The Intestinal Microvasculature as a Therapeutic Target in Inflammatory Bowel Disease

Division of Gastroenterology & Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 09/2006; 1072(1):78-97. DOI: 10.1196/annals.1326.003
Source: PubMed


Chronic inflammation is a complex biologic process which involves immune as well as non-immune cells including the microvasculature and its endothelial lining. Growing evidence suggests that the microvasculature plays an integral role in the pathophysiology of inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis). The microvasculature contributes to chronic inflammation through altered leukocyte recruitment, impaired perfusion, and angiogenesis leading to tissue remodeling. These diverse areas of IBD microvascular biology represent therapeutic targets that are currently undergoing investigation.

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    • "The microcirculation and its lining endothelium play a central role in the initiation and perpetuation of the inflammatory response, as well as in tissue remodelling during chronic inflammation. Investigation into the cellular and molecular mechanisms in human inflammatory bowel disease , such as ulcerative colitis, has demonstrated a central role for the intestinal microvascular endothelium in both normal mucosal immunity and the dysregulated chronic inflammation that characterizes IBD [10]. There is now increasing evidence to suggest that neovascularization in response to tissue damage may involve bone marrow-derived endothelial progenitor cells [14]. "
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    ABSTRACT: Ulcerative colitis (UC) is a chronic, idiopathic, inflammatory bowel disease, characterized by alternating stages of clinically active and inactive disease. UC exhibits several inflammatory characteristics, including immune activation, leukocyte infiltration, and altered vascular density. In UC, many of the upregulated inflammatory cytokines are proangiogenic and are released by diverse cell populations, such as infiltrating immune cells and endothelial cells (EC). Increasing evidences suggest that neovascularisation may involve also endothelial progenitor cells (EPCs). In this study we evaluated EPCs recruitment and homing, assessed by CXCR4 expression, in both acute and remitting phase of UC. We report an overall decrease of EPCs in UC patients (controls = 97,94 ± 37,34 cells/mL; acute = 31,10 ± 25,38 cells/mL; remitting = 30,33 ± 19,02 cells/mL; for both UC groups versus controls). Moreover CXCR4+-EPCs, committed to home in inflammatory conditions, were found to be reduced in acute UC patients compared to both remitting patients and controls (acute = 3,13 ± 4,61 cells/mL; controls = 20,12 ± 14,0; remitting = 19,47 ± 12,83; ). Interestingly, we found that administration of anti-inflammatory drugs in acute UC is associated with an increase in circulating EPCs, suggesting that this therapy may exert a strong influence on the progenitor cells response to inflammatory processes.
    Gastroenterology Research and Practice 02/2015; 2015:1-6. DOI:10.1155/2015/843980 · 1.75 Impact Factor
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    • "VEGF-A is a fundamental mediator of pathologic angiogenesis in several inflammatory disorders, including neoplasia, chronic inflammation, and IBD [8], [12]. The microvasculature in IBD likely contributes to bowel inflammation by affecting innate immunity, leukocyte infiltration, coagulation, and vascular permeability [13]–[15]. A number of studies have demonstrated that direct inhibition of VEGF or its primary receptor VEGFR2 decreases inflammation and can potentially lessen colonic tissue damage by reducing vascularization or by altering vessel permeability [16], [17]. "
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    ABSTRACT: Allyl isothiocyanate (AITC) is a phytochemical found in cruciferous vegetables that has known chemopreventive and chemotherapeutic activities. Thus far, the antiangiogenic activity of AITC has not been reported in in vivo studies. Herein, we investigated the effect of AITC on angiogenesis and inflammation in a mouse model of colitis. Experimental colitis was induced in mice by administering 3% dextran sulfate sodium via drinking water. To monitor the activity of AITC in this model, we measured body weight, disease activity indices, histopathological scores, microvascular density, myeloperoxidase activity, F4/80 staining, inducible nitric oxide synthase (iNOS) expression, cyclooxygenase-2 (COX-2) expression, and vascular endothelial growth factor (VEGF)-A/VEGF receptor 2 (VEGFR2) expression in the mice. We found that AITC-treated mice showed less weight loss, fewer clinical signs of colitis, and longer colons than vehicle-treated mice. AITC treatment also significantly lessened the disruption of colonic architecture that is normally associated with colitis and repressed the microvascularization response. Further, AITC treatment reduced both leukocyte recruitment and macrophage infiltration into the inflamed colon, and the mechanism these activities involved repressing iNOS and COX-2 expression. Finally, AITC attenuated the expression of VEGF-A and VEGFR2. Thus, AITC may have potential application in treating conditions marked by inflammatory-driven angiogenesis and mucosal inflammation.
    PLoS ONE 07/2014; 9(7):e102975. DOI:10.1371/journal.pone.0102975 · 3.23 Impact Factor
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    • "Vascular lesions and microvascular changes, such as granulomatous vasculitis, neovascularization, and dilatation of arteries and veins, are well known to be features of the pathogenesis of CD. According to recent reports [35,36], there is new understanding regarding the induction of vascular proliferation during chronic CD inflammation, although there is no general consensus regarding its mechanism. Clinically, we often experience serious bleeding incidents from active CD lesions showing “hyper-flow” according to color Doppler US; such lesions are rapidly and successfully stabilized by administration of anti-TNF-α antibodies. "
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    ABSTRACT: Background Crohn’s disease (CD) is routinely evaluated using clinical symptoms, laboratory variables, and the CD activity index (CDAI). However, clinical parameters are often nonspecific and do not precisely reflect the actual activity of CD small-intestinal lesions. The purposes of this prospective study were to compare color Doppler ultrasound (US) findings with histological findings from surgically resected specimens and confirm the hypothesis that color Doppler US can distinguish tissue inflammation and fibrosis. Methods Among 1764 consecutive patients who underwent color Doppler US examinations, 10 patients with CD (12 small-intestinal CD lesions) who underwent US examinations before elective small-intestine resection were evaluated in the present study. Areas of thickened intestinal walls were evaluated in terms of blood flow using color Doppler US imaging. The blood flow was semiquantitatively classified as “hyper-flow” and “hypo-flow” according to the Limberg score. Resected lesions were macroscopically and histopathologically processed. Inflammatory cell infiltration, fibrosis and vascularity were evaluated by myeloperoxidase (granulocytes), CD163 (macrophages), CD79a (B cells), CD3 (T cells), Masson’s trichrome (fibrosis), and factor VIII staining (vascular walls). All histopathological images were entered into virtual slide equipment and quantified using a quantitative microscopy integrated system (TissueMorph™). Results There were no significant differences in disease features or laboratory findings between “hypo-flow” lesions (n = 4) and “hyper-flow” lesions (n = 8). Histopathologically, “hyper-flow” lesions showed significantly greater bowel wall vascularity (factor VIII) (p = 0.047) and inflammatory cell infiltration, including CD163 macrophages (p = 0.008), CD3 T cells, and CD79a B cells (p = 0.043), than did “hypo-flow” lesions. There was no apparent association between the blood flow and CDAI. Conclusions In this study, active CD lesions were macroscopically visible in surgical specimens of patients with increased blood flow on preoperative color Doppler US imaging. Additionally, these CD lesions exhibited significantly greater vascularity and numbers of inflammatory leukocytes microscopically. Color Doppler US may predict tissue inflammation and fibrosis in small-intenstinal CD lesions.
    BMC Research Notes 06/2014; 7(1):363. DOI:10.1186/1756-0500-7-363
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