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Pathology of Human Endothelium in Septic Organ Failure

  • Chapter
Forensic Pathology Reviews

Part of the book series: Forensic Pathology Reviews ((FPR,volume 4))

Abstract

Human sepsis is a spectrum of pathophysiological changes in the host system resulting from a generalized activation and systemic expression of the host’s inflammatory pathways in response to infection. The endothelium plays a key role in the pathogenesis of sepsis, and studies of endothelial derangement and its underlying pathophysiological mechanisms in sepsis have become of considerable interest in both the clinical and pathological fields. Recognition, as well as contact formation, between leukocytes and the endothelium is dependent on the presence of both cytokines and adhesion molecules that mediate leukocyte-endothelial cell adhesive interactions. The adherence of leukocytes on the vascular endothelial cell surface and the transmigration through the endothelial layer is regulated by at least three adhesion molecule families: the selectins (E-Selectin, L-Selectin, P-Selectin), the integrins (e.g., lymphocyte function-associated antigen-1, Mac-1, very late activation antigen-4), and the immunoglobulin superfamily (e.g., intercellular adhesion molecule-1, vascular cell adhesion molecule-1). The constitutively expressed platelet endothelial cell adhesion molecule-1, already strongly expressed by endothelial cells lacking inflammatory stimuli, is localized at the cell-to-cell borders of endothelial cells and mediates a common final step in the extravasation of monocytes and neu-trophils during the inflammatory response from the vascular lumen through the endothelium. In addition, platelet-activating factor, released in response to endotoxin, is another mediator of considerable relevance for endotoxin-induced leukocyte recruitment into tissue in sepsis, leading to loss of fluid from the intravascular into the extravascular space, thus contributing to the progressive loss of circulating blood and, thereby, to a depression of cardiac output. Studies have demonstrated that this loss of fluid is not the result of changes in hydrostatic and/or osmotic pressures within the vascular compartment, but rather thebreakdown of endothelial barrier function, thus allowing emigration of fluid and macromolecules—including proteins—into the extravascular space. Separation of tight junctions between endothelial cells, influenced by inflammatory mediators and white blood cells, and dysfunction rather than destructive changes of endothelial cells leading to defects in endothelial cell volume regulation are discussed as the main underlying pathophysiological mechanisms. Two major pathways are involved in initiation of apoptosis in sepsis: a receptor-initiated caspase-8-mediated pathway and a mitochondrial-initiated caspase-9-mediated pathway. In vitro studies have revealed apoptotic cell death of endothelial cells in response to LPS and tumor necrosis factor-α, as well as to certain microorganisms. A number of studies suggest that endotoxin induces expression of antiapoptotic molecules in microvascular endothelial cells and neutrophils. The latter could play a role in the accumulation of neutrophils during sepsis, as well as in prolongation and/or augmentation of the inflammatory response.

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  1. Institute of Pathology, University Clinic Bergmannsheil, Ruhr-University Bochum, Bochum, Germany

    Annette M. Müller MD

  2. Institute of Legal Medicine, University of Hamburg, Hamburg, Germany

    Michael Tsokos MD

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  1. Institute of Legal Medicine, University of Hamburg, Hamburg, Germany

    Michael Tsokos MD

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Müller, A.M., Tsokos, M. (2006). Pathology of Human Endothelium in Septic Organ Failure. In: Tsokos, M. (eds) Forensic Pathology Reviews. Forensic Pathology Reviews, vol 4. Humana Press. https://doi.org/10.1007/978-1-59259-921-9_7

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  • DOI: https://doi.org/10.1007/978-1-59259-921-9_7

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