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Am J Physiol Heart Circ Physiol 285: H1791-H1796, 2003; doi:10.1152/ajpheart.00552.2003
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SPECIAL MEDICAL EDITORIALS

The vascular contribution in the pathogenesis of inflammatory bowel disease

Ossama A. Hatoum, Hiroto Miura, and David G. Binion

Division of Cardiovascular Medicine and Division of Gastroenterology and Hepatology, Department of Medicine, Cardiovascular Research Center, and Digestive Disease Center, Froedtert Memorial Lutheran Hospital, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

THE TWO MAJOR FORMS of human inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), represent classic chronic inflammatory disorders, characterized by progressive destructive inflammation in the gastrointestinal tract. Although the majority of research into IBD pathogenesis has focused on immune dysregulation, vascular involvement in IBD has also been recognized over the past four decades, as these disorders have been associated with hypercoagulability and vasculitis. Advances in vascular biology have delineated a central role for the microcirculation in the initiation and perpetuation of the inflammatory process. Investigation in the molecular and cellular mechanisms underlying human IBD has demonstrated an important role for the intestinal microvascular endothelium in both mucosal immunity as well as the chronic inflammation that characterizes IBD. Chronically inflamed microvessels and endothelial cells in the setting of IBD show significant alterations in physiology and function compared with microvessels and cells from uninvolved the intestine, where IBD microvessels demonstrate an enhanced capacity to adhere leukocytes. Understanding of leukocyte-endothelial interaction in IBD is presently leading to new antiadhesion molecule agents that target the vasculature for therapy.

The intestinal microvasculature may contribute to impaired mucosal healing in CD and UC as both forms of IBD are characterized by refractory mucosal ulceration and damage. Previous work has demonstrated an abnormal, remodeled intestinal vascular architecture characterized by stenotic microvessels and significantly decreased mucosal perfusion, which may underlie chronic ischemia and impaired wound healing in IBD. We review the role of the vasculature in the pathogenesis of human IBD, focusing on hypercoagulability, tissue ischemia, and a proinflammatory phenotype in the intestinal microvascular endothelium.

THE SYSTEMIC VASCULATURE IN IBD PATHOGENESIS

Hypercoagulability and Thrombosis in IBD

IBD is recognized to be a hypercoagulable state, and thromboembolic disease is a significant cause of morbidity and mortality in patients with both CD and UC. Deep venous thrombosis and pulmonary embolism are the most frequent thromboembolic manifestations, which readily explains the high rates of morbidity and mortality associated with these complications (70, 73). Hypercoagulability in IBD has been attributed to a variety of factors including thrombocytosis as well as increased levels of clotting factors V and VIII, fibrinogen (52–54), accelerated thromboplastin generation, acquired antithrombin III deficiency (15, 37, 72), and decreased protein C and protein S (1, 2, 44, 74). However, no single consistent coagulation abnormality has been identified (45, 57). Other potential mechanisms include the presence of anti-phospholipid antibodies and lupus anticoagulant invoking the involvement of autoimmune mechanisms (16, 18, 80). Elevated anti-cardiolipin antibodies have been detected in some IBD patient populations (3, 48, 49). A more recent study (79) has focused on elevation in plasma homocysteine in IBD patients, which may also contribute to underlying hypercoagulability.

It is not known whether hypercoagulability in IBD is a secondary phenomenon associated with chronic intestinal inflammation or may represent an underlying, mechanistic factor that contributes to disease pathogenesis. The potential protective effect of an underlying bleeding diathesis in preventing the development of IBD was investigated by Thompson et al. (75), who found a significantly decreased risk of development of either CD or UC among patients with either hemophilia or von Willebrand's disease. The authors concluded that a congenital bleeding diathesis exerted a protective effect against development of IBD, suggesting an important role of inappropriate thrombosis and vascular occlusion in the pathogenesis of human IBD.

The potential pathogenic contribution of thrombosis in IBD pathogenesis has been explored through the use of anticoagulation therapy in the treatment of IBD patients. Heparin treatment of thromboembolic complications in IBD patients resulted in clinical improvement in their bowel disease in open-label as well as randomized clinical trials (28, 47, 52) using both unfractioned (25, 27) and low-molecular-weight heparin (76). We previously reported the therapeutic success of unfractioned heparin therapy in a female CD patient who experienced a refractory colitis flare during the first trimester of pregnancy, an additional major risk for hypercoagulability. Whether this treatment modality exerted direct antithrombotic effects or potentially exerted alternative anti-inflammatory effects is not known (67).

Vasculitis, Atherosclerosis, and IBD Pathogenesis

The association between IBD and systemic vasculitis is well known and includes necrotizing vasculitis of the skin (7), lung, and penis; chronic polyneuropathy; iritis; polyserositis; cerebral vasculitis (62); Takayasu's arteritis (71); and retinal vasculitis, a particularly devastating ocular complication (21). Examination of the resected intestine of CD patients has found evidence of granulomatous microvasculitis (82), which suggests common pathophysiological mechanisms (29, 46).

