title: Early activation of the alveolar macrophage is critical to the development of lung ischemia-reperfusion injury.
abstract: OBJECTIVE
  Activation of the alveolar macrophage is critical to the development of nonischemic inflammatory lung injury. The present studies were undertaken to determine whether the alveolar macrophage plays a similarly important role in lung ischemia-reperfusion injury.
  
  
  METHODS
  The left lungs of male rats were rendered ischemic for 90 minutes and reperfused for up to 4 hours. Treated animals received liposome-encapsulated clodronate, which depletes alveolar macrophages. Injury was quantitated in terms of vascular permeability, tissue neutrophil accumulation, and bronchoalveolar lavage fluid leukocyte, chemokine, and cytokine content. Lung homogenates were also analyzed for nuclear translocation of the transcription factors nuclear factor kappaB and activator of protein 1.
  
  
  RESULTS
  Depletion of alveolar macrophages reduced lung vascular permeability by 53% compared with that seen in control animals (permeability indices: 0.88 +/- 0.07 to 0.46 +/- 0.04, P <.001). The protective effects of alveolar macrophage depletion correlated with a 50% reduction in tissue myeloperoxidase content (0.62 +/- 0.07 to 0.33 +/- 0.03, P <.006) and marked reductions in bronchoalveolar lavage fluid leukocyte accumulation. Alveolar macrophage-depleted animals also demonstrated marked reductions of the elaboration of multiple proinflammatory chemokines and cytokines in the lavage effluent and nuclear transcription factors in lung homogenates.
  
  
  CONCLUSIONS
  It is likely that the alveolar macrophage is the key early source of multiple proinflammatory mediators that orchestrate lung ischemia-reperfusion injury. Depleting alveolar macrophages is protective against injury, supporting its central role in oxidant stress-induced cytokine and chemokine release and the subsequent development of lung injury.
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Washington, Seattle 98195, USA.
authors.forename: Babu V
authors.initials: BV
authors.lastname: Naidu
authors.forename: Baiya
authors.initials: B
authors.lastname: Krishnadasan
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Farivar
authors.forename: Steven M
authors.initials: SM
authors.lastname: Woolley
authors.forename: Robert
authors.initials: R
authors.lastname: Thomas
authors.forename: Nico
authors.initials: N
authors.lastname: Van Rooijen
authors.forename: Edward D
authors.initials: ED
authors.lastname: Verrier
authors.forename: Michael S
authors.initials: MS
authors.lastname: Mulligan
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002199:Capillary Permeability / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007958:Leukocyte Count; D008081:Liposomes / Q000493:pharmacokinetics; D008171:Lung Diseases / Q000378:metabolism* / Q000503:physiopathology*; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008955:Models, Cardiovascular; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D015427:Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D016207:Cytokines; D008081:Liposomes; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D009195:Peroxidase