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Inhibition of IκB kinase reduces the multiple organ dysfunction caused by sepsis in the mouse

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 inhib...

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Autores principales: Coldewey, Sina M., Rogazzo, Mara, Collino, Massimo, Patel, Nimesh S. A., Thiemermann, Christoph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Limited 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701222/
https://www.ncbi.nlm.nih.gov/pubmed/23649820
http://dx.doi.org/10.1242/dmm.012435
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author Coldewey, Sina M.
Rogazzo, Mara
Collino, Massimo
Patel, Nimesh S. A.
Thiemermann, Christoph
author_facet Coldewey, Sina M.
Rogazzo, Mara
Collino, Massimo
Patel, Nimesh S. A.
Thiemermann, Christoph
author_sort Coldewey, Sina M.
collection PubMed
description 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.
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spelling pubmed-37012222013-07-15 Inhibition of IκB kinase reduces the multiple organ dysfunction caused by sepsis in the mouse Coldewey, Sina M. Rogazzo, Mara Collino, Massimo Patel, Nimesh S. A. Thiemermann, Christoph Dis Model Mech Research Article 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. The Company of Biologists Limited 2013-07 2013-05-02 /pmc/articles/PMC3701222/ /pubmed/23649820 http://dx.doi.org/10.1242/dmm.012435 Text en © 2013. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Coldewey, Sina M.
Rogazzo, Mara
Collino, Massimo
Patel, Nimesh S. A.
Thiemermann, Christoph
Inhibition of IκB kinase reduces the multiple organ dysfunction caused by sepsis in the mouse
title Inhibition of IκB kinase reduces the multiple organ dysfunction caused by sepsis in the mouse
title_full Inhibition of IκB kinase reduces the multiple organ dysfunction caused by sepsis in the mouse
title_fullStr Inhibition of IκB kinase reduces the multiple organ dysfunction caused by sepsis in the mouse
title_full_unstemmed Inhibition of IκB kinase reduces the multiple organ dysfunction caused by sepsis in the mouse
title_short Inhibition of IκB kinase reduces the multiple organ dysfunction caused by sepsis in the mouse
title_sort inhibition of iκb kinase reduces the multiple organ dysfunction caused by sepsis in the mouse
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701222/
https://www.ncbi.nlm.nih.gov/pubmed/23649820
http://dx.doi.org/10.1242/dmm.012435
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