The worldwide distribution of IBD has paralleled the incidence and prevalence of atherosclerosis, targeting primarily Western populations over the second half of the 20th century. Recent investigation into mechanisms underlying atherosclerosis has focused on the potential contribution of inflammation in vascular disease (61). Data from population-based studies suggest that patients suffering from either CD or UC will experience increased rates of atherosclerosis and ischemic heart disease at earlier ages in both males and females compared with age- and sex-matched controls (64, 65).

The correlation between atherosclerosis and IBD has prompted investigation of potential shared molecular and cellular mechanisms contributing to pathogenesis. The role of dietary lipids and lipoproteins in vascular disease is a well-established mechanism that is believed to contribute to atherosclerosis. We (10) have previously demonstrated that oxidized lipoproteins induce activation of microvascular endothelial cells isolated from the human intestine, leading to increased expression of cell adhesion molecules (CAMs) and chemokines that mediate leukocyte adhesion, a critical early step in both inflammation and atherosclerosis. An additional potential mechanism that may be shared in the pathogenesis of both atherosclerosis and IBD involves CD40 and its ligand (CD40L), a molecule that is felt to mediate thrombosis, inflammation, and vascular remodeling. Urbich et al. (77) suggested that the CD40 pathway is involved in the vascular restenotic process, as CD40L is found in thrombi developing on the surface of atherosclerotic plaques (4, 38). Danese et al. (19) demonstrated that IBD patients express CD40L in their circulating platelets and the inflamed mucosa, where microthrombosis may be a prominent feature, further propagating an inflammatory response and may also contribute to vessel remodeling, which is a common feature in both atherosclerosis and IBD (77, 81).

THE INTESTINAL CIRCULATION AND MICROVASCULATURE IN IBD: CONTRIBUTION TO GUT ISCHEMIA

The Splanchnic Circulation and Intestinal Angiography

The human bowel is highly vascularized, receiving a significant proportion of cardiac output, which varies in response to physiological need. At rest, intestinal perfusion via the superior mesenteric artery will range from 29 to 70 ml · min–1 · 100 g intestinal tissue–1 (33, 41–43), whereas in the fed state, splanchnic hyperemia increases perfusion by 28–132% (33). Angiographic studies of the IBD intestine performed over the past three decades have demonstrated preserved anatomy in the superior and inferior mesenteric arteries, with significant disease-related abnormalities in the vasa recta, which correspond with disease extent and severity. In early IBD, angiographic studies (35, 40, 59, 60) have demonstrated tortuous, dilated vessels, bizarre distribution, and small luminal irregulaties in the peripheral branches, together with loss of normal tapering, right-angle bifurcations, and terminal coiling as the vessels penetrate the bowel wall. In contrast, advanced IBD lesions demonstrate reduced vessel diameter (24, 55, 56), decreased vascular density, and diminished blood flow in the involved segments (12). These angiographic studies suggest that a relative lack of perfusion emerges in the course of chronic inflammation in IBD.

Intestinal Microvascular Perfusion

Measurements of intestinal blood flow using direct and indirect methods have characterized a loss of intestinal perfusion, which emerges during the progression of chronic inflammation in IBD. With the use of intraoperative isotope washout techniques (43), in vivo abdominal angiography, and endoscopic Doppler flow-metry (5, 34), distinct patterns of vascular perfusion have been correlated with discrete phases of both CD and UC. Early fulminant colitis with severe inflammation is characterized by increased vascular perfusion, whereas paradoxically reduced regional blood flow is typically seen in chronically inflamed and remodeled tissues (6). These observations have been confirmed in a subsequent study (5), where the most severe decrease in vascular perfusion was found in association with fibrotic strictures. This potential contribution of ischemia to IBD chronic inflammation was evaluated by Wakefield et al. (82) using scanning electron micrographs of corrosion microcasts after bowel resection; they identified occlusive fibrinoid lesions in the arteries supplying areas of the intestine affected by CD, which were not found in uninvolved areas of bowel. The identification of microvascular damage was demonstrated as an early pathological finding that preceded the development of mucosal ulceration. The interrelationship among vascular perfusion, tissue homeostasis, and wound healing has prompted evaluation of intestinal perfusion in the setting of human IBD. The poorly healing, refractory inflammatory ulceration and damage in the IBD intestine strongly suggest that microvascular dysfunction with diminished vasodilatory capacity will result in tissue hypoperfusion. Hatoum et al. (36) examined vasodilator responses in human intestinal microvessels by measuring in vitro vasodilatory response to ACh from pressurized submucosal intestinal arterioles (50–150 µm in diameter) rapidly isolated from resected gut specimens. Normal intestinal microvessels vasodilate in response to ACh using nitric oxide (NO)- and cyclooxygenase (COX)-dependent mechanisms, whereas chronically inflamed IBD arterioles (both CD and UC) demonstrated a diminished vasodilatory capacity (maximum dilation: 81 ± 3% vs. 16 ± 3% in IBD arterioles, P < 0.05). This decreased vasodilatory capacity in 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. This microvascular endothelial dysfunction was associated with excess levels of oxidative stress, which was not present in vessels isolated from the normal intestine, uninvolved areas of IBD bowel, and non-IBD acute inflammation (Fig. 1) (36).



