Alveolar macrophage activation is a key initiation signal for acute lung ischemia-reperfusion injury

Minqing Zhao, Lucas G. Fernandez, Allan Doctor, Ashish K. Sharma, Alexander Zarbock, Curtis G. Tribble, Irving L. Kron, Victor E. Laubach

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160 Scopus citations


Lung ischemia-reperfusion (I/R) 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 I/R 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 I/R by producing key cytokines and chemokines and that depletion of AMs would reduce cytokine/chemokine expression and lung injury after I/R. To test this, using a buffer-perfused, isolated mouse lung model, we studied the impact of AM depletion by liposome-clodronate on I/R-induced lung dysfunction/injury and expression of cytokines/chemokines. I/R caused a significant increase in pulmonary artery pressure, wet-to-dry weight ratio, vascular permeability, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-2 expression, as well as decreased pulmonary compliance, when compared with sham lungs. After AM depletion, the changes in each of these parameters between I/R and sham groups were significantly attenuated. Thus AM depletion protects the lungs from I/R-induced dysfunction and injury and significantly reduces cytokine/chemokine production. Protein expression of TNF-α and MCP-1 are positively correlated to I/R-induced lung injury, and AMs are a major producer/initiator of TNF-α, MCP-1, and MIP-2. We conclude that AMs are an essential player in the initiation of acute lung I/R injury.

Original languageEnglish
Pages (from-to)L1018-L1026
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number5
StatePublished - 2006


  • Chemokines
  • Clodronate
  • Inflammation
  • Pulmonary transplantation


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