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Molecular Medicine

, Volume 21, Issue 1, pp 563–575 | Cite as

Inhibition of IκB Kinase Attenuates the Organ Injury and Dysfunction Associated with Hemorrhagic Shock

  • Regina Sordi
  • Fausto Chiazza
  • Florence L. Johnson
  • Nimesh S. A. Patel
  • Karim Brohi
  • Massimo Collino
  • Christoph Thiemermann
Research Article

Abstract

Nuclear factor-kappa B (NF-κB) activation is widely implicated in multiple organ failure (MOF); however, a direct inhibitor of IκB kinase (IKK), which plays a pivotal role in the activation of NF-κB, has not been investigated in shock. Thus, the aim of the present work was to investigate the effects of an IKK inhibitor on the MOF associated with hemorrhagic shock (HS). Therefore, rats were subjected to HS and were resuscitated with the shed blood. Rats were treated with the inhibitor of IKK or vehicle at resuscitation. Four hours later, blood and organs were assessed for organ injury and signaling events involved in the activation of NF-κB. Additionally, survival following serum deprivation was assessed in HK-2 cells treated with the inhibitor of IKK. HS resulted in renal dysfunction, lung, liver and muscular injury, and increases in serum inflammatory cytokines. Kidney and liver tissue from HS rats revealed increases in phosphorylation of IKKαβ and IκBα, nuclear translocation of NF-κB and expression of inducible isoform of nitric oxide synthase (iNOS). IKK16 treatment upon resuscitation attenuated NF-κB activation and activated the Akt survival pathway, leading to a significant attenuation of all of the above parameters. Furthermore, IKK16 exhibited cytoprotective effects in human kidney cells. In conclusion, the inhibitor of IKK complex attenuated the MOF associated with HS. This effect may be due to the inhibition of the NF-κB pathway and activation of the survival kinase Akt. Thus, the inhibition of the IKK complex might be an effective strategy for the prevention of MOF associated with HS.

Notes

Acknowledgments

R Sordi is supported by the program Science without Borders, CAPES Foundation, Ministry of Education of Brazil, Brasilia/DF, Brazil; NSA Patel is, in part, supported by the Bart’s and The London Charity (753/1722). The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007–2013) under REA grant agreement n° 608765, from the William Harvey Research Foundation and University of Turin (Ricerca Locale ex-60%). This work contributes to the Organ Protection research theme of the Barts Centre for Trauma Sciences, supported by the Barts and The London Charity (Award 753/1722) and forms part of the research themes contributing to the translational research portfolio of Barts and the London Cardiovascular Biomedical Research Unit, which is supported and funded by the National Institute of Health Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  • Regina Sordi
    • 1
    • 2
  • Fausto Chiazza
    • 3
  • Florence L. Johnson
    • 1
  • Nimesh S. A. Patel
    • 1
  • Karim Brohi
    • 4
  • Massimo Collino
    • 3
  • Christoph Thiemermann
    • 1
  1. 1.Barts and The London School of Medicine & Dentistry, The William Harvey Research InstituteQueen Mary University of LondonLondonUK
  2. 2.Capes FoundationMinistry of Education of BrazilBrasiliaBrazil
  3. 3.Department of Drug Science and TechnologyUniversity of TurinTurinItaly
  4. 4.Blizard Institute, Barts and The London School of Medicine & DentistryQueen Mary University of LondonLondonUK

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