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  		Fig. 1. Cellular and molecular mechanisms involved in the normal intestinal microvascular vasodilatory response (blue) to acetylcholine (ACh) and the alterations found in inflammatory bowel disease (IBD; orange). Microvascular dysfunction in IBD is characterized by an impaired vasodilatory response to ACh, with loss of nitric oxide (NO) generation, and markedly enhanced reliance on a cyclooxygenase (COX)-dependent vasodilatory mechanism. AA, arachidonic acid; PLA2, phospholipase A2; CYP450, cytochrome P-450; NOS, NO synthase; AC, adenyl cyclase; GC, guanylate cyclase.

 

MICROVASCULAR ENDOTHELIUM IN IBD PATHOGENESIS: CONTRIBUTION TO LEUKOCYTE RECRUITMENT IN INFLAMMATION

Human Intestinal Microvascular Endothelial Cells in IBD Pathogenesis

Endothelial cells play an early and rate-limiting step in the inflammatory process. Pioneering work by Bevilacqua et al. (9) demonstrated that endothelial activation in response to cytokines and inflammatory mediators was a critical step in circulating leukocyte recruitment. Initial investigation into the potential role of endothelial cells in IBD pathogenesis focused on histological evaluation, characterizing the morphology of the microvasculature in chronically inflamed bowel. Using transmission electron microscopy, Dvorak et al. (23) demonstrated abnormalities in endothelial cells from the CD gut microcirculation that included loss of endothelial monolayer integrity with tissue edema, extravasation of red blood cells, focal venular endothelial necrosis, and endothelial cell hypertrophy.

Subsequent work has focused on intestinal microvascular endothelial cells and their expression of CAMs, which play a major role in mucosal leukocyte recruitment (31, 66). Immunolocalization of CAMs demonstrated a marked increase in E-selectin and intercellular adhesion molecule (ICAM)-1 expression in the IBD intestine, whereas vascular CAM (VCAM)-1 expression was less clearly demonstrated. Investigation by Briskin et al. (13) has demonstrated an increase in the gut-specific homing molecule mucosal addressin CAM-1, which plays a major role in the recruitment of leukocytes expressing {alpha}4-integrin into the mucosal immune compartment (13).

Studies investigating potential alterations in leukocyte homing patterns in IBD were carried out by Salmi et al. (69). This work demonstrated that naïve lymphocytes were recruited by the IBD intestinal microvascular endothelium compared with control gut microvessels, which preferentially bound memory lymphocytes. These findings were confirmed by Burgio et al. (14), who also demonstrated an altered pattern of leukocyte binding in CD, where naïve monocytes and T cells were again preferentially recruited to the chronically inflamed intestine.

To more fully define the contribution of microvascular endothelial cells in chronic intestinal inflammation, our laboratory (10, 31, 32, 51) developed protocols for the routine isolation and long-term culture of pure populations of human intestinal microvascular endothelial cells (HIMECs). HIMECs isolated from both chronically inflamed CD and UC intestines demonstrated a significantly enhanced capacity to adhere leukocytes compared with control HIMECs, a phenomenon that was only elicited after activation with cytokines (IL-1{beta} and TNF-{alpha}) and bacterial LPS and was not present in unstimulated cells. Leukocyte "hyperadhesion" was only present in chronically inflamed IBD HIMECs, as cultures derived from uninvolved areas in close proximity failed to demonstrate increased leukocyte binding (11).

The mechanisms underlying leukocyte hyperadhesion in the chronically inflamed IBD HIMECs failed to show alterations in patterns of CAM expression between normal and IBD HIMECs. Investigation shifted to focus on NO generation in HIMECs, an alternate pathway that would influence the activation status of these tissue-specific endothelial cells, and their capacity to bind circulating leukocytes (50). Control HIMECs displayed distinct patterns of NO generation through both constitutive endothelial NO synthase (eNOS or NOS3) as well as inducible NO synthase (iNOS or NOS2). In marked contrast, IBD HIMECs demonstrated a loss of iNOS gene expression after activation that corresponded with diminished NO generation and enhanced leukocyte binding.

