Exploring cellular and molecular mechanisms underlying endothelial heterogeneity in sepsis

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    Patients suffering from sepsis (‘blood poisoning’) are often confronted with organ dysfunction, and kidney and lung are vulnerable to sepsis-associated injuries. The pathophysiology of kidney and lung organ dysfunction is incompletely understood, hampering the development of effective therapy to stop the onset of sepsis to organs failure.
    In health, endothelial cells (EC) keep vascular integrity, coagulation, and inflammation in check, but during sepsis, these processes are all compromised to different degrees. Organs fail differently in sepsis despite being exposed to the same insult, which suggests that impaired endothelial-regulated processes are distinctively controlled both at organ and at microvascular segment levels. The precise molecular control of inflammatory response of different microvascular segments of sepsis-affected organs remains elusive.
    In this thesis, I investigated heterogenous response of EC to sepsis-related inflammatory stimuli and the underlying molecular mechanism(s) that may contribute to these differences. I showed that endothelial inflammatory activation in murine sepsis was organ- and microvascular bed-specific. In vitro exposure of EC to lipopolysaccharide (LPS), a sepsis endotoxin, resulted in the formation of EC subpopulations that each express a specific repertoire of inflammatory genes.
    Tyrosine kinases (TK) are important endothelial signalling molecules that relay signals in response to external stimuli to induce changes in cellular behaviour, such as in inflammation. I identified two TK that can be pharmacologically targeted to attenuate LPS-induced inflammatory activation of EC in vitro. Unravelling the molecular control of endothelial heterogeneity at microvascular bed and cellular levels will assist in development of therapies targeting specific microvascular beds affected by sepsis.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    • Molema, Ingrid, Supervisor
    • Moser, Jill, Co-supervisor
    • van Meurs, Matijs, Co-supervisor
    Award date24-Mar-2021
    Place of Publication[Groningen]
    Publication statusPublished - 2021

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