastname: Ji
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D018994:Myosin Light Chains / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects; D010766:Phosphorylation; D051381:Rats; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D062725:Tight Junction Proteins / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects* / Q000648:ultrastructure; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D015850:Interleukin-6; D018994:Myosin Light Chains; D009942:Organometallic Compounds; D062725:Tight Junction Proteins; D014409:Tumor Necrosis Factor-alpha; C447082:tricarbonyldichlororuthenium (II) dimer