Anti-adhesion Molecule Therapy in IBD

Targeting endothelial-leukocyte interaction for therapeutic benefit in patients with IBD has received intense interest as three experimental agents have been evaluated in controlled trials (78). ICAM-1 expression in CD patients was targeted using alicaforsen (ISIS 2302, ISIS Pharmaceuticals; Carlsbad, CA) (22, 68, 20, 58), a phosphorothioate oligodeoxynucleotide designed to specifically hybridize to the 3'-untranslated region of human ICAM-1 mRNA, which leads to rapid degradation and the prevention of translation (8, 17, 39, 63, 63). Initial clinical attempts using alicaforsen in CD treatment demonstrated a steroid-sparing effect and induced remission in up to 40% of patients (83). Subsequent clinical trials have not repeated this level of success, but studies with increased dosages of this agent continue at present.

Early investigation of leukocyte-endothelial interaction in IBD focused on leukocyte {alpha}4-integrin, which plays a major role in mucosal immune homing to the intestinal microvascular endothelium and has demonstrated therapeutic potential in ameliorating the chronic colitis that develops spontaneously in the cotton-top tamarind (66). The success of anti-{alpha}4-integrin treatment with monoclonal antibodies in this primate model of IBD has provided the rationale for developing human trials of this strategy. Monoclonal antibodies targeting leukocyte expression of {alpha}4-integrin include the humanized anti-{alpha}4-integrin antibody natalizumab (Antegren, Elan Pharmaceuticals; San Diego, CA) as well as LDP-02 (Millenium Pharmaceuticalsl Cambridge, MA), both of which continue in clinical trials at the present time (26, 30).

SUMMARY AND FUTURE DIRECTIONS

The vasculature plays a central role in human IBD and may contribute to pathogenesis through thrombotic, ischemic, or inflammatory mechanisms. Investigation has defined an altered microvascular anatomy in the affected IBD bowel that corresponds with diminished perfusion in the setting of chronic, longstanding inflammation. The intestinal microvasculature exposed to repeated injury and repair undergoes extensive remodeling that corresponds with impaired vasoperfusion as well as enhanced and sustained inflammatory activation. This is linked to impaired wound healing and may underlie the refractory, mucosal ulceration that is the hallmark of both CD and UC (Fig. 2).



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  		Fig. 2. Proposed scheme demonstrating the potential vascular contribution to acute and chronic intestinal inflammation. Chronically inflamed IBD microvessels demonstrate microvascular dysfunction, which contributes to chronic intestinal inflammation through ischemic and inflammatory mechanisms.

 

Investigation of microvascular dysfunction in IBD will provide important insights into the microvascular biology and physiology of chronic inflammatory disease. Our understanding of the role of the vasculature in IBD pathogenesis is also paving the way for the development of novel strategies targeting the microvasculature, specifically endothelial-leukocyte interaction with the development of antiadhesion molecule biological agents for clinical use.


   FOOTNOTES
 

Address for reprint requests and other correspondence: O. A. Hatoum or D. G. Binion, Medical College of Wisconsin, 9200 W. Wisconsin Ave., Milwaukee, WI 53226 (E-mail: oabuhato{at}mcw.edu or dbinion{at}mcw.edu).

