Cardiothoracic transplantation
Early tumor necrosis factor-α release from the pulmonary macrophage in lung ischemia-reperfusion injury

https://doi.org/10.1016/j.jtcvs.2003.08.019Get rights and content
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Abstract

Objective

Tumor necrosis factor-α 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-α 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-α 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-α 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-α and microphage inflammatory protein-1α 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-α 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-α elaboration, resulting in significant protection against lung ischemia-reperfusion injury.

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