title: Contribution of Toll-like receptor activation to lung damage after donor brain death.
abstract: BACKGROUND
  Donor brain death is the first injurious event that can produce inflammatory dysfunction after pulmonary transplantation. This study was designed to determine whether stimulation of the toll-like receptor (TLR) system contributes to the changes produced by brain death.
  
  
  METHODS
  Rats were repeatedly treated with specific agonists for TLR4 or TLR2/6 to desensitize these receptors. Brain death was then induced by inflation of a balloon catheter within the extradural space. Mean arterial pressure changes and inflammatory markers were measured serially by protein and mRNA analysis.
  
  
  RESULTS
  Both desensitizing pretreatments prevented the neurogenic hypotension (P<0.001) and metabolic acidosis (P<0.001) observed in control animals after brain death. These treatments also reduced the levels of tumor necrosis factor-α and CXCL1 in serum and bronchoalveolar lavage fluid, although desensitization of TLR4 produced a greater inhibition than desensitization of TLR2. Desensitization of TLR4 also reduced (P<0.05) expression of the adhesive integrin CD11b on blood neutrophils after brain death. Examination of mRNA levels in lung tissue 5 hr after brain death showed that desensitization of TLR4 limited the expression of interferon (IFN)-γ, IFNβ, and CXCL10, whereas desensitization of TLR2/6 reduced only the expression of IFNγ.
  
  
  CONCLUSIONS
  These results indicate that activation of TLR signaling pathways can contribute to the lung damage produced by brain death; this may increase subsequent graft injury after transplantation.
authors.affiliation: Applied Immunobiology and Transplant Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Rostron
authors.forename: David M W
authors.initials: DM
authors.lastname: Cork
authors.forename: Vassilios S
authors.initials: VS
authors.lastname: Avlonitis
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Fisher
authors.forename: John H
authors.initials: JH
authors.lastname: Dark
authors.forename: John A
authors.initials: JA
authors.lastname: Kirby
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D001926:Brain Death / Q000473:pathology*; D039481:CD11b Antigen / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D006439:Hemodynamics / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000473:pathology* / Q000502:physiology; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000502:physiology; D051193:Toll-Like Receptors / Q000502:physiology*
chemical_list: D039481:CD11b Antigen; D015815:Cell Adhesion Molecules; D016207:Cytokines; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D012313:RNA