title: Maintenance of IKKβ activity is necessary to protect lung grafts from acute injury.
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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Huang
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Sugimoto
authors.forename: Jiaming
authors.initials: J
authors.lastname: Lai
authors.forename: Mikio
authors.initials: M
authors.lastname: Okazaki
authors.forename: Sumiharu
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Krupnick
authors.forename: Daniel
authors.initials: D
authors.lastname: Kreisel
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Gelman
mesh_terms: D055371:Acute Lung Injury / Q000517:prevention & control*; D000818:Animals; D001665:Binding Sites; D051550:I-kappa B Kinase / Q000737:chemistry / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D016040:Lung Transplantation / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D015427:Reperfusion Injury / Q000517:prevention & control*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse