Early activation of the alveolar macrophage is critical to the development of lung ischemia-reperfusion injury.
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.
Naidu
Babu V
BV
Division of Cardiothoracic Surgery, Department of Surgery, University of Washington, Seattle 98195, USA.
Krishnadasan
Baiya
B
Farivar
Alexander S
AS
Woolley
Steven M
SM
Thomas
Robert
R
Van Rooijen
Nico
N
Verrier
Edward D
ED
Mulligan
Michael S
MS
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
D016207:Cytokines; D008081:Liposomes; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D009195:Peroxidase