REFERENCES

  1. Aadland E, Odegaard OR, Roseth A, and Try K. Free protein S deficiency in patients with chronic inflammatory bowel disease. Scand J Gastroenterol 27: 957–960, 1992.[Web of Science][Medline]
  2. Aadland E, Odegaard OR, Roseth A, and Try K. Free protein S deficiency in patients with Crohn's disease. Scand J Gastroenterol 29: 333–335, 1994.[Web of Science][Medline]
  3. Aichbichler BW, Petritsch W, Reicht GA, Wenzl HH, Eherer AJ, Hinterleitner TA, Auer-Grumbach P, and Krejs GJ. Anti-cardiolipin antibodies in patients with inflammatory bowel disease. Dig Dis Sci 44: 852–856, 1999.[Web of Science][Medline]
  4. Andre P, Nannizzi-Alaimo L, Prasad SK, and Phillips DR. Platelet-derived CD40L: the switch-hitting player of cardiovascular disease. Circulation 106: 896–899, 2002.[Free Full Text]
  5. Angerson WJ, Allison MC, Baxter JN, and Russell RI. Neoterminal ileal blood flow after ileocolonic resection for Crohn's disease. Gut 34: 1531–1534, 1993.[Abstract/Free Full Text]
  6. Bacaner MB. Quantitative measurement of regional colon blood flow in the normal and pathological human bowel. Gastroenterology 51: 764–777, 1966.[Web of Science][Medline]
  7. Basler RS. Ulcerative colitis and the skin. Med Clin North Am 64: 941–954, 1980.[Web of Science][Medline]
  8. Bennett CF, Condon TP, Grimm S, Chan H, and Chiang MY. Inhibition of endothelial cell adhesion molecule expression with antisense oligonucleotides. J Immunol 152: 3530–3540, 1994.[Abstract]
  9. Bevilacqua MP, Pober JS, Wheeler ME, Cotran RS, and Gimbrone MA Jr. Interleukin 1 acts on cultured human vascular endothelium to increase the adhesion of polymorphonuclear leukocytes, monocytes, and related leukocyte cell lines. J Clin Invest 76: 2003–2011, 1985.[Web of Science][Medline]
  10. Binion DG, West GA, Ina K, Ziats NP, Emancipator SN, and Fiocchi C. Enhanced leukocyte binding by intestinal microvascular endothelial cells in inflammatory bowel disease. Gastroenterology 112: 1895–1907, 1997.[Web of Science][Medline]
  11. Binion DG, West GA, Volk EE, Drazba JA, Ziats NP, Petras RE, and Fiocchi C. Acquired increase in leucocyte binding by intestinal microvascular endothelium in inflammatory bowel disease. Lancet 352: 1742–1746, 1998.[Web of Science][Medline]
  12. Brahme F. Mesenteric angiography in regional enterocolitis. Radiology 87: 1037–1042, 1966.[Web of Science][Medline]
  13. Briskin M, Winsor-Hines D, Shyjan A, Cochran N, Bloom S, Wilson J, McEvoy LM, Butcher EC, Kassam N, Mackay CR, Newman W, and Ringler DJ. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol 151: 97–110, 1997.[Abstract]
  14. Burgio VL, Fais S, Boirivant M, Perrone A, and Pallone F. Peripheral monocyte and naive T-cell recruitment and activation in Crohn's disease. Gastroenterology 109: 1029–1038, 1995.[Web of Science][Medline]
  15. Chamouard P, Grunebaum L, Wiesel ML, Frey PL, Wittersheim C, Sapin R, Baumann R, and Cazenave JP. Prothrombin fragment 1 + 2 and thrombin-antithrombin III complex as markers of activation of blood coagulation in inflammatory bowel diseases. Eur J Gastroenterol Hepatol 7: 1183–1188, 1995.[Web of Science][Medline]
  16. Chamouard P, Grunebaum L, Wiesel ML, Freyssinet JM, Duclos B, Cazenave JP, and Baumann R. Prevalence and significance of anticardiolipin antibodies in Crohn's disease. Dig Dis Sci 39: 1501–1504, 1994.[Web of Science][Medline]
  17. Chiang MY, Chan H, Zounes MA, Freier SM, Lima WF, and Bennett CF. Antisense oligonucleotides inhibit intercellular adhesion molecule 1 expression by two distinct mechanisms. J Biol Chem 266: 18162–18171, 1991.[Abstract/Free Full Text]
  18. Dalekos GN, Manoussakis MN, Goussia AC, Tsianos EV, and Moutsopoulos HM. Soluble interleukin-2 receptors, antineutrophil cytoplasmic antibodies, and other autoantibodies in patients with ulcerative colitis. Gut 34: 658–664, 1993.[Abstract/Free Full Text]
  19. Danese S, de la MC, Sturm A, Vogel JD, West GA, Strong SA, Katz JA, and Fiocchi C. Platelets trigger a CD40-dependent inflammatory response in the microvasculature of inflammatory bowel disease patients. Gastroenterology 124: 1249–1264, 2003.[Web of Science][Medline]
  20. Diamond MS, Staunton DE, de Fougerolles AR, Stacker SA, Garcia-Aguilar J, Hibbs ML, and Springer TA. ICAM-1 (CD54): a counter-receptor for Mac-1 (CD11b/CD18). J Cell Biol 111: 3129–3139, 1990.[Abstract/Free Full Text]
