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NADPH Oxidase in Bone Marrow–Derived Cells Mediates Pulmonary Ischemia-Reperfusion Injury

¹ Department of Surgery and ² Cardiovascular Research Center, University of Virginia Health System, Charlottesville, Virginia

Correspondence and requests for reprints should be addressed to Victor E. Laubach, Ph.D., Department of Surgery, University of Virginia Health System, P.O. Box 801359, Charlottesville, VA 22908. E-mail: laubach{at}virginia.edu

Reactive oxygen species (ROS) play a crucial role in ischemia-reperfusion (IR) injury after lung transplantation. We hypothesized that NADPH oxidase derived from bone marrow (BM) cells contributes importantly to lung IR injury. An in vivo mouse model of lung IR injury was employed. Wild-type C57BL/6 (WT) mice, p47^phox knockout (p47^phox–/–) mice, or chimeras created by BM transplantation between WT and p47^phox–/– mice were assigned to either Sham (left thoracotomy) or six study groups that underwent IR (1 h left hilar occlusion and 2 h reperfusion). After reperfusion, pulmonary function was assessed using an isolated, buffer-perfused lung system. Lung injury was assessed by measuring vascular permeability (via Evans blue dye), edema, neutrophil infiltration (via myeloperoxidase [MPO]), lipid peroxidation (via malondialdyhyde [MDA]), and expression of proinflammatory cytokines. Lung IR resulted in significantly increased MDA in WT mice, indicative of oxidative stress. WT mice treated with apocynin (an NADPH oxidase inhibitor) and p47^phox–/– mice displayed significantly reduced pulmonary dysfunction and injury (vascular permeability, edema, MPO, and MDA). In BM chimeras, significantly reduced pulmonary dysfunction and injury occurred after IR in p47^phox–/–WT chimeras (donorrecipient) but not WTp47^phox–/– chimeras. Induction of TNF-, IL-17, IL-6, RANTES (CCL5), KC (CXCL1), MIP-2 (CXCL2), and MCP-1 (CCL2) was significantly reduced after IR in NADPH oxidase–deficient mice and p47^phox–/–WT chimeras but not WTp47^phox–/– chimeras. These results indicate that NADPH oxidase–generated ROS specifically from BM-derived cells contributes importantly to lung IR injury. NADPH oxidase may represent a novel therapeutic target for the treatment of IR injury after lung transplantation.

Key Words: NADPH oxidase • lung ischemia-reperfusion injury • bone marrow transplant • reactive oxygen species

CLINICAL RELEVANCE This study shows that NADPH oxidase–generated reactive oxygen species from bone marrow–derived cells initiates lung reperfusion injury. NADPH oxidase may be a novel therapeutic target for the treatment of reperfusion injury after lung transplantation.