Maintenance of IKKβ activity is necessary to protect lung grafts from acute injury

Howard J. Huang, Seiichiro Sugimoto, Jiaming Lai, Mikio Okazaki, Sumiharu Yamamoto, Alexander S. Krupnick, Daniel Kreisel, Andrew E. Gelman

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Background. Signaling pathways that target I-κB kinase β (IKKβ) activation stimulate the expression of nuclear factor (NF)-κB-dependent genes and are thus believed to primarily promote inflammation and injury in solid organ grafts. Methods. We examined the role of IKKβ in a mouse model of lung transplantation-mediated ischemia-reperfusion injury using NF-κB 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 IKKβ gene deletion on acute lung graft injury by transplanting mutant mice. Results. When NBD was administered at a dose that partially inhibits IKKβ 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 IKKβ activation, graft inflammation, and injury were significantly worse compared with recipients treated with control peptide. Similar to lung recipients with pharmacologically ablated IKKβ activity, donor-recipient transplant combinations with a myeloid cell-specific IKKβ gene deletion had marked intragraft inflammation and poor lung function. Conclusions. Our data show maintenance of IKKβ activity is critical for promoting graft homeostasis with important implications for targeting NF-κB-dependent signaling pathways for treating acute lung injury.

Original languageEnglish
Pages (from-to)624-631
Number of pages8
JournalTransplantation
Volume91
Issue number6
DOIs
Publication statusPublished - Mar 27 2011
Externally publishedYes

Keywords

  • Acute lung injury
  • IKKβ
  • Ischemia-reperfusion
  • Lung transplantation
  • Primary graft dysfunction

ASJC Scopus subject areas

  • Transplantation

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