title: Toll-like receptor 4 mediates lung ischemia-reperfusion injury.
abstract: BACKGROUND
  We have previously reported that nuclear factor (NF)-kappaB activation and inflammatory cytokine expression were involved in the development of lung ischemia-reperfusion injury (LIRI). Because Toll-like receptor 4 (TLR4) activates NF-kappaB-dependent transcription of inflammatory cytokine genes during myocardial ischemia-reperfusion injury, we examined whether absence of TLR4 in TLR4-deficient mice protects against LIRI.
  
  
  METHODS
  Left lungs of wild-type (C57BL/6J) mice or TLR4-null (TLR4-/-) mice were made ischemic for 60 minutes and then reperfused for 180 minutes. Response to injury was quantified by tissue myeloperoxidase activity, vascular permeability ([125I]-bovine serum albumin extravasation), and leukocyte and inflammatory mediator accumulation in bronchoalveolar lavage expression. Lung homogenates were also analyzed for activation of mitogen-activated protein kinases and nuclear translocation of the transcription factors NF-kappaB and activator protein-1.
  
  
  RESULTS
  After LIRI, lungs from TLR4-/- mice demonstrated a 52.4% reduction in vascular permeability (p = 0.001), a 52.6% reduction in lung myeloperoxidase activity (p = 0.006), and a marked reduction in bronchoalveolar lavage leukocyte accumulation when compared with lungs from wild-type mice. The TLR4-/- mice lungs, subjected to LIRI, also demonstrated marked reductions in amounts of several proinflammatory cytokines/chemokines in bronchoalveolar lavage samples. Phosphorylation of c-Jun NH2-terminal kinase, and activation of NF-kappaB and activator protein-1 were also significantly reduced in homogenates of lungs from TLR4-/- mice injured by ischemia and reperfusion (p < 0.05).
  
  
  CONCLUSIONS
  These data suggest that TLR4 plays a role in LIRI. Thus, TLR4 may be a potential therapeutic target to minimize ischemic-reperfusion-induced tissue damage and organ dysfunction.
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Mie University Graduate School of Medicine, Tsu, Japan. jj6jdv@clin.medic.mie-u.ac.jp
authors.forename: Akira
authors.initials: A
authors.lastname: Shimamoto
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Pohlman
authors.forename: Shin
authors.initials: S
authors.lastname: Shomura
authors.forename: Tomohito
authors.initials: T
authors.lastname: Tarukawa
authors.forename: Motoshi
authors.initials: M
authors.lastname: Takao
authors.forename: Hideto
authors.initials: H
authors.lastname: Shimpo
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D004195:Disease Models, Animal; D008171:Lung Diseases / Q000276:immunology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology; D015427:Reperfusion Injury / Q000276:immunology* / Q000503:physiopathology; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000276:immunology
chemical_list: D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1