ABSTRACT
Until recently, the endothelium was perceived to be a passive, metabolically inert permeability barrier whose function was primarily to contain blood and plasma. However, endothelial cells are now recognised as metabolically and physiologically dynamic, playing a primary and fundamental role in the vascular response to sepsis and systemic inflammation (Figure 12.1). In addition to responding rapidly (in seconds to minutes) to inflammatory agonists such as bradykinin and histamine; upon exposure to endotoxin or cytokines, endothelial cells undergo profound alterations of function that involve changes in gene expression and protein synthesis (Mantovani et al., 1992; Pober and Cotran, 1990; Introna et al., 1994). The endothelial cell responds to endotoxin via a direct, lipopolysaccharide binding protein (LBP) and a soluble CD-14 (sCD-14)-dependent pathway (Kielian and Blecha, 1995); inhibition of this binding by monoclonal antibodies against CD-14 has been shown to reduce the production of cytokines by endothelial cells in vitro as well as the hypotension and end organ dysfunction in primate models of endotoxaemia (Leturcq et al., 1996). Most of the metabolic effects of endotoxin are mediated by endothelial and smooth muscle production of cytokines. The pro-inflammatory cytokines such as IL-1, TNF IL-6 and interferon are synthesised by cultured human endothelial cells in vitro (Pober and Cotran, 1990; Introna et al., 1994).
