Modulation of the inflammatory response in hibernation and calorie restriction: lessons for sepsis from metabolic extremes

Vera Annemarie Reitsema

    Research output: ThesisThesis fully internal (DIV)

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    Abstract

    Sepsis is a life-threatening condition caused by a dysregulated immune response to an infection, resulting in mitochondrial failure and organ dysfunction. Here, I explored the role of hydrogen sulfide (H2S) in preventing organ injury from sepsis by regulation of inflammation and mitochondrial function.
    The protective properties of H2S were established in hibernation, a physiological model characterized by extreme changes in metabolic rate, while avoiding oxidative organ injury. I showed increased flux through the transsulfuration pathway in hibernating Syrian hamsters, promoting H2S release during arousal (the metabolic active phase of hibernation). Additionally, neutrophil activation was suppressed during arousal, avoiding oxidative stress by immune activation and preventing a downward spiral into organ failure. In adult mice, I showed that administration of H2S as well as boosting endogenous H2S-production by calorie restriction, lowered the pro-inflammatory response during sepsis and protected against kidney damage. Moreover, a higher level of intracellular H2S in neutrophils was associated with improved functionality. Unexpectedly, calorie restriction in progeroid mice exaggerated the (neuro)inflammatory response to sepsis.
    Collectively, in this thesis I reveal the potential of H2S to modulate mitochondrial and neutrophil function, which may have relevance as a therapeutic target to prevent organ injury in sepsis. Yet, despite promising effects of calorie restriction on sepsis outcome in adult mice, a similar approach had detrimental effects in progeroid mice. Unravelling the pleiotropic effects of calorie restriction and H2S on regulation of immunity and mitochondria might lead to novel therapeutic targets to avoid organ failure in sepsis.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Henning, Rob, Supervisor
    • Bouma, Hjalmar, Co-supervisor
    Award date23-Dec-2021
    Place of Publication[Groningen]
    Publisher
    DOIs
    Publication statusPublished - 2021

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