Role of the microcirculation in chronic gut inflammation

Abstract

Active episodes of inflammatory bowel disease (IBD; Crohn's disease (CD), ulcerative colitis (UC)) are characterized by rectal bleeding, severe diarrhea, exudation, fever, abdominal pain, and weight loss. Histopathological inspection of tissue obtained from the involved segment of the small and/or large bowel reveals vasodilation, venocongestion, edema, infiltration of large numbers of inflammatory cells and erosions and ulcerations [1]. Although the pathogenetic mechanisms responsible for the microvascular dysfunction, mucosal inflammation and injury are not entirely clear at the present time, there is an accumulating body of experimental and clinical data to suggest that IBD may result from the dysregulated immune response to components of the normal gut flora [1-5]. It has been proposed that the inability to regulate the normally protective cell-mediated immune response results in activation of the CD4+ T cells with subsequent release of interleukin-2 (IL- 2), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) [6]. These Thl-type cytokines in turn activate tissue macrophages to release a variety of proinflammatory mediators including TNF-α, IL-β, IL-12, platelet-activating factor (PAP), leukotriene B4 (LTB4), reactive oxygen species (ROS), nitric oxide (NO) and prostaglandins [6-8]. Some of these inflammatory mediators (e.g. histamine, bradykinin, nitric oxide, prostaglandins) will increase blood flow (hyperemia), thereby producing erythema. Another consequence of enhanced arteriolar blood flow is an increased hydrostatic pressure in the downstream capillaries resulting in fluid movement across intestinal capillaries and interstitial edema. Certain proinflammatory cytokines (TNF, IFN-γ, IL-12) released by activated mast cells, macrophages and lymphocytes activate venular endothelial cells and increase expression of endothelial cell adhesion molecules that mediate leukocyte- endothelial cell adhesion and eventual emigration (tissue infiltration) of leukocytes. Leukocyte emigration is often associated with vascular protein leak (extravasation) and the accumulation of albumin and other plasma proteins in the gut interstitium. The resultant increase in interstitial oncotic pressure further promotes fluid filtration across capillaries and accelerates the development of interstitial edema. Taken together, these pathophysiological considerations suggest that the intestinal microcirculation contributes, in a large part, to much of the pathophysiology of chronic gut inflammation (Fig. 1). This chapter reviews the current state of knowledge regarding the mechanisms that regulate the three structurally and functionally important elements of the microcirculation, i.e. the arterioles, capillaries and venules. This discussion wiU focus on the potential role of the microvasculature in inflammatory bowel disease. © 2005 Springer Science+Business Media, Inc.