  21. Duker JS, Brown GC, and Brooks L. Retinal vasculitis in Crohn's disease. Am J Ophthalmol 103: 664–668, 1987.[Web of Science][Medline]
  22. Dustin ML, Rothlein R, Bhan AK, Dinarello CA, and Springer TA. Induction by IL 1 and interferon-gamma: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1). J Immunol 137: 245–254, 1986.[Abstract]
  23. Dvorak AM, Monahan RA, Osage JE, and Dickersin GR. Crohn's disease: transmission electron microscopic studies. II. Immunologic inflammatory response. Alterations of mast cells, basophils, eosinophils, and the microvasculature. Hum Pathol 11: 606–619, 1980.[Web of Science][Medline]
  24. Erikson U, Fagerberg S, Krause U, and Olding L. Angiographic studies in Crohn's disease and ulcerative colitis. Am J Roentgenol Radium Ther 110: 385–392, 1970.[Web of Science][Medline]
  25. Evans RC, Wong VS, Morris AI, and Rhodes JM. Treatment of corticosteroid-resistant ulcerative colitis with heparin–a report of 16 cases. Aliment Pharmacol Ther 11: 1037–1040, 1997.[Web of Science][Medline]
  26. Feagan BG, McDonald J, Greenberg G, Wild G, Pare P, Fedorak RN, Landau SB, and Brettman LR. An ascending dose trial of a humanized A4B7 antibody in ulcerative colitis (UC) (Abstract). Gastroenterology 118: A874, 2000.
  27. Folwaczny C, Wiebecke B, and Loeschke K. Unfractioned heparin in the therapy of patients with highly active inflammatory bowel disease. Am J Gastroenterol 94: 1551–1555, 1999.[Web of Science][Medline]
  28. Gaffney PR, Doyle CT, Gaffney A, Hogan J, Hayes DP, and Annis P. Paradoxical response to heparin in 10 patients with ulcerative colitis. Am J Gastroenterol 90: 220–223, 1995.[Web of Science][Medline]
  29. Geller SA and Cohen A. Arterial inflammatory-cell infiltration in Crohn's disease. Arch Pathol Lab Med 107: 473–475, 1983.[Web of Science][Medline]
  30. Ghosh S, Goldin E, Gordon FH, Malchow HA, Rask-Madsen J, Rutgeerts P, Vyhnalek P, Zadorova Z, Palmer T, and Donoghue S. Natalizumab for active Crohn's disease. N Engl J Med 348: 24–32, 2003.[Abstract/Free Full Text]
  31. Granger DN. Cell adhesion and migration. II. Leukocyte-endothelial cell adhesion in the digestive system. Am J Physiol Gastrointest Liver Physiol 273: G982–G986, 1997.[Abstract/Free Full Text]
  32. Granger DN and Kubes P. The microcirculation and inflammation: modulation of leukocyte-endothelial cell adhesion. J Leukoc Biol 55: 662–675, 1994.[Abstract]
  33. Granger DN, Richardson PD, Kvietys PR, and Mortillaro NA. Intestinal blood flow. Gastroenterology 78: 837–863, 1980.[Web of Science][Medline]
  34. Guslandi M, Polli D, Sorghi M, and Tittobello A. Rectal blood flow in ulcerative colitis. Am J Gastroenterol 90: 579–580, 1995.[Web of Science][Medline]
  35. Harvey JC, Rotstein L, Steinhardt M, Reingold MM, Rubin E, and Stone RM. Massive lower gastrointestinal bleeding: an unusual complication of Crohn's disease. Can J Surg 21: 444–445, 1978.[Web of Science][Medline]
  36. Hatoum OA, Binion DG, Otterson MF, and Gutterman DD. Acquired microvascular dysfunction in inflammatory bowel disease: loss of nitric oxide mediated vasodilation. Gastroenterology. 125: 58–69, 2003.[Web of Science][Medline]
  37. Heneghan MA, Cleary B, Murray M, O'Gorman TA, and McCarthy CF. Activated protein C resistance, thrombophilia, and inflammatory bowel disease. Dig Dis Sci 43: 1356–1361, 1998.[Web of Science][Medline]
  38. Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, and Kroczek RA. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391: 591–594, 1998.[Medline]
  39. Hoke GD, Draper K, Freier SM, Gonzalez C, Driver VB, Zounes MC, and Ecker DJ. Effects of phosphorothioate capping on antisense oligonucleotide stability, hybridization and antiviral efficacy versus herpes simplex virus infection. Nucleic Acids Res 19: 5743–5748, 1991.[Abstract/Free Full Text]
  40. Homan WP, Tang CK, and Thorbjarnarson B. Acute massive hemorrhage from intestinal Crohn disease. Report of seven cases and review of the literature. Arch Surg 111: 901–905, 1976.[Abstract/Free Full Text]
  41. Hulten L, Jodal M, Lindhagen J, and Lundgren O. Blood flow in the small intestine of cat and man as analyzed by an inert gas washout technique. Gastroenterology 70: 45–51, 1976.[Web of Science][Medline]
