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

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.

Ribonuclease 1 attenuates septic cardiomyopathy and cardiac apoptosis in a murine model of polymicrobial sepsis

“…Protein isolation and Western blot analysis. Semiquantitative Western blot analysis of caspase-3, caspase-9, Bax, and Bcl-2 was performed in murine heart tissue as previously before (48,49). For protein isolation, the tissue was homogenized in homogenization buffer (20 mM HEPES, pH 7.9, 1 mM MgCl 2 , 0.5 mM EDTA, 1% Nonidet P-40, 1 mM EGTA, 1 mM DTT, 0.5 mM PMSF, 1 μL/mL PIC) and centrifuged by 18,800 g for 40 minutes at 4°C.…”

IκK-16 decreases miRNA-155 expression and attenuates the human monocyte inflammatory response

“…IκK-16 is a new therapy recently studied in animal models of sepsis and shock [ 9 , 10 ] that reduces nuclear factor-κB (NFκB) activation by selectively blocking inhibitor of kappa-B kinase (IκK), and thus decrease the magnitude of the pro-inflammatory response. The beneficial effects of IκK-16 have included decreased lung injury, renal dysfunction, and cardiac failure; however, this treatment has not been applied to humans [ 11 , 12 ].…”

Molecular mechanisms of trauma-induced acute kidney injury: Inflammatory and metabolic insights from animal models

“…Within 30 minutes Akt and Bad phosphorylation was increased in kidneys from ischemic mice [124]. Conversely, Akt phosphorylation in the kidney was not increased in HS rats 4 hours after reperfusion when compared to sham animals [78].…”

“…Additionally, MPO positive cells in the kidney medulla, but not cortex, are elevated by 5 hours following HS [78].…”

“…infusion of the molecular inhibitor IKK16 (Figure 2) [78]. Treatment with IKK16 significantly enhanced Akt phosphorylation and activity in the kidney of HS rats.…”