title: Tumor necrosis factor-alpha mediates hyperglycemia-augmented gut barrier dysfunction in endotoxemia.
abstract: OBJECTIVE
  To examine whether hyperglycemia would augment gut barrier dysfunction and inflammatory responses in endotoxemic rats, and simultaneously to clarify the roles of tumor necrosis factor (TNF)-alpha in alterations of gut mucosal permeability associated with hyperglycemia.
  
  
  METHODS
  Prospective randomized animal study.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  : Male Wistar rats treated with lipopolysaccharide (LPS) injection.
  
  
  METHODS
  After LPS injection (4 mg/kg), rats were randomly allocated into group S (n = 6), group G (n = 7), or group GI (n = 8) with continuous infusion of different fluid solutions: normal saline, 40% glucose or 10% glucose mixed with insulin, respectively. Blood glucose, insulin, and proinflammatory cytokines, accompanied by gut mucosal permeability using an in situ loop preparation of gut with fluorescence isothiocyanate-conjugated dextran, were measured. Bacterial growth or alterations in mesenteric lymph nodes and cecal contents were also assessed. We further determined the roles of TNF-alpha using an inhibitor of TNF-alpha converting enzyme in gut barrier dysfunction under the same experimental settings.
  
  
  RESULTS
  Hyperglycemia over 400 mg/dL was achieved and kept in group G during the study period whereas normoglycemia was preserved in group S and GI, the latter of which showed the similar extent of hyperinsulinemia to group G. Plasma concentrations of fluorescence-labeled dextran and TNF-alpha in group G were significantly higher vs. group S and GI, and the number of bacteria found in mesenteric lymph nodes in group G was greater compared with group S. Intestinal environments including microflora and organic acids were not altered by blood glucose or insulin level. Inhibiting conversion of membrane-bound to soluble type of TNF-alpha restored gut mucosal permeability augmented by hyperglycemia.
  
  
  CONCLUSIONS
  These findings indicate that hyperglycemia deteriorates LPS-elicited gut barrier dysfunction and bacterial translocation independently of plasma insulin level, and that TNF-alpha mediates such mucosal dysfunction of gut in endotoxemia.
authors.affiliation: Departments of Anesthesiology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yajima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Morisaki
authors.forename: Ryohei
authors.initials: R
authors.lastname: Serita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Katori
authors.forename: Takashi
authors.initials: T
authors.lastname: Asahara
authors.forename: Koji
authors.initials: K
authors.lastname: Nomoto
authors.forename: Fujio
authors.initials: F
authors.lastname: Kobayashi
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Ishizaka
authors.forename: Junzo
authors.initials: J
authors.lastname: Takeda
mesh_terms: D000818:Animals; D019446:Endotoxemia / Q000097:blood / Q000150:complications / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D006943:Hyperglycemia / Q000097:blood / Q000150:complications / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000382:microbiology; D008297:Male; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D014409:Tumor Necrosis Factor-alpha