Mitochondrial dysfunction in sepsis: identifying mechanisms and novel therapies

    Research output: ThesisThesis fully internal (DIV)

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    Abstract

    Sepsis is a life-threatening condition with an in-hospital mortality rate of up to 30%. The global incidence of sepsis is estimated to be approximately 50 million cases. Sepsis is on the rise due to increased antibiotic resistance, lifespans, chronic diseases, the use of immunosuppressive therapy, chemotherapy, and invasive procedures (e.g., mechanical ventilation and dialyses). Currently, the treatment options for sepsis are limited to antibiotics and supportive care, with no targeted treatment available. Furthermore, survivors of sepsis face a significant risk of cardiovascular events, with a 3-year mortality rate as high as 47% after hospital discharge. This places sepsis as a major burden on healthcare and a significant global cause of death.

    This thesis is shedding light on new mechanisms behind sepsis and potential therapeutics, with a specific focus on mitochondrial dysfunction in sepsis. Mitochondria are the powerhouses of cells responsible for the body's energy production and organ function. This research revealed increased mitochondrial damage and damage markers (oxidative stress) in patients with sepsis and acute kidney injury, which is linked to sepsis severity and long-term mortality. Further, this research showed endothelial cells, lining the blood vessels, involved in the development of acute kidney injury in sepsis. Furthermore, a direct interaction between bacterial endotoxin and mitochondria in endothelial cells and kidney was demonstrated, inducing mitochondrial dysfunction. Therapeutic interventions showed promising results to preserve mitochondria using hydrogen sulfide (H2S) donors and SUL138 in pre-clinical sepsis models. This research revealed mitochondrial therapeutic targets to develop new therapies in patients with sepsis to improve outcome.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Henning, Rob, Supervisor
    • Bouma, Hjalmar, Supervisor
    Award date15-Nov-2023
    Place of Publication[Groningen]
    Publisher
    Print ISBNs978-94-6483-439-0
    DOIs
    Publication statusPublished - 2023

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