title: Early tumor necrosis factor-alpha release from the pulmonary macrophage in lung ischemia-reperfusion injury.
abstract: OBJECTIVE
  Tumor necrosis factor-alpha is a proinflammatory mediator required for the development of experimental lung ischemia-reperfusion injury. The alveolar macrophage is a rich source of tumor necrosis factor-alpha in multiple models of acute lung injury. The present study was undertaken to determine whether the alveolar macrophage is an important source of tumor necrosis factor-alpha in lung ischemia-reperfusion injury and whether suppression of its function protects against injury.
  
  
  METHODS
  Left lungs of Long-Evans rats underwent normothermic ischemia for 90 minutes and reperfusion for up to 4 hours. Treated animals received gadolinium chloride, a rare earth metal that inhibits macrophage function. Injury was quantitated via lung tissue neutrophil accumulation (myeloperoxidase content), lung vascular permeability, and bronchoalveolar lavage fluid leukocyte, cytokine, and chemokine content. Separate samples were generated for immunohistochemistry.
  
  
  RESULTS
  Tumor necrosis factor-alpha secretion occurred at 15 minutes of reperfusion and was localized to the alveolar macrophage by immunohistochemistry. In gadolinium-treated animals, lung vascular permeability was reduced by 66% at 15 minutes (P <.03) of reperfusion and by 34% at 4 hours (P <.02) of reperfusion. Suppression of macrophage function resulted in a 35% reduction in lung myeloperoxidase content (P <.03) and similar reductions in bronchoalveolar lavage leukocyte accumulation. Tumor necrosis factor-alpha and microphage inflammatory protein-1alpha protein levels were markedly reduced in the bronchoalveolar lavage of gadolinium-treated animals by enzyme-linked immunosorbent assay.
  
  
  CONCLUSIONS
  The alveolar macrophage secretes tumor necrosis factor-alpha protein by 15 minutes of reperfusion, which orchestrates the early events that eventually result in lung ischemia-reperfusion injury at 4 hours. Gadolinium pretreatment markedly reduces tumor necrosis factor-alpha elaboration, resulting in significant protection against lung ischemia-reperfusion injury.
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Washington Medical Center, Seattle 98195, USA.
authors.forename: Babu V
authors.initials: BV
authors.lastname: Naidu
authors.forename: Steven M
authors.initials: SM
authors.lastname: Woolley
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Farivar
authors.forename: Robert
authors.initials: R
authors.lastname: Thomas
authors.forename: Charles H
authors.initials: CH
authors.lastname: Fraga
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Goss
authors.forename: Michael S
authors.initials: MS
authors.lastname: Mulligan
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002199:Capillary Permeability; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D054407:Chemokine CCL4; D004797:Enzyme-Linked Immunosorbent Assay; D005682:Gadolinium / Q000494:pharmacology; D007150:Immunohistochemistry; D007958:Leukocyte Count; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000378:metabolism*; D019402:Macrophage Inflammatory Proteins / Q000032:analysis; D016676:Macrophages, Alveolar / Q000378:metabolism*; D009504:Neutrophils; D009195:Peroxidase / Q000032:analysis; D051381:Rats; D020318:Rats, Long-Evans; D015427:Reperfusion Injury / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D014409:Tumor Necrosis Factor-alpha; D005682:Gadolinium; D009195:Peroxidase; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C038958:gadolinium chloride