Baricitinib protects mice from sepsis-induced cardiac dysfunction and multiple-organ failure
Sepsis is one of the major complications of surgery resulting in high morbidity and mortality, but there are no specific therapies for sepsis-induced organ dysfunction. Data obtained under Gene Expression Omnibus accession GSE131761 were re-analyzed and showed an increased gene expression of Janus K...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1223014/full |
| _version_ | 1797687695898574848 |
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| author | Chiara Verra Shireen Mohammad Gustavo Ferreira Alves Elisa Porchietto Sina Maren Coldewey Sina Maren Coldewey Massimo Collino Christoph Thiemermann |
| author_facet | Chiara Verra Shireen Mohammad Gustavo Ferreira Alves Elisa Porchietto Sina Maren Coldewey Sina Maren Coldewey Massimo Collino Christoph Thiemermann |
| author_sort | Chiara Verra |
| collection | DOAJ |
| description | Sepsis is one of the major complications of surgery resulting in high morbidity and mortality, but there are no specific therapies for sepsis-induced organ dysfunction. Data obtained under Gene Expression Omnibus accession GSE131761 were re-analyzed and showed an increased gene expression of Janus Kinase 2 (JAK2) and Signal Transducer and Activator of Transcription 3 (STAT3) in the whole blood of post-operative septic patients. Based on these results, we hypothesized that JAK/STAT activation may contribute to the pathophysiology of septic shock and, hence, investigated the effects of baricitinib (JAK1/JAK2 inhibitor) on sepsis-induced cardiac dysfunction and multiple-organ failure (MOF). In a mouse model of post-trauma sepsis induced by midline laparotomy and cecal ligation and puncture (CLP), 10-week-old male (n=32) and female (n=32) C57BL/6 mice received baricitinib (1mg/kg; i.p.) or vehicle at 1h or 3h post-surgery. Cardiac function was assessed at 24h post-CLP by echocardiography in vivo, and the degree of MOF was analyzed by determination of biomarkers in the serum. The potential mechanism underlying both the cardiac dysfunction and the effect of baricitinib was analyzed by western blot analysis in the heart. Trauma and subsequent sepsis significantly depressed the cardiac function and induced multiple-organ failure, associated with an increase in the activation of JAK2/STAT3, NLRP3 inflammasome and NF- κβ pathways in the heart of both male and female animals. These pathways were inhibited by the administration of baricitinib post the onset of sepsis. Moreover, treatment with baricitinib at 1h or 3h post-CLP protected mice from sepsis-induced cardiac injury and multiple-organ failure. Thus, baricitinib may be repurposed for trauma-associated sepsis. |
| first_indexed | 2024-03-12T01:21:24Z |
| format | Article |
| id | doaj.art-4ef0100d45e3499884b9ee1742671c7f |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-12T01:21:24Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-4ef0100d45e3499884b9ee1742671c7f2023-09-13T04:32:03ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-09-011410.3389/fimmu.2023.12230141223014Baricitinib protects mice from sepsis-induced cardiac dysfunction and multiple-organ failureChiara Verra0Shireen Mohammad1Gustavo Ferreira Alves2Elisa Porchietto3Sina Maren Coldewey4Sina Maren Coldewey5Massimo Collino6Christoph Thiemermann7William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomWilliam Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomDepartment of Neurosciences “Rita Levi Montalcini”, University of Turin, Turin, ItalyPharmacology Unit, School of Pharmacy, University of Camerino, Camerino, ItalyDepartment of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, GermanySeptomics Research Center, Jena University Hospital, Jena, GermanyDepartment of Neurosciences “Rita Levi Montalcini”, University of Turin, Turin, ItalyWilliam Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomSepsis is one of the major complications of surgery resulting in high morbidity and mortality, but there are no specific therapies for sepsis-induced organ dysfunction. Data obtained under Gene Expression Omnibus accession GSE131761 were re-analyzed and showed an increased gene expression of Janus Kinase 2 (JAK2) and Signal Transducer and Activator of Transcription 3 (STAT3) in the whole blood of post-operative septic patients. Based on these results, we hypothesized that JAK/STAT activation may contribute to the pathophysiology of septic shock and, hence, investigated the effects of baricitinib (JAK1/JAK2 inhibitor) on sepsis-induced cardiac dysfunction and multiple-organ failure (MOF). In a mouse model of post-trauma sepsis induced by midline laparotomy and cecal ligation and puncture (CLP), 10-week-old male (n=32) and female (n=32) C57BL/6 mice received baricitinib (1mg/kg; i.p.) or vehicle at 1h or 3h post-surgery. Cardiac function was assessed at 24h post-CLP by echocardiography in vivo, and the degree of MOF was analyzed by determination of biomarkers in the serum. The potential mechanism underlying both the cardiac dysfunction and the effect of baricitinib was analyzed by western blot analysis in the heart. Trauma and subsequent sepsis significantly depressed the cardiac function and induced multiple-organ failure, associated with an increase in the activation of JAK2/STAT3, NLRP3 inflammasome and NF- κβ pathways in the heart of both male and female animals. These pathways were inhibited by the administration of baricitinib post the onset of sepsis. Moreover, treatment with baricitinib at 1h or 3h post-CLP protected mice from sepsis-induced cardiac injury and multiple-organ failure. Thus, baricitinib may be repurposed for trauma-associated sepsis.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1223014/fullsepsisbaricitinibJanus Kinasecardiac dysfunctionmultiple-organ failure |
| spellingShingle | Chiara Verra Shireen Mohammad Gustavo Ferreira Alves Elisa Porchietto Sina Maren Coldewey Sina Maren Coldewey Massimo Collino Christoph Thiemermann Baricitinib protects mice from sepsis-induced cardiac dysfunction and multiple-organ failure Frontiers in Immunology sepsis baricitinib Janus Kinase cardiac dysfunction multiple-organ failure |
| title | Baricitinib protects mice from sepsis-induced cardiac dysfunction and multiple-organ failure |
| title_full | Baricitinib protects mice from sepsis-induced cardiac dysfunction and multiple-organ failure |
| title_fullStr | Baricitinib protects mice from sepsis-induced cardiac dysfunction and multiple-organ failure |
| title_full_unstemmed | Baricitinib protects mice from sepsis-induced cardiac dysfunction and multiple-organ failure |
| title_short | Baricitinib protects mice from sepsis-induced cardiac dysfunction and multiple-organ failure |
| title_sort | baricitinib protects mice from sepsis induced cardiac dysfunction and multiple organ failure |
| topic | sepsis baricitinib Janus Kinase cardiac dysfunction multiple-organ failure |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1223014/full |
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