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J Thorac Cardiovasc Surg 2008;135:656-665
© 2008 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Stress-activated protein kinase inhibition to ameliorate lung ischemia reperfusion injury

Patrick S. Wolf, MD, Heather E. Merry, MD, Alexander S. Farivar, MD, Anton S. McCourtie, MD, Michael S. Mulligan, MD*

Division of Thoracic Surgery, University of Washington, Seattle, Wash

Received for publication July 16, 2007; revisions received November 9, 2007; accepted for publication November 26, 2007.

* Address for reprints: Michael S. Mulligan, MD, University of Washington Medical Center, 1959 NE Pacific St, Box 356310, Seattle, WA 98195. (Email: msmmd{at}u.washington.edu).

Objective: Inhibition of cytokines offers modest protection from injury in animal models of lung ischemia–reperfusion. Improved strategies would selectively inhibit the transcriptional activation response to oxidative stress. Mitogen-activated protein kinases (p38, c-jun N-terminal kinase, extracellular signal–regulated kinase) have been shown to be activated after oxidative stress and in animal models of acute inflammatory lung injury. We hypothesized that mitogen-activated protein kinase inhibition would block downstream transcriptional activation, providing robust protection from lung ischemia–reperfusion injury.

Methods: Experimental rats received inhibitors of p38, c-jun kinase, or extracellular signal–regulated kinase before in situ left lung ischemia–reperfusion. Immunohistochemistry localized cellular sites of mitogen-activated protein kinase activation. Several markers of lung injury were assessed. Enzyme-linked immunosorbent assay measured soluble cytokine and chemokine contents. Western blotting assessed mitogen-activated protein kinase phosphorylation. Electromobility shift assays measured transcription factor nuclear translocation.

Results: Immunohistochemistry localized p38 and c-jun kinase activations in positive controls to alveolar macrophages. Extracellular signal–regulated kinase was activated in endothelial and epithelial cells. Animals treated with p38 or c-jun kinase inhibitor demonstrated significant reductions in transcription factor activation and markers of lung injury. Extracellular signal–regulated kinase inhibition was not protective. Western blotting confirmed inhibitor specificity.

Conclusion: Inhibition of p38 and c-jun kinase provided significant protection from injury. The alveolar macrophage appears to be the key coordinator of injury in response to oxidative stress. Therapeutically targeting specific cell population (macrophage) responses to oxidative stress has the potential benefit of reducing lung reperfusion injury severity while leaving host immune responses intact.

Abbreviations and Acronyms AM = alveolar macrophage; AP-1 = activator protein 1; BSA = bovine serum albumin; CINC = cytokine-induced neutrophil chemoattractant; DMSO = dimethylsulfoxide; ERK1/2 = extracellular signal–regulated kinase; IL-1β = interleukin 1β; JNK = c-jun N-terminal kinase; LIRI = lung ischemia–reperfusion injury; MAPK = mitogen-activated protein kinase; MPO = myeloperoxidase; NF-{kappa}B = nuclear factor {kappa}B; PBS = phosphate-buffered saline solution; SAPK = stress-activated protein kinase


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Discussion
J. Thorac. Cardiovasc. Surg. 2008 135: 664-665. [Extract] [Full Text] [PDF]





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