  42. Hulten L, Jodal M, Lindhagen J, and Lundgren O. Colonic blood flow in cat and man as analyzed by an inert gas washout technique. Gastroenterology 70: 36–44, 1976.[Web of Science][Medline]
  43. Hulten L, Lindhagen J, Lundgren O, Fasth S, and Ahren C. Regional intestinal blood flow in ulcerative colitis and Crohn's disease. Gastroenterology 72: 388–396, 1977.[Web of Science][Medline]
  44. Jorens PG, Hermans CR, Haber I, Kockx MM, Vermylen J, and Parizel GA. Acquired protein C and S deficiency, inflammatory bowel disease and cerebral arterial thrombosis. Blut 61: 307–310, 1990.[Web of Science][Medline]
  45. Kermode AG, Ives FJ, Taylor B, Davis SJ, and Carroll WM. Progressive dural venous sinus thrombosis treated with local streptokinase infusion. J Neurol Neurosurg Psychiatry 58: 107–108, 1995.[Free Full Text]
  46. Knutson H, Lunderquist A, and Lunderquist A. Vascular changes in Crohn's disease. Am J Roentgenol Radium Ther 103: 380–385, 1968.[Web of Science][Medline]
  47. Koutroubakis IE. Role of thrombotic vascular risk factors in inflammatory bowel disease. Dig Dis 18: 161–167, 2000.[Web of Science][Medline]
  48. Koutroubakis IE, Kritikos H, Mouzas IA, Spanoudakis SM, Kapsoritakis AN, Petinaki E, Kouroumalis EA, and Manousos ON. Association between ulcerative colitis and systemic lupus erythematosus: report of two cases. Eur J Gastroenterol Hepatol 10: 437–439, 1998.[Web of Science][Medline]
  49. Koutroubakis IE, Petinaki E, Anagnostopoulou E, Kritikos H, Mouzas IA, Kouroumalis EA, and Manousos ON. Anti-cardiolipin and anti-beta2-glycoprotein I antibodies in patients with inflammatory bowel disease. Dig Dis Sci 43: 2507–2512, 1998.[Web of Science][Medline]
  50. Kubes P and McCafferty DM. Nitric oxide and intestinal inflammation. Am J Med 109: 150–158, 2000.[Web of Science][Medline]
  51. Kvietys PR and Granger DN. Endothelial cell monolayers as a tool for studying microvascular pathophysiology. Am J Physiol Gastrointest Liver Physiol 273: G1189–G1199, 1997.[Abstract/Free Full Text]
  52. Lake AM, Stauffer JQ, and Stuart MJ. Hemostatic alterations in inflammatory bowel disease: response to therapy. Am J Dig Dis 23: 897–902, 1978.[Web of Science][Medline]
  53. Lam A, Borda IT, Inwood MJ, and Thomson S. Coagulation studies in ulcerative colitis and Crohn's disease. Gastroenterology 68: 245–251, 1975.[Web of Science][Medline]
  54. Lee JS and Duncan KM. Lymphatic and venous transport of water from rat jejunum: a vascular perfusion study. Gastroenterology 54: 559–567, 1968.[Web of Science][Medline]
  55. Lunderquist A and Knutsson H. Angiography in Crohn's disease of the small bowel and colon. Am J Roentgenol Radium Ther 101: 338–344, 1967.[Web of Science][Medline]
  56. Lunderquist A and Lunderquist A. Angiography in ulcerative colitis. Am J Roentgenol Radium Ther 99: 18–23, 1967.[Web of Science][Medline]
  57. Markowitz RL, Ment LR, and Gryboski JD. Cerebral thromboembolic disease in pediatric and adult inflammatory bowel disease: case report and review of the literature. J Pediatr Gastroenterol Nutr 8: 413–420, 1989.[Web of Science][Medline]
  58. Marlin SD and Springer TA. Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1). Cell 51: 813–819, 1987.[Web of Science][Medline]
  59. McGarrity TJ, Manasse JS, Koch KL, and Weidner WA. Crohn's disease and massive lower gastrointestinal bleeding: angiographic appearance and two case reports. Am J Gastroenterol 82: 1096–1099, 1987.[Web of Science][Medline]
  60. Mellor JA, Chandler GN, Chapman AH, and Irving HC. Massive gastrointestinal bleeding in Crohn's disease: successful control by intra-arterial vasopressin infusion. Gut 23: 872–874, 1982.[Abstract/Free Full Text]
  61. Murray DR and Freeman GL. Proinflammatory cytokines: predictors of a failing heart? Circulation 107: 1460–1462, 2003.[Free Full Text]
  62. Nelson J, Barron MM, Riggs JE, Gutmann L, and Schochet SS Jr. Cerebral vasculitis and ulcerative colitis. Neurology 36: 719–721, 1986.[Abstract/Free Full Text]
  63. Nestle FO, Mitra RS, Bennett CF, Chan H, and Nickoloff BJ. Cationic lipid is not required for uptake and selective inhibitory activity of ICAM-1 phosphorothioate antisense oligonucleotides in keratinocytes. J Invest Dermatol 103: 569–575, 1994.[Web of Science][Medline]
