title: Increased intestinal permeability and tight junction disruption by altered expression and localization of occludin in a murine graft versus host disease model.
abstract: BACKGROUND
  Hematopoietic stem cell transplantation is increasingly performed for hematologic diseases. As a major side effect, acute graft versus host disease (GvHD) with serious gastrointestinal symptoms including diarrhea, gastrointestinal bleeding and high mortality can be observed. Because surveillance and biopsies of human gastrointestinal GvHD are difficult to perform, rare information of the alterations of the gastrointestinal barrier exists resulting in a need for systematic animal models.
  
  
  METHODS
  To investigate the effects of GvHD on the intestinal barrier of the small intestine we utilized an established acute semi allogenic GvHD in C57BL/6 and B6D2F1 mice.
  
  
  RESULTS
  By assessing the differential uptake of lactulose and mannitol in the jejunum, we observed an increased paracellular permeability as a likely mechanism for disturbed intestinal barrier function. Electron microscopy, immunohistochemistry and PCR analysis indicated profound changes of the tight-junction complex, characterized by downregulation of the tight junction protein occludin without any changes in ZO-1. Furthermore TNF-α expression was significantly upregulated.
  
  
  CONCLUSIONS
  This analysis in a murine model of GvHD of the small intestine demonstrates serious impairment of intestinal barrier function in the jejunum, with an increased permeability and morphological changes through downregulation and localization shift of the tight junction protein occludin.
authors: Department of Internal Medicine, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors: Rainer
authors: R
authors: Noth
authors: Julia
authors: J
authors: Lange-Grumfeld
authors: Eckhard
authors: E
authors: Stüber
authors: Marie-Luise
authors: ML
authors: Kruse
authors: Mark
authors: M
authors: Ellrichmann
authors: Robert
authors: R
authors: Häsler
authors: Jochen
authors: J
authors: Hampe
authors: Burkhard
authors: B
authors: Bewig
authors: Philip
authors: P
authors: Rosenstiel
authors: Stefan
authors: S
authors: Schreiber
authors: Alexander
authors: A
authors: Arlt
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D006086:Graft vs Host Disease / Q000378:metabolism*; D007150:Immunohistochemistry; D007583:Jejunum / Q000378:metabolism*; D007792:Lactulose / Q000378:metabolism; D008353:Mannitol / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D062793:Occludin; D010539:Permeability; D016133:Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D014409:Tumor Necrosis Factor-alpha; D008353:Mannitol; D007792:Lactulose