The endothelial cell (EC) lining of the vascular system—while displaying variations in the properties of ECs among different tissues and among different types of vascular segments (e.g. arterial, microvascular, venous) within particular tissues—performs a number of important, common functions that warrant consideration of the EC as a specific cell type. These common functions include: regulation of underlying smooth muscle cell (SMC) tone; control of transendothelial cell movement of fluid, solutes and macromolecules; maintenance of blood fluidity; presentation of a non-interactive surface to the formed elements (e.g. erythrocytes, leucocytes and platelets) of the blood; and display of tissue antigens to circulating memory T cells as part of immune surveillance (Choi et al. 2004). The constitutive functions of ECs are dependent upon active metabolic processes, and all may be impaired by EC injury such as that which occurs in inflammation. For example, ECs normally produce nitric oxide (NO), a mediator that, among other effects, reduces basal SMC tone (Stamler et al. 1994). Injured ECs may produce inadequate quantities of NO which increases SMC tone and causes pathological elevation of blood pressure (Panza et al.

1990). This particular perturbation is commonly referred to as "endothelial dysfunction". However, other behaviours of the EC may also exhibit dysfunction. For example, endothelial injury may lead to loss of the EC barrier that retains plasma proteins within the intravascular space, leading to vascular leak-iness (Joris et al. 1990). Failure to block intravascular coagulation, leading to thrombosis, is yet another example of endothelial dysfunction (Aird 2003). The ultimate form of injury is one which causes cell death, and dead ECs are globally dysfunctional, failing in performance of all normal functions. However, not all injury is lethal and there is a spectrum of EC injury and concomitant endothelial dysfunction. Importantly, endothelial dysfunction is a common feature of many disease states and is a harbinger of adverse cardiovascular outcomes (Endemann and Schiffrin 2004).

The idea that injury can cause endothelial dysfunction is clear, but confusion may arise because of phenotypic overlap with another type of EC response to stimuli known as "endothelial activation" (Pober 1988). As originally defined, endothelial activation referred to a state in which ECs, responding to various mediators, acquire the capacity to perform new functions. Stimuli that produce activation include autacoids and cytokines. Tumour necrosis factor (TNF) is a prototypical inflammatory cytokine, and TNF-activated ECs display new surface adhesion molecules and chemokines that lead to recruitment and activation of circulating leucocytes. Thus, while a normal EC may produce signals that minimise leucocyte activation, such as NO release (Kubes et al.

1991), and a dysfunctional EC that produces too little NO may fail to adequately inhibit leucocyte binding to the EC surface, an activated EC has been modified to actively promote leucocyte binding and transendothelial migration. This kind of activation is a desirable response at the site of local infection where leucocytes mediate host defence, but can become pathological in an inflammatory disease such a rheumatoid arthritis. The key point is that activated and dysfunctional ECs may share a common feature, namely enhanced recruitment of leucocytes. Nevertheless, activated ECs are not necessarily injured and the outcome, as in the case of leucocyte recruitment at a site of infection, may actually be beneficial. Similarly, a healthy EC will display on its luminal surface anti-coagulant heparan sulphate moieties that bind anti-thrombin III and actively inhibit coagulation, whereas antibody-mediated injury may produce endothelial dysfunction by triggering the shedding of heparan sulphate and promoting thrombosis (Platt et al. 1991). A TNF-activated EC may synthesise and display tissue factor, an initiating catalyst for thrombosis (Nawroth and Stern 1986). In the case of TNF, this activation of coagulation can be an important part of the mechanism by which infectious organisms may be locally contained. The point is again that an activated EC and a dysfunctional EC may contribute to a common result, namely thrombosis.

While dysfunction is generally a result of injury and activation is normally associated with host defence, this distinction can become blurred. For example, host defence mechanisms may cause EC injury, and both processes are often present in the same vessel segment or even the same EC. For example, the same EC that sheds heparan sulphate may express tissue factor. Even more confusing is that some agents generally associated with activation, such as TNF, may in certain contexts cause EC injury and dysfunction. For example, TNF not only induces tissue factor, leucocyte adhesion molecules, and chemokines (Pober 1988), but it also destabilises the messenger RNA (mRNA) molecules encoding endothelial nitric oxide synthase (eNOS), the enzyme responsible for NO synthesis in the EC (Yoshizumi et al. 1993). Since TNF can act in an endocrine manner (i.e. at a distance), it may promote host defence at a local site and simultaneously cause endothelial dysfunction elsewhere in the vasculature.

In this chapter, we will focus on the biochemistry of EC injury and death, i.e. the processes which underlie dysfunction. We will begin the discussion with a consideration of apoptotic vs other forms of cell death in the EC. We will specifically review common major pathways of EC injury that occur in various forms of inflammation. We will first describe the response of ECs to TNF, a key macrophage-derived effector molecule, which as we have noted can be both an EC activator and a mediator of EC dysfunction. We will then consider injury by reactive oxygen species (ROS), a major effector pathway of phagocytic leucocytes, especially neutrophils. Finally, we will review injury mediated by immune effector T cells, a major component of the adaptive immune response. Since many responses to injury are cell type-specific, we will emphasise those features that seem to distinguish ECs from other cell types.

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