Exploring mechanisms of and therapeutic interventions for microvascular endothelial activation in shock

Yan, R., 2019, [Groningen]: University of Groningen. 180 p.

Research output: ThesisThesis fully internal (DIV)Academic

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  • Title and contents

    Final publisher's version, 262 KB, PDF-document

  • Chapter 1

    Final publisher's version, 623 KB, PDF-document

  • Chapter 2

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  • Chapter 3

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  • Chapter 4

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  • Chapter 5

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    Embargo ends: 28/01/2020

  • Chapter 6

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  • Appendices

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  • Complete thesis

    Final publisher's version, 11 MB, PDF-document

    Embargo ends: 28/01/2020

  • Propositions

    Final publisher's version, 157 KB, PDF-document

Patients suffering from hemorrhagic shock (HS) and septic shock often develop multiple organ failure, which leads to high mortality in Intensive Care units. The kidney is one of the malfunctioning organs. The precise cellular and molecular mechanisms causing this acute kidney injury are unknown. A thorough understanding of these mechanisms will enable us to identify new molecular targets for the treatment of critically-ill patients.
This thesis aimed to investigate the molecular mechanisms of endothelial activation during shock development and explore potential molecular targets for the treatment of shock induced organ failure. Endothelial cells cover all blood vessels in our body. In organs they play a major role in homeostasis, while in response to shock conditions they actively engage in the following disease processes. We investigated microvascular endothelial inflammatory activation in hemorrhagic shock and sepsis mouse models and the effects of therapeutic interventions on these endothelial inflammatory responses.
We showed that the endothelium in different renal microvascular segments display different responses to disease stimuli and drug intervention. The most pronounced inflammatory responses were seen in glomerular and venule compartments. Inhibition of the major inflammation-associated cell activation pathway NF-κB may have limited effects as this molecular pathway already becomes activated in the early phase of renal injury. Furthermore, we identified multiple activation pathways in endothelial cells in vitro that are activated by lipopolysaccharide, a bacterial wall component implicated in sepsis. These so-called kinase pathways identified in this thesis could be promising new targets for therapeutic intervention to prevent sepsis-associated kidney injury.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
Award date28-Jan-2019
Place of Publication[Groningen]
Print ISBNs978-94-034-1322-8
Electronic ISBNs978-94-034-1321-1
Publication statusPublished - 2019

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