General Thoracic Surgery
The role of proinflammatory cytokines in lung ischemia-reperfusion injury,☆☆

https://doi.org/10.1067/mtc.2003.16Get rights and content
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Abstract

Objective: Proinflammatory cytokines are known to play roles in ischemia-reperfusion injury of the heart, kidney, small bowel, skin, and liver. Little is known about their roles in ischemia-reperfusion injury of the lung. This study was undertaken to define the role of 2 proinflammatory cytokines, tumor necrosis factor α and interleukin 1β, in ischemia-reperfusion injury of the lung. Methods: Left lungs of male rats were rendered ischemic for 90 minutes and reperfused for up to 4 hours. Treated animals received anti-tumor necrosis factor α or anti-interleukin 1β antibody before reperfusion. Increased vascular permeability in the lung was measured by using iodine 125-labeled bovine serum albumin. Neutrophil sequestration in the lung parenchyma was determined on the basis of activity. Bronchoalveolar lavage was performed to measure cell counts. Separate tissue samples were processed for histology, cytokine protein, and messenger RNA content by using Western blotting and the ribonuclease protection assay. Results: Animals receiving anti-tumor necrosis factor α and anti-interleukin 1β demonstrated reduced injury compared with that seen in positive control animals (vascular permeability of 48.7% and 29.4% lower, respectively; P <.001). Vascular injury was reduced by 71% when antibodies to tumor necrosis factor α and interleukin 1β were administered together. Lung neutrophil accumulation was markedly reduced among animals receiving anti-tumor necrosis factor α and anti-interleukin 1β (myeloperoxidase content of 30.9% and 38.5% lower, respectively; P <.04) and combination blockade afforded even greater protection (52.4% decrease, P <.01). Bronchoalveolar lavage leukocyte content was also reduced by treatment with anti-tumor necrosis factor α, anti-interleukin 1β, and combination treatment. Reductions in permeability, myeloperoxidase, and bronchoalveolar lavage leukocyte content also resulted in a decrease in a histologic injury. Finally, anti-tumor necrosis factor α and anti-interleukin 1β treatment resulted in decreased messenger RNA expression for a number of early response and regulatory cytokines. Conclusion: Tumor necrosis factor α and interleukin 1β help regulate the development of lung ischemia-reperfusion injury. They appear to promote injury by altering expression of proinflammatory and anti-inflammatory cytokines and influencing tissue neutrophil recruitment.

J Thorac Cardiovasc Surg 2003;125:261-72

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Address for reprints: Michael S. Mulligan, MD, Division of Cardiothoracic Surgery, University of Washington Medical Center, 1959 NE Pacific St, Seattle, WA 98195 (E-mail: [email protected]).

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0022-5223/2003 $30.00+0