Endothelial cells are now understood to play an early and rate-limiting step in the inflammatory process, as endothelial activation in response to cytokines and inflammatory mediators results in expression of cell adhesion molecules and chemokines, which play a critical role in leukocyte recruitment from the circulation. Early investigation into the role of endothelial cells in IBD pathogenesis focused on histologic evaluation, characterizing the morphology of the microvasculature in chronically inflamed bowel. Using transmission electron microscopy, Dvorak et al. evaluated intestinal specimens resected from CD patients , demonstrating abnormalities in the endothelial cells lining the microcirculation. These included loss of monolayer integrity with tissue edema, extravasation of red blood cells, focal venular endothelial necrosis adjacent to areas of undamaged endothelial cells, and endothelial cell hypertrophy.
Research focusing on the role of microvascular endothe-lial cells in leukocyte recruitment to the gut has characterized increased expression of cell adhesion molecules (CAM) . Immunolocalization of CAM demonstrated marked increase in E-selectin and ICAM-1 expression in IBD intestine, while VCAM-1 expression was less clearly demonstrated. Subsequent investigation by Briskin et al has demonstrated an increase in the gut-specific homing molecule MAdCAM-1 (mucosal addressin cell adhesion molecule 1), which plays a major role in the recruitment of leukocytes expressing the alpha 4 integrin into the mucosal immune compartment .
Alterations in leukocyte homing patterns in IBD gut were characterized by Salmi et al, who demonstrated that naive lymphocytes are preferentially recruited to the chronically inflamed intestinal microvascular endothelium, whereas control intestinal microvessels preferentially bind memory lymphocytes . These findings were confirmed by Burgio et al., who demonstrated an altered pattern of leukocyte binding in Crohn's disease, where naive monocytes and T cells were again preferentially recruited to the chronically inflamed intestine . These authors also demonstrated increased expression of ICAM-1, E-selectin, and CD34 in the IBD gut microvessels.
To more fully define the contribution of microvascular endothelial cells in chronic intestinal inflammation, studies have been carried out in intestinal and disease-specific cultures of microvascular endothelial cells. Human intestinal microvascular endothelial cells (HIMECs) have been inso-lated and characterized, demonstrating classic endothelial markers including factor VIII associated antigen, Weibel-Palade bodies, expression of PECAM-1 (CD31), E-selectin, ICAM-1, and VCAM-1 as well as unique patterns of leukocyte adhesion and growth compared to human umbilical vein endothelial cells (HUVEC) [6, 7]. More importantly, HIMECs have also been isolated from involved and unin-volved CD and UC intestine. HIMECs isolated from both chronically inflamed CD and UC demonstrated a significantly enhanced capacity to adhere leukocytes, compared to control HIMECs, a phenomenon that was only elicited following activation with proinflammatory cytokines (interleukin-1b, tumor necrosis factor-a) and bacterial lipopolysaccharide. Leukocyte "hyperadhesion" appears to be an acquired phenomenon, as uninvolved IBD intestinal segments failed to demonstrate increased leukocyte binding . The mechanisms underlying leukocyte hyperadhesion in the chronically inflamed IBD HIMECs did not appear to involve increased levels of CAM expression, compared to control cultures, which prompted investigation of possible alterations in the intracellular mechanisms that govern the downregulation of inflammatory activation in endothelial cells. NO plays a central role in the regulation of endothelial activation and the maintenance of vascular homeostasis, exerting a potent anti-inflammatory effect, downregulating the activation of vascular endothelial cells as well as their capacity to bind circulating leukocytes, normally an early and rate-limiting step in the inflammatory process. Control HIMECs displayed distinct patterns of NO generation through both constitutive endothelial (e) nitric oxide syn-thase (eNOS; NOS3) as well as inducible NOS (iNOS; NOS2), which was expressed following inflammatory activation . In marked contrast, IBD HIMECs failed to express iNOS and increased levels of NO following inflam matory activation . This loss in NO generation in IBD HIMECs was linked to enhanced leukocyte binding, as administration of NO donors restored a normal binding pattern in the activated IBD HIMECs. Further investigation demonstrated that iNOS-derived NO in the IBD HIMECs appears to function as an endogenous antioxidant, quenching superoxide anion, which is a central mediator of inflammatory activation in gut microvascular endothelial cells. The mechanisms that lead to altered iNOS expression in the chronically inflamed IBD HIMECs have not been fully defined.
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