The Role of Microvascular Dysfunction and Tissue Ischemia in Chronic Intestinal Inflammation

The human bowel receives a significant proportion of cardiac output, which varies with physiologic need. At rest, intestinal perfusion via the superior mesenteric artery will range from 29 to 70mL/min/100g intestinal tissue, whereas in the fed state, splanchnic hyperemia increases perfusion from 28 to 132 percent. Investigation of intestinal perfusion in the setting of chronic inflammation in IBD has been carried out using a variety of in vivo and in vitro techniques. Angiographic studies of the IBD intestine have demonstrated preserved anatomy in the superior and inferior mesenteric arteries, with significant abnormalities in the vasa recta, characterized by tortuous, dilated vessels together with loss of normal tapering and terminal coiling as they penetrate the bowel wall. In early stages of IBD, angio-graphic studies have demonstrated arteries that abruptly taper as the vessels reach the bowel wall with right-angle bifurcation, bizarre distribution, and small luminal irregularities in the peripheral branches. Furthermore, advanced IBD lesions demonstrate reduced vessel diameter, decreased vascular density, and diminished blood flow in the involved segments, which may contribute to an impaired capacity to heal and resolve the chronic inflammatory "wound."

The microvascular architecture was characterized by Wakefield et al [11] using scanning electron micrographs of corrosion microcasts from control and CD patients, identifying occlusive fibrinoid lesions in the arterioles supplying affected intestine, which were not demonstrated in un-involved areas of bowel. Morphologically, the chronically inflamed microvessels were tapered and stenosed compared to vessels from uninvolved and control bowel. Vascular damage was demonstrated as an early pathologic finding, which preceded the development of mucosal ulceration. Vascular damage appeared to be highest where vessels penetrated through the muscularis propria, and bursts of angio-genic vessels were seen in distal areas of the mucosal circulation. These authors concluded that multifocal gastrointestinal infarction plays a pathogenic role in the chronic inflammatory lesion in CD, with the extent of vascular damage correlating with the severity of intestinal injury. The concept of microvascular dysfunction and relative tissue ischemia was further investigated by Funayama et al., who used tissue histometry to describe remodeling in the CD intestinal microcirculation [12]. Assuming that medial atrophy is an indirect measure of decreased vascular perfusion and pressure, these investigators characterized atrophy of arterial media in the submucosal CD vessels, which indirectly suggests ischemia and increased vascular resistance in deeper submucosal arteries. Taken together, these studies suggest that the microvascular anatomy in the chronically inflamed CD intestine has undergone extensive remodeling. However, these studies did not directly define microvascular function, or potential factors that would lead to these alterations in vascular architecture.

Assessment of intestinal microvascular physiology in human IBD has been characterized using direct and indirect methods to assess microvascular blood flow. Hulten et al. used an intraoperative isotope washout technique as well as in vivo abdominal angiography to demonstrate alterations of intestinal blood flow, including perfusion patterns associated with distinct phases of disease [13]. Early fulminant IBD with severe inflammation was characterized by increased vascular perfusion, which is typical of an acute inflammatory response. In contrast, reduced regional blood flow was seen in chronically inflamed and remodeled tissues, particularly areas of CD stricture. These observations have been confirmed in subsequent studies, demonstrating diminished vascular perfusion associated with fibrosis and long-standing inflammation. Using endoscopic laser Doppler flowmetry [14], decreased mucosal blood flow was seen in the neoterminal ileum after ileocolectomy and in rectal mucosal perfusion in patients with long-standing UC [15].

The poorly healing, refractory inflammatory ulceration and damage in the IBD intestine suggests that microvascu-lar dysfunction resulting in diminished vasodilatory capacity and tissue hypoperfusion are found in the IBD gut. The molecular physiology underlying microvascular dysfunction in IBD was assessed directly by Hatoum et al., who characterized vasodilator responses in human intestinal microvessels, by measuring in vitro vasodilatory capacity in response to acetylcholine from perfused 50- to 150-|mm diameter arterioles isolated from intestinal resections [16]. Normal intestinal microvessels vasodilate in response to Ach using NO- and cyclooxygenase (COX)-dependent mechanisms, while chronically inflamed IBD arterioles (both CD and UC) demonstrated a significantly diminished vasodilatory capacity. This decreased vasodilatory capacity in the chronically inflamed IBD microvessels was directly related to a loss of NO-dependent function, and these same vessels were found to be heavily dependent on COX to maintain their vascular tone. Microvascular endothelial dysfunction in chronically inflamed IBD tissues was associated with excess levels of oxidative stress as measured by intravital dyes and confocal fluorescence microscopy, which was not present in vessels isolated from normal intestine or un-involved areas of IBD bowel. The microvascular dysfunction identified in arterioles from chronically inflamed IBD

gut was not a generalized response to inflammation, as it was not demonstrated in vessels isolated from acute inflammation (i.e., diverticulitis) and uninvolved areas of IBD. This demonstrates that medications used to treat IBD patients at the time of surgery did not contribute directly to the microvascular dysfunction, and further substantiates that intrinsic, acquired alterations in the chronically inflamed and remodeled microcirculation underlie this pathophysiology.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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