Nuclear factor κB (NF-κB) plays a pivotal role in
sepsis. Activation of NF-κB is initiated by the signal-induced ubiquitylation 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 and/or 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 and
peptidoglycan (LPS/PepG)] or underwent cecal
ligation and
puncture (CLP) to induce
sepsis-associated MOD. At 1 hour after LPS/PepG or CLP, mice were treated with the IKK inhibitor IKK 16 (1 mg/kg
body weight). At 24 hours, parameters of organ dysfunction and/or injury were assessed in both models. Mice developed a significant impairment in systolic contractility (echocardiography), and significant increases in serum
creatinine, serum
alanine aminotransferase and lung
myeloperoxidase activity, thus indicating cardiac dysfunction, renal dysfunction, hepatocellular injury and
lung inflammation, respectively. Treatment with IKK 16 attenuated the impairment in systolic contractility, renal dysfunction, hepatocellular injury and
lung inflammation in LPS/PepG-induced MOD and in polymicrobial
sepsis. Compared with mice that were injected with LPS/PepG or underwent CLP, immunoblot analyses of heart and liver tissues from mice that were injected with LPS/PepG or underwent CLP and were also treated with IKK 16 revealed: (1) significant attenuation of the increased phosphorylation of IκBα; (2) significant attenuation of the increased nuclear translocation of the NF-κB subunit p65; (3) significant attenuation of the increase in
inducible nitric oxide synthase (iNOS) expression; and (4) 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 decrease in iNOS expression and the activation of the Akt-eNOS survival pathway.