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

The 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, IκB, nuclear translocation of NF-κB and expression of 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 NF-κB pathway and activation of the survival kinase Akt. Thus, the inhibition of IKK complex might be an effective strategy for the prevention of MOF associated with HS.