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. 2021 Jan 1;117(1):60-73.
doi: 10.1093/cvr/cvaa070.

The effects of sepsis on endothelium and clinical implications

Elena V Dolmatova  1 , Keke Wang  1 , Rohan Mandavilli  1 , Kathy K Griendling  1
Affiliations

The effects of sepsis on endothelium and clinical implications

Elena V Dolmatova et al. Cardiovasc Res. .

Abstract

Sepsis accounts for nearly 700 000 deaths in Europe annually and is caused by an overwhelming host response to infection resulting in organ failure. The endothelium is an active contributor to sepsis and as such represents a major target for therapy. During sepsis, endothelial cells amplify the immune response and activate the coagulation system. They are both a target and source of inflammation and serve as a link between local and systemic immune responses. In response to cytokines produced by immune cells, the endothelium expresses adhesion molecules and produces vasoactive compounds, inflammatory cytokines, and chemoattractants, thus switching from an anticoagulant to procoagulant state. These responses contribute to local control of infection, but systemic activation can lead to microvascular thrombosis, capillary permeability, hypotension, tissue hypoxia, and ultimately tissue damage. This review focuses on the role of the endothelium in leucocyte adhesion and transmigration as well as production of reactive oxygen and nitrogen species, microRNAs and cytokines, formation of signalling microparticles, and disseminated intravascular coagulation. We also discuss alterations in endothelial permeability and apoptosis. Finally, we review the diagnostic potential of endothelial markers and endothelial pathways as therapeutic targets for this devastating disease.

Keywords: Diagnosis; Endothelium; Mechanism; Sepsis; Treatment.

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Figures

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Graphical abstract
Figure 1
Figure 1
Inflammatory cascade in sepsis. Bacterial components activate both immune cells and endothelium inducing cytokine production, which is self-perpetuating. Endothelial cells become activated and express adhesion molecules, to which immune cells bind. This initiates the process of transmigration of immune cells to the site of injury. ROS secreted by immune cells and endothelium further augment the inflammatory response. The combination of these insults leads to shedding of glycocalyx, induction of adhesion molecules, increased endothelial permeability, and endothelial apoptosis. Chemokines secreted by immune cells and endothelium recruit immune cells from the bone marrow. The shift in the eNOS/iNOS balance results in excess NO synthesis and vasodilation.
Figure 2
Figure 2
Examples of inflammatory pathways within endothelial cells during sepsis (TLR4 and TNF-α). LPS and cytokines trigger intracellular pathways that ultimately lead to the activation of number of transcription factors (NF-κB, AP-1, and IRF3), resulting in increased cytokine production and adhesion molecule expression. These pathways also likely contribute to mitochondrial dysfunction and ROS production (see text for details).
Figure 3
Figure 3
Endothelial permeability in sepsis. ROS and bacterial components (i.e. LPS) damage the glycocalyx. LPS and inflammatory cytokines result in disruption of tight junctions (TJ), adherence junctions (AJ), and gap junctions (GJ) via activation of TNF-α and Ang2 pathways. The above effects increase endothelial permeability (see text for details).
Figure 4
Figure 4
Endothelium and coagulation cascade in sepsis. When endothelial integrity is compromised by membrane attack complexes and endothelial apoptosis, a prothrombotic state ensues: endothelial cells express adhesion molecules and platelets become activated. Activated platelets release a number of active compounds contributing to the inflammatory cascade. Bacterial components, ROS, and cytokines lead to acquired ADAMTS13 deficiency and accumulation of vWF multimers that are secreted from the activated endothelium. Activated endothelium also secretes PAI-1, further contributing to a prothrombotic state (see text for details).
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