Nuclear factor (NF)-κB plays a pivotal role in sepsis. Activation of NF-κB is initiated by the signal-induced ubiquitination and subsequent degradation of inhibitors of kappa B (IκBs) primarily via activation of the IκB kinase (IKK). This study was designed to investigate the effects of IKK inhibition on sepsis-associated multiple organ dysfunction/injury (MOD) and to elucidate underlying signaling mechanisms in two different in vivo models: Male C57BL/6 mice were subjected to either bacterial cell wall components [lipopolysaccharide (LPS)/peptidoglycan (PepG)] or underwent cecal ligation and puncture (CLP) to induce sepsis-associated MOD. One hour after LPS/PepG or CLP mice were treated with the IKK inhibitor IKK 16 (1 mg/kg). At 24 hours parameters of organ dysfunction/injury were assessed in both models. Mice developed a significant impairment in systolic contractility (echocardiography), a significant increase in serum creatinine, alanine aminotransferase as well as lung myeloperoxidase activity, and, thus, cardiac dysfunction, renal dysfunction and hepatocellular injury as well as lung inflammation, respectively. Treatment with IKK 16 attenuated the impairment in systolic contractility, renal dysfunction, hepatocellular injury and lung inflammation in LPS/PepG induced multiple organ dysfunction/injury and in polymicrobial sepsis. Compared with mice that were injected with LPS/PepG or underwent CLP, immunoblot analyzes of heart and liver tissues from mice that were injected with LPS/PepG or underwent CLP and treated with IKK 16 revealed a significant attenuation of the i) increased phosphorylation of IκBα; ii) increased nuclear translocation of the NF-κB subunit p65; iii) significant increase in inducible nitric oxide synthase (iNOS) expression; and iv) revealed a significant increase in the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS). Here, we report for the first time that delayed IKK inhibition reduces MOD in experimental sepsis. We suggest that this protective effect is (at least in part) attributable to inhibition of inflammation through NF-κB, the subsequent decreased iNOS expression and the activation of the Akt/eNOS survival pathway.
- Received March 14, 2013.
- Accepted April 20, 2013.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.