title: Exposure to bacterial DNA before hemorrhagic shock strongly aggravates systemic inflammation and gut barrier loss via an IFN-gamma-dependent route.
abstract: OBJECTIVE
  To investigate the role of bacterial DNA in development of an excessive inflammatory response and loss of gut barrier loss following systemic hypotension.
  
  
  BACKGROUND
  Bacterial infection may contribute to development of inflammatory complications following major surgery; however, the pathogenesis is not clear. A common denominator of bacterial infection is bacterial DNA characterized by unmethylated CpG motifs. Recently, it has been shown that bacterial DNA or synthetic oligodeoxynucleotides containing unmethylated CpG motifs (CpG-ODN) are immunostimulatory leading to release of inflammatory mediators.
  
  
  METHODS
  Rats were exposed to CpG-ODN prior to a nonlethal hemorrhagic shock. The role of interferon-gamma (IFN-gamma) was investigated by administration of anti IFN-gamma antibodies.
  
  
  RESULTS
  Exposure to CpG-ODN prior to hemorrhagic shock significantly augmented shock-induced release of IFN-gamma, tumor necrosis factor-alpha (TNF-alpha) (P < 0.05), interleukin (IL)-6 (P < 0.05), and nitrite levels (P < 0.05), while there was a defective IL-10 response (P < 0.05). Simultaneously, expression of Toll-like receptor (TLR) 4 in the liver was markedly enhanced. Furthermore, intestinal permeability for HRP significantly increased and bacterial translocation was enhanced in hemorrhagic shock rats pretreated with CpG-ODN. Interestingly, inhibition of IFN-gamma in CpG-treated animals reduced TNF-alpha (P < 0.05), IL-6 (P < 0.05), nitrite (P < 0.05), and intestinal permeability following hemorrhagic shock (P < 0.05) and down-regulated expression of TLR4.
  
  
  CONCLUSIONS
  Exposure to bacterial DNA strongly aggravates the inflammatory response, disrupts the intestinal barrier, and up-regulates TLR4 expression in the liver following hemorrhagic shock. These effects are mediated via an IFN-gamma-dependent route. In the clinical setting, bacterial DNA may be important in development of inflammatory complications in surgical patients with bacterial infection.
authors: Department of Surgery, Nutrition and Toxicology Research Institute Maastricht, University of Maastricht and University Hospital Maastricht, 6200 MD Maastricht, the Netherlands. M.Luyer@ah.unimaas.nl
authors: Misha D
authors: MD
authors: Luyer
authors: Wim A
authors: WA
authors: Buurman
authors: M'hamed
authors: M
authors: Hadfoune
authors: T
authors: T
authors: Wolfs
authors: Cornelis
authors: C
authors: van't Veer
authors: Jan A
authors: JA
authors: Jacobs
authors: Cornelis H
authors: CH
authors: Dejong
authors: Jan Willem M
authors: JW
authors: Greve
mesh_terms: D000818:Animals; D018988:Bacterial Translocation / Q000502:physiology*; D016207:Cytokines / Q000097:blood; D004269:DNA, Bacterial; D006735:Horseradish Peroxidase; D007371:Interferon-gamma / Q000097:blood / Q000502:physiology*; D007421:Intestine, Small / Q000378:metabolism*; D008297:Male; D009838:Oligodeoxyribonucleotides; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000150:complications*; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000503:physiopathology*
chemical_list: C408982:CPG-oligonucleotide; D016207:Cytokines; D004269:DNA, Bacterial; D009838:Oligodeoxyribonucleotides; D007371:Interferon-gamma; D006735:Horseradish Peroxidase