Fig. 2.
Fig. 2. The endothelium as a therapeutic target. / An understanding of the endothelial response to pathogens provides a foundation for therapeutic design. For purposes of illustration and discussion, the temporal sequence of events is depicted from left to right. In sepsis, the endothelium is activated by LPS-mediated engagement of the toll-like receptor (TLR4) or by the interaction of inflammatory mediators (IL-6, TNF-α, IL-1, kinins, and C5a are shown) with their respective receptors (drawn as a single representative receptor). At the same time (or later during the sepsis cascade), the endothelium may be conditioned by other environmental factors, such as hypoxia, low blood flow, changes in temperature, acid-base/electrolyte abnormalities, and/or hyperglycemia. The interaction of extracellular mediators with their receptors leads to activation of downstream signaling pathways (including MAPK and PKC), which in turn promote posttranscriptional changes in cell function or alter gene expression profiles through a number of transcription factors, including NF-κB, GATA-2, and AP-1. The up-regulation of cell adhesion molecules on the surface of the endothelium (P-selectin, E-selectin, VCAM-1, and ICAM-1 are shown) promotes increased adhesion, rolling, and transmigration of circulating leukocytes. Leukocyte-endothelial interactions further modulate the phenotype of these cells. The release of cytokines from the endothelium results in additional activation of monocytes and endothelial cells. Increased expression of procoagulants (eg, TF) and/or reduced expression of anticoagulants (eg, TM, EPCR) promote increased thrombin generation and fibrin formation. Various components of the coagulation pathway (including serine proteases, fibrin, and platelets) may signal directly in the endothelium through protease-activated receptors (PAR-1 is shown). Changes in the expression of proapoptotic and antiapoptotic genes (along with a multitude of posttranscriptional changes) may result in a shift in balance toward programmed cell death. During the process of activation, NADPH oxidase may induce the formation of reactive oxygen species (ROS), nitric oxide (NO) is released, and cell permeability is increased. In keeping with the theme of spatial and temporal dynamics, the relative activity of the various pathways will vary between different endothelial cells and from one moment to the next. Not shown are the critical interactions between the endothelium and underlying extracellular matrix and parenchymal cells. Temp indicates temperature; ICAM-1, intracellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule; EC, endothelial cell; TF, tissue factor; TM, thrombomodulin; EPCR, endothelial protein C receptor; NO, nitric oxide; PGI2, prostacyclin. Receptors are labeled in light font.

The endothelium as a therapeutic target.

An understanding of the endothelial response to pathogens provides a foundation for therapeutic design. For purposes of illustration and discussion, the temporal sequence of events is depicted from left to right. In sepsis, the endothelium is activated by LPS-mediated engagement of the toll-like receptor (TLR4) or by the interaction of inflammatory mediators (IL-6, TNF-α, IL-1, kinins, and C5a are shown) with their respective receptors (drawn as a single representative receptor). At the same time (or later during the sepsis cascade), the endothelium may be conditioned by other environmental factors, such as hypoxia, low blood flow, changes in temperature, acid-base/electrolyte abnormalities, and/or hyperglycemia. The interaction of extracellular mediators with their receptors leads to activation of downstream signaling pathways (including MAPK and PKC), which in turn promote posttranscriptional changes in cell function or alter gene expression profiles through a number of transcription factors, including NF-κB, GATA-2, and AP-1. The up-regulation of cell adhesion molecules on the surface of the endothelium (P-selectin, E-selectin, VCAM-1, and ICAM-1 are shown) promotes increased adhesion, rolling, and transmigration of circulating leukocytes. Leukocyte-endothelial interactions further modulate the phenotype of these cells. The release of cytokines from the endothelium results in additional activation of monocytes and endothelial cells. Increased expression of procoagulants (eg, TF) and/or reduced expression of anticoagulants (eg, TM, EPCR) promote increased thrombin generation and fibrin formation. Various components of the coagulation pathway (including serine proteases, fibrin, and platelets) may signal directly in the endothelium through protease-activated receptors (PAR-1 is shown). Changes in the expression of proapoptotic and antiapoptotic genes (along with a multitude of posttranscriptional changes) may result in a shift in balance toward programmed cell death. During the process of activation, NADPH oxidase may induce the formation of reactive oxygen species (ROS), nitric oxide (NO) is released, and cell permeability is increased. In keeping with the theme of spatial and temporal dynamics, the relative activity of the various pathways will vary between different endothelial cells and from one moment to the next. Not shown are the critical interactions between the endothelium and underlying extracellular matrix and parenchymal cells. Temp indicates temperature; ICAM-1, intracellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule; EC, endothelial cell; TF, tissue factor; TM, thrombomodulin; EPCR, endothelial protein C receptor; NO, nitric oxide; PGI2, prostacyclin. Receptors are labeled in light font.

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