Targeting protein kinase C-α prolongs survival and restores liver function in sepsis: Evidence from preclinical models
Sepsis is a life-threatening organ failure resulting from a poorly regulated infection response. Organ dysfunction includes hepatic involvement, weakening the immune system due to excretory liver failure, and metabolic dysfunction, increasing the death risk. Although experimental studies correlated...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825000064 |
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| author | Ling Xiong Dustin Beyer Na Liu Tina Lehmann Sophie Neugebauer Sascha Schaeuble Oliver Sommerfeld Philipp Ernst Carl-Magnus Svensson Sandor Nietzsche Sebastian Scholl Tony Bruns Nikolaus Gaßler Markus H. Gräler Marc Thilo Figge Gianni Panagiotou Michael Bauer Adrian T. Press |
| author_facet | Ling Xiong Dustin Beyer Na Liu Tina Lehmann Sophie Neugebauer Sascha Schaeuble Oliver Sommerfeld Philipp Ernst Carl-Magnus Svensson Sandor Nietzsche Sebastian Scholl Tony Bruns Nikolaus Gaßler Markus H. Gräler Marc Thilo Figge Gianni Panagiotou Michael Bauer Adrian T. Press |
| author_sort | Ling Xiong |
| collection | DOAJ |
| description | Sepsis is a life-threatening organ failure resulting from a poorly regulated infection response. Organ dysfunction includes hepatic involvement, weakening the immune system due to excretory liver failure, and metabolic dysfunction, increasing the death risk. Although experimental studies correlated excretory liver functionality with immune performance and survival rates in sepsis, the proteins and pathways involved remain unclear. This study identified protein kinase C-α (PKCα) as a novel target for managing excretory liver function during sepsis. Using a preclinical murine sepsis model, we found that both PKCα knockout and the use of a PKCα-inhibitor midostaurin successfully restored liver function without hindering the host’s response or ability to clear the pathogen, highlighting PKCα’s vital role in excretory liver failure. In septic animals, both approaches significantly boosted survival rates. Midostaurin is the clinically approved active pharmaceutical ingredient in Rydapt, approved for the adjuvant treatment of FTL3-mutated AML. Here, it reduced plasma bile acids and related inflammation in those patients, opening a translational avenue for therapeutics in sepsis. Conclusively, our research underscores the significance of PKCα in controlling excretory liver function during inflammation. This suggests that targeting this protein could restore liver function without compromising the immune system, thereby decreasing sepsis mortality and supporting the recent paradigm that the liver is a hub for the host response to infection that might, in the future, result in novel host-directed therapies supporting the current state-of-the-art intensive care medicine in patients with sepsis-associated liver failure. |
| format | Article |
| id | doaj-art-6101aa1e181141dea91f752741a4d8e5 |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-6101aa1e181141dea91f752741a4d8e52025-02-08T04:59:40ZengElsevierPharmacological Research1096-11862025-02-01212107581Targeting protein kinase C-α prolongs survival and restores liver function in sepsis: Evidence from preclinical modelsLing Xiong0Dustin Beyer1Na Liu2Tina Lehmann3Sophie Neugebauer4Sascha Schaeuble5Oliver Sommerfeld6Philipp Ernst7Carl-Magnus Svensson8Sandor Nietzsche9Sebastian Scholl10Tony Bruns11Nikolaus Gaßler12Markus H. Gräler13Marc Thilo Figge14Gianni Panagiotou15Michael Bauer16Adrian T. Press17Jena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Friedrich-Schiller-University Jena, Jena, Germany; Jena University Hospital, Center for Sepsis Control and Care, Friedrich-Schiller-University Jena, Jena, GermanyJena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Friedrich-Schiller-University Jena, Jena, Germany; Jena University Hospital, Center for Sepsis Control and Care, Friedrich-Schiller-University Jena, Jena, GermanyJena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Friedrich-Schiller-University Jena, Jena, Germany; Jena University Hospital, Center for Sepsis Control and Care, Friedrich-Schiller-University Jena, Jena, GermanyJena University Hospital, Electron Microscopy Center, Friedrich-Schiller-University Jena, Jena, GermanyJena University Hospital, Institute of Clinical Chemistry and Laboratory Diagnostics, Friedrich-Schiller-University Jena, Jena, GermanyDepartment of Microbiome Dynamics at Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (Leibniz-HKI), Jena, GermanyJena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Friedrich-Schiller-University Jena, Jena, Germany; Jena University Hospital, Center for Sepsis Control and Care, Friedrich-Schiller-University Jena, Jena, GermanyJena University Hospital, Clinic for Internal Medicine II, Department of Hematology and Internal Oncology, Friedrich-Schiller-University Jena, Jena, GermanyResearch Group Applied Systems Biology at Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (Leibniz-HKI), Jena, GermanyJena University Hospital, Electron Microscopy Center, Friedrich-Schiller-University Jena, Jena, GermanyJena University Hospital, Clinic for Internal Medicine II, Department of Hematology and Internal