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1 Surgery, University of Virginia, Charlottesville, Virginia, United States
2 Pediatrics, University of Virginia, Charlottesville, Virginia, United States
3 Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, United States
* To whom correspondence should be addressed. E-mail: mz2v{at}virginia.edu.
Lung ischemia-reperfusion (IR) injury is a biphasic inflammatory process. Previous studies indicate that the later phase is neutrophil-dependent and that alveolar macrophages (AMs) likely contribute to the acute phase of lung IR injury. However, the mechanism is unclear. AMs become activated and produce various cytokines and chemokines in many inflammatory responses including transplantation. We hypothesize that AMs respond to IR by producing key cytokines and chemokines and that depletion of AMs would reduce cytokine/chemokine expression and lung injury after IR. To test this, using a buffer-perfused, isolated mouse lung model, we studied the impact of AM depletion by lipsome-clodronate on IR-induced lung dysfunction/injury and expression of cytokines/chemokines. IR caused a significant increase in pulmonary artery pressure, wet/dry weight ratio, vascular permeability and TNF-
, MCP-1 and MIP-2 expression as well as decreased pulmonary compliance, when compared to sham lungs. After AM depletion, the changes in each of these parameters between IR and sham groups were significantly attenuated. Thus AM depletion protects the lungs from IR-induced dysfunction and injury and significantly reduces cytokine/chemokine production. Protein expression of TNF- and MCP-1 are positively correlated to IR-induced lung injury, and AMs are a major producer/initiator of TNF-, MCP-1 and MIP-2. We conclude that AMs are an essential player in the initiation of acute lung IR injury.
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