ReviewEndothelial injury in the initiation and progression of vascular disorders
Introduction
The endothelium participates actively in homeostatic mechanisms such as the regulation of vascular tone, maintenance of a non-thrombotic environment and in directing biological responses such as leukocyte trafficking to inflammatory sites (Argenbright and Barton, 1992, Harper and Savage, 1999, Widlansky, 2003). Endothelial cell participates through the expression of constitutive or induced molecules on its surface, and the synthesis and secretion of soluble mediators bound to or released from the cell surface. The vascular endothelium synthesizes nitric oxide (NO), prostaglandins, endothelium-derived hyperpolarizing factor (EDHF), endothelin and a range of other substances responsible for vascular homeostasis including smooth muscle tone, antiproliferative effects, vascular permeability and cellular adhesion molecules (Widlansky, 2003, Lum and Roebuck, 2001, Blann et al., 2005). In addition to regulating vascular tone, endothelial cells regulate leukocytes entering during basal, immune reactions and inflammation by responding to chemokines that modify expression of adhesion molecules. The involvement of various agents to induce vascular injury could be provoked either by direct cytotoxicity, induction of an immune process or expression of adhesion molecules (Harper and Savage, 1999, Coll-Vinent et al., 1998, Heeringa et al., 2005).
The endothelium comprises the largest homogenous surface of the body for actively mediating the immune defense. Immunologically mediated endothelial cell activation has been implicated as an important process in the initiation of vascular injury (Blann et al., 2005, Cines et al., 1998, Constans and Conri, 2006). Studies have shown that activated endothelial cells participate in T cell-mediated immune reactions and also serve as antigen-specific cells (Matsuki et al., 2005, Pober et al., 2001). The antigens on the activated endothelial cells interact with CD4 and CD8 T lymphocytes to propagate cell-mediated immune responses (Pober et al., 2001). Moreover, activated endothelial cells upregulate the expression of major histocompatibility complex (MHC) encoded molecules (Pober et al., 2001). Upon activation, endothelial cells express a number of immunologically relevant surface molecules such as adhesion molecules of the immunoglobulin gene superfamily as well as secrete cytokines and growth factors (Blann et al., 2005). Secreted cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNFα) and interferon (IFNγ) induce the secretion of MHC class I antigens. The latter can activate neutrophils and trigger an acute inflammatory cascade which subsequently leads to endothelial cell injury (Heeringa et al., 2005, Bratt and Palmblad, 1997). These events alter the morphology of the membrane, cytoskeleton structure and cell matrix organization leading to permeability of molecules. It has been demonstrated that cytokine-dependent stimulation of endothelial cell activates cytotoxic capacity of polymorphonuclear leukocytes (Argenbright and Barton, 1992, Matsuki et al., 2005). This process depends on the expression of adhesion molecules including intracellular adhesion molecule-1 (ICAM), E-selectin and vascular cell adhesion molecule-1 (VCAM) which are sequentially upregulated and enhance the recruitment of neutrophils (Bratt and Palmblad, 1997). Thus, endothelial dysfunction is integrally associated with inflammatory events which culminate in vascular injury (Harper and Savage, 1999, Widlansky, 2003, Constans and Conri, 2006) (Fig. 1).
Section snippets
Endothelial injury in vasculitis
Vasculitis is a pathologic process characterized by inflammatory damage to blood vessels which may occur spontaneously possibly due to genetic abnormalities, autoimmune or after exposure to infectious agents (bacteria, virus, parasites) and irradiation. Vasculitis has been reported in response to various drugs (antibiotics, polythiouracil, hydralazine) and biologics (interferons, monoclonal antibody, hematopoietic growth factors) (Albassam et al., 2001, Dogterom et al., 1992, Mesfin et al., 1996
Initiation of vascular injury
Acute drug-induced injury of the vasculature has been shown using histological methods in animal toxicological evaluation of new drugs in which lesions can be induced within short period of time following drug administration (Harper and Savage, 1999, Langford, 2003). In general, animals exhibit no clinical signs and routine clinical pathology data are normal. At least, three mechanistic pathways may contribute to drug-induced vascular injury including high shear stress, direct cytotoxicity from
T-cells' activation and endothelial injury
Activation of endothelial cells and neutrophils is implicated in the early development of vasculitic lesions and the progression of lesions is accompanied by T cell and monocyte recruitment. Endothelial cells present antigens to activated T cells, and in turn, provide signals to modulate normal endothelial cell function via recruitment of inflammatory leukocytes. In this context, endothelial cell activation is considered as an immunological event and can serve as antigen presenting cells by
Adhesion molecules and chemokines
Accompanying inflammation of the vascular wall are several local and systemic physiologic processes that also contribute to initiation of the sequence of events of injury. A series of cell surface molecules on endothelial cells provides attachment, adhesion and migration of leukocytes through the intima. Expression of these molecules (selectins, integrins and intercellular adhesion molecules) and their ligands provide specificity for the type of cell recruited and for the location of the blood
Endothelium-derived mediators
The endothelium synthesizes NO by the oxidation of l-arginine by a Ca2+-activated NADPH-dependent constitutive NO synthase. NO has several functions including vasodilation, inhibition of platelet aggregation, thrombus formation, leukocyte adhesion, smooth muscle cell proliferation and LDL oxidation (Constans and Conri, 2006, Forstermann, 2006, Gunnett et al., 2005). During inflammation excessive amounts of NO are produced by inducible NO synthase by activated endothelial cells, neutrophils and
Free radical generation in endothelium
Oxidant stress increases vascular endothelial permeability and promotes leukocyte adhesion, which trigger alterations in endothelial signal transduction and redox-regulated transcription factors (Lum and Roebuck, 2001). Cytokines at the inflammatory site may contribute to the generation of reactive oxygen species particularly by polymorphonuclear leukocytes. The products of degranulation including proteinase, elastase and MPO which are cationic tend to localize and bind non-covalently to the
Search for biomarkers
In the absence of specific and sensitive biomarkers, an understanding of pathogenesis of vascular injury in animals has become a challenge in the drug development process. The monitoring of blood pressure and heart rate may not be a predictive indicator of vascular injury in humans. Due to the prevalence of underlying cardiovascular disease in humans, the detection of vascular injury caused by therapeutic agents is a significant safety issue (Kerns et al., 2005, Louden et al., 2006).
Several
Conclusions
Endothelial cell injury is the earliest detectable physiological abnormality which leads to the development of vascular disorders. The precise etiology of initiation of endothelial cell inflammatory damage remains an enigma. Various stimuli including shear stress, drug-induced toxicity, immune-mediated effector cells could potentially be processes that lead to the initiation of endothelial cell injury. The evidence favors an autoimmune inflammatory response characterized by specific mediators
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