title: Experimental TLR4 inhibition improves intestinal microcirculation in endotoxemic rats.
abstract: BACKGROUND
  Toll like receptor 4 (TLR4) represents a critical cellular link for endotoxin-induced pathology. The aim of this study was to evaluate the potential role of TLR4 inhibition on the intestinal microcirculation during experimental endotoxemia.
  
  
  METHODS
  The intestinal microcirculation was studied by intravital microscopy in four groups of Lewis rats (n=10 per group): healthy controls (CON group), endotoxemic animals (15mg/kg lipopolysaccharide, LPS group), endotoxemic animals treated with a TLR4 antagonist (1mg/kg CRX-526, LPS+CRX526 group), and controls treated with CRX-526 (C-CRX526 group). Plasma samples were obtained for cytokine measurements at the end of the experiments.
  
  
  RESULTS
  Endotoxemia significantly increased leukocyte adhesion in intestinal submucosal venules (e.g., V1 venules: CON 20.4±6.5n/mm(2), LPS 237.5±36.2n/mm(2), p<0.05) and reduced capillary perfusion of the intestinal wall (e.g., longitudinal muscular layer: CON 112.5±5.9cm/cm(2), LPS 71.3±11.0cm/cm(2), p<0.05) at 2h. TLR4 inhibition significantly reduced endotoxemia-associated leukocyte adhesion (V1 venules: 104.3±7.8n/mm(2)) and improved capillary perfusion (longitudinal muscular layer: 111.0±12.3cm/cm(2)). Cytokine release was not significantly affected.
  
  
  CONCLUSIONS
  The TLR4 pathway may be a target in clinical Gram-negative sepsis since administration of the TLR4 antagonist CRX-526 improved intestinal microcirculation parameters in experimental endotoxemia.
authors.affiliation: Department of Anesthesia, Dalhousie University, 5850 College St., Halifax, B3H 4R2 Nova Scotia, Canada; Department of Microbiology & Immunology, Dalhousie University, 5850 College St., Halifax, B3H 4R2 Nova Scotia, Canada.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Anesthesia and Intensive Care Medicine, Ernst-Moritz-Arndt-University, Loefflerstr. 23, 17475 Greifswald, Germany.
authors.forename: Marieke
authors.initials: M
authors.lastname: Soltow
authors.affiliation: Department of Anesthesia and Intensive Care Medicine, Ernst-Moritz-Arndt-University, Loefflerstr. 23, 17475 Greifswald, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Zimmermann
authors.affiliation: Department of Anesthesia and Intensive Care Medicine, Ernst-Moritz-Arndt-University, Loefflerstr. 23, 17475 Greifswald, Germany.
authors.forename: Dragan
authors.initials: D
authors.lastname: Pavlovic
authors.affiliation: Department of Microbiology & Immunology, Dalhousie University, 5850 College St., Halifax, B3H 4R2 Nova Scotia, Canada.
authors.forename: Brent
authors.initials: B
authors.lastname: Johnston
authors.affiliation: Department of Anesthesia, Dalhousie University, 5850 College St., Halifax, B3H 4R2 Nova Scotia, Canada; Department of Microbiology & Immunology, Dalhousie University, 5850 College St., Halifax, B3H 4R2 Nova Scotia, Canada. Electronic address: chlehmann@mac.com.
authors.forename: Christian
authors.initials: C
authors.lastname: Lehmann
mesh_terms: D000818:Animals; D002196:Capillaries / Q000473:pathology; D002448:Cell Adhesion; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000188:drug therapy* / Q000473:pathology*; D005944:Glucosamine / Q000031:analogs & derivatives / Q000737:chemistry; D006090:Gram-Negative Bacteria; D007249:Inflammation; D007422:Intestines / Q000098:blood supply*; D000069416:Intravital Microscopy; D007962:Leukocytes / Q000166:cytology; D008070:Lipopolysaccharides / Q000737:chemistry; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D010477:Perfusion; D051381:Rats; D011917:Rats, Inbred Lew; D018805:Sepsis / Q000382:microbiology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C501717:CRX-526; D016207:Cytokines; D008070:Lipopolysaccharides; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D005944:Glucosamine
keywords: Endotoxemia; Functional capillary density (FCD); Intestinal microcirculation; Introvital microscopy; Leukocyte adhesion; Toll like receptor 4