Oncology, Friedrich-Schiller-University Jena, Jena, GermanyUniversity Hospital RWTH Aachen, Department of Medicine III, Aachen, GermanyJena University Hospital, Section of Pathology, Institute of Forensic Medicine, Friedrich-Schiller-University Jena, Jena, GermanyJena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Friedrich-Schiller-University Jena, Jena, Germany; Jena University Hospital, Center for Sepsis Control and Care, Friedrich-Schiller-University Jena, Jena, GermanyJena University Hospital, Center for Sepsis Control and Care, Friedrich-Schiller-University Jena, Jena, Germany; Research Group Applied Systems Biology at Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (Leibniz-HKI), Jena, Germany; Friedrich-Schiller-University Jena, Institute of Microbiology, Faculty of Biological Sciences, Jena, Germany; Friedrich-Schiller-University Jena, Cluster of Excellence Balance of the Microverse, Jena, GermanyDepartment of Microbiome Dynamics at Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (Leibniz-HKI), Jena, Germany; Friedrich-Schiller-University Jena, Institute of Microbiology, Faculty of Biological Sciences, Jena, Germany; Friedrich-Schiller-University Jena, Cluster of Excellence Balance of the Microverse, Jena, GermanyJena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Friedrich-Schiller-University Jena, Jena, Germany; Jena University Hospital, Center for Sepsis Control and Care, Friedrich-Schiller-University Jena, Jena, GermanyJena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Friedrich-Schiller-University Jena, Jena, Germany; Jena University Hospital, Center for Sepsis Control and Care, Friedrich-Schiller-University Jena, Jena, Germany; Friedrich-Schiller-University Jena, Faculty of Medicine, Jena, Germany; Correspondence to: Jena University Hospital, Am Klinikum 1, Jena, DE 07747, Germany.Sepsis is a life-threatening organ failure resulting from a poorly regulated infection response. Organ dysfunction includes hepatic involvement, weakening the immune system due to excretory liver failure, and metabolic dysfunction, increasing the death risk. Although experimental studies correlated excretory liver functionality with immune performance and survival rates in sepsis, the proteins and pathways involved remain unclear. This study identified protein kinase C-α (PKCα) as a novel target for managing excretory liver function during sepsis. Using a preclinical murine sepsis model, we found that both PKCα knockout and the use of a PKCα-inhibitor midostaurin successfully restored liver function without hindering the host’s response or ability to clear the pathogen, highlighting PKCα’s vital role in excretory liver failure. In septic animals, both approaches significantly boosted survival rates. Midostaurin is the clinically approved active pharmaceutical ingredient in Rydapt, approved for the adjuvant treatment of FTL3-mutated AML. Here, it reduced plasma bile acids and related inflammation in those patients, opening a translational avenue for therapeutics in sepsis. Conclusively, our research underscores the significance of PKCα in controlling excretory liver function during inflammation. This suggests that targeting this protein could restore liver function without compromising the immune system, thereby decreasing sepsis mortality and supporting the recent paradigm that the liver is a hub for the host response to infection that might, in the future, result in novel host-directed therapies supporting the current state-of-the-art intensive care medicine in patients with sepsis-associated liver failure.http://www.sciencedirect.com/science/article/pii/S1043661825000064SepsisExcretory liver dysfunctionImmune responsePKC-alphaMidostaurinAML |
| spellingShingle | Ling Xiong Dustin Beyer Na Liu Tina Lehmann Sophie Neugebauer Sascha Schaeuble Oliver Sommerfeld Philipp Ernst Carl-Magnus Svensson Sandor Nietzsche Sebastian Scholl Tony Bruns Nikolaus Gaßler Markus H. Gräler Marc Thilo Figge Gianni Panagiotou Michael Bauer Adrian T. Press Targeting protein kinase C-α prolongs survival and restores liver function in sepsis: Evidence from preclinical models Pharmacological Research Sepsis Excretory liver dysfunction Immune response PKC-alpha Midostaurin AML |
| title | Targeting protein kinase C-α prolongs survival and restores liver function in sepsis: Evidence from preclinical models |
| title_full | Targeting protein kinase C-α prolongs survival and restores liver function in sepsis: Evidence from preclinical models |
| title_fullStr | Targeting protein kinase C-α prolongs survival and restores liver function in sepsis: Evidence from preclinical models |
| title_full_unstemmed | Targeting protein kinase C-α prolongs survival and restores liver function in sepsis: Evidence from preclinical models |
| title_short | Targeting protein kinase C-α prolongs survival and restores liver function in sepsis: Evidence from preclinical models |
| title_sort | targeting protein kinase c α prolongs survival and restores liver function in sepsis evidence from preclinical models |
| topic | Sepsis Excretory liver dysfunction Immune response PKC-alpha Midostaurin AML |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825000064 |
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