  64. Nuutinen H, Reunanen M, Farkkila M, and Seppala K. Association of ulcerative colitis and ischemic heart disease (Abstract). Gastroenterology 108: A886, 1995.
  65. Nuutinen H, Reunanen M, Farkkila M, and Seppala K. Association of Crohn's disease and ischemic heart disease (Abstract). Gastroenterology 110: A981, 1996.
  66. Podolsky DK, Lobb R, King N, Benjamin CD, Pepinsky B, Sehgal P, and deBeaumont M. Attenuation of colitis in the cotton-top tamarin by anti-alpha 4 integrin monoclonal antibody. J Clin Invest 92: 372–380, 1993.[Web of Science][Medline]
  67. Prajapati DN, Newcomer JR, Emmons J, Abu-Hajir M, and Binion DG. Successful treatment of an acute flare of steroid-resistant Crohn's colitis during pregnancy with unfractionated heparin. Inflamm Bowel Dis 8: 192–195, 2002.[Web of Science][Medline]
  68. Rothlein R, Dustin ML, Marlin SD, and Springer TA. A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. J Immunol 137: 1270–1274, 1986.[Abstract]
  69. Salmi M, Granfors K, MacDermott R, and Jalkanen S. Aberrant binding of lamina propria lymphocytes to vascular endothelium in inflammatory bowel diseases. Gastroenterology 106: 596–605, 1994.[Web of Science][Medline]
  70. Schapira M, Henrion J, Ravoet C, Maisin JM, Ghilain JM, De Maeght S, and Heller F. Thromboembolism in inflammatory bowel disease. Acta Gastroenterol Belg 62: 182–186, 1999.[Medline]
  71. Soloway M, Moir TW, and Linton DS Jr. Takayasu's arteritis. Report of a case with unusual findings. Am J Cardiol 25: 258–263, 1970.[Medline]
  72. Souto JC, Martinez E, Roca M, Mateo J, Pujol J, Gonzalez D, and Fontcuberta J. Prothrombotic state and signs of endothelial lesion in plasma of patients with inflammatory bowel disease. Dig Dis Sci 40: 1883–1889, 1995.[Web of Science][Medline]
  73. Suarez Crespo JF, Nogueras LF, Teresa Galvan FJ, Sola Earle CM, Gonzalez GA, Pinel Julian LM, and Ruiz-Cabello JM. [Thromboembolic complications in inflammatory bowel disease.] Gastroenterol Hepatol 20: 180–183, 1997.[Medline]
  74. Talbot RW, Heppell J, Dozois RR, and Beart RW Jr. Vascular complications of inflammatory bowel disease. Mayo Clin Proc 61: 140–145, 1986.[Web of Science][Medline]
  75. Thompson NP, Wakefield AJ, and Pounder RE. Inherited disorders of coagulation appear to protect against inflammatory bowel disease. Gastroenterology 108: 1011–1015, 1995.[Web of Science][Medline]
  76. Torkvist L, Thorlacius H, Sjoqvist U, Bohman L, Lapidus A, Flood L, Agren B, Raud J, and Lofberg R. Low molecular weight heparin as adjuvant therapy in active ulcerative colitis. Aliment Pharmacol Ther 13: 1323–1328, 1999.[Web of Science][Medline]
  77. Urbich C, Dernbach E, Aicher A, Zeiher AM, and Dimmeler S. CD40 ligand inhibits endothelial cell migration by increasing production of endothelial reactive oxygen species. Circulation 106: 981–986, 2002.[Abstract/Free Full Text]
  78. Van Assche G and Rutgeerts P. Antiadhesion molecule therapy in inflammatory bowel disease. Inflamm Bowel Dis 8: 291–300, 2002.[Web of Science][Medline]
  79. Vasilopoulos S, Saiean K, Emmons J, Berger WL, Abu-Hajir M, Seetharam B, and Binion DG. Terminal ileum resection is associated with higher plasma homocysteine levels in Crohn's disease. J Clin Gastroenterol 33: 132–136, 2001.[Web of Science][Medline]
  80. Vecchi M, Cattaneo M, de Franchis R, and Mannucci PM. Risk of thromboembolic complications in patients with inflammatory bowel disease. Study of hemostasis measurements. Int J Clin Lab Res 21: 165–170, 1991.[Web of Science][Medline]
  81. Vogel JD, Majors A, and Sturm A. Collagen synthesis by human intestinal fibroblast is medulated by T-cells through the CD40/CD40 ligand pathway (Abstract). Gastroenterology 120: A719, 2001.
  82. Wakefield AJ, Sankey EA, Dhillon AP, Sawyerr AM, More L, Sim R, Pittilo RM, Rowles PM, Hudson M, and Lewis AA. Granulomatous vasculitis in Crohn's disease. Gastroenterology 100: 1279–1287, 1991.[Web of Science][Medline]
  83. Yacyshyn BR, Bowen-Yacyshyn MB, Jewell L, Tami JA, Bennett CF, Kisner DL, and Shanahan WR Jr. A placebocontrolled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn's disease. Gastroenterology 114: 1133–1142, 1998.[Web of Science][Medline]



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