Journal
TRANSPLANTATION
Volume 91, Issue 6, Pages 624-631Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/TP.0b013e31820ba2a0
Keywords
Primary graft dysfunction; Ischemia-reperfusion; Acute lung injury; Lung transplantation; IKK beta
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Funding
- National Institutes of Health, National Heart, Lung and Blood Institute [R01 HL041281, K12 HL089968]
- International Society for Heart and Lung Transplantation
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Background. Signaling pathways that target I-kappa B kinase beta (IKK beta) activation stimulate the expression of nuclear factor (NF)-kappa B-dependent genes and are thus believed to primarily promote inflammation and injury in solid organ grafts. Methods. We examined the role of IKK beta in a mouse model of lung transplantation-mediated ischemia-reperfusion injury using NF-kappa B essential modulator (NEMO)-binding domain (NBD) peptide to pharmacologically inhibit IKK activation. As myeloid cells are primarily responsible for the production of acute inflammatory mediators after lung transplantation, we also investigated the effects of myeloid cell-specific IKK beta gene deletion on acute lung graft injury by transplanting mutant mice. Results. When NBD was administered at a dose that partially inhibits IKK beta activation, we observed attenuated lung graft injury and blunted expression of intragraft proinflammatory mediators. Surprisingly, when the dose of NBD was increased to a level that ablates intragraft IKK beta activation, graft inflammation, and injury were significantly worse compared with recipients treated with control peptide. Similar to lung recipients with pharmacologically ablated IKK beta activity, donor-recipient transplant combinations with a myeloid cell-specific IKK beta gene deletion had marked intragraft inflammation and poor lung function. Conclusions. Our data show maintenance of IKK beta activity is critical for promoting graft homeostasis with important implications for targeting NF-kappa B-dependent signaling pathways for treating acute lung injury.
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