the Vasculature and Inflammatory Bowel Disease. Contribution to Pathogenesis and Clinical Pathology

Hatoum, Ossama A.; Binion, David G.

doi:10.1097/01.mib.0000160772.78951.61

Cited by 127 publications

(98 citation statements)

References 146 publications

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“…This integration has been confirmed in murine models, where inhibition of CD40 signaling decreases inflammatory infiltrates in established atherosclerotic lesions (45) and TNF-␣ blockade reduces progression of atherosclerosis (46). A recent but growing body of evidence indicates that vascular inflammation is also an important component of IBD pathogenesis (47). We have previously shown that the CD40/ CD40L system is involved in several proinflammatory events in IBD, including chemokine and cytokine production, cell adhesion molecule up-regulation, chemokine mobilization on the endothelial surface, and T cell adhesion to and transmigration across endothelial monolayers (8,10).…”

Section: Discussionmentioning

confidence: 84%

TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

Danese¹,

Sans

Scaldaferri³

et al. 2006

The Journal of Immunology

153

101

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The CD40/CD40 ligand (CD40L) pathway is involved in Crohn’s disease (CD) pathogenesis. In the patients’ circulation, soluble CD40L (sCD40L) levels are elevated and surface CD40L is increased in platelets and T cells, whereas in the intestine CD40 is overexpressed in the microvasculature and CD40L in platelets and T cells. The therapeutic effects of infliximab in CD are attributed to its systemic anti-TNF-α action, but because TNF-α modulates both CD40 and CD40L, we investigated whether infliximab affects the CD40/CD40L pathway in the intestine. Eighteen CD patients were evaluated before and after infliximab therapy. Plasma sCD40L was measured by ELISA and platelet and peripheral blood T cell (PBT) CD40L expression by flow cytometry. Microvascular CD40 and VCAM-1 expression were assessed in mucosal biopsies by immunohistochemistry and by flow cytometry in human intestinal microvascular endothelial cells (HIMEC). Cell cultures were performed in the presence and absence of infliximab. Infliximab treatment significantly reduced plasma sCD40L levels and eliminated CD40 and VCAM-1 from mucosal microvessels. In vitro infliximab prevented TNF-α-induced CD40 and VCAM-1 expression by HIMEC, and reduced PBT, but not platelet, surface CD40L expression and sCD40L release. In addition, infliximab decreased T cell-induced VCAM-1 expression in HIMEC by down-regulating CD40L in T cells and promoting T cells apoptosis. These findings point to a novel mechanism of action of infliximab, i.e., the disruption of CD40/CD40L-dependent cognate interactions between intestinal microvessels and T cells. Thus, in addition to neutralizing TNF-α and inducing T cell death, the therapeutic effects of infliximab in CD appear to be also mediated by inhibition of vascular inflammation in the gut.

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Section: Discussionmentioning

confidence: 84%

TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

Danese¹,

Sans

Scaldaferri³

et al. 2006

The Journal of Immunology

153

101

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“…and animal models of IBD have revealed alterations in gastrointestinal (GI) blood flow (2,15,22,26) and angiogenesis (4 -6). These changes may contribute to disease pathogenesis, inasmuch as defects in mucosal perfusion render the mucosal barrier susceptible to breakdown.…”

Section: Studies Of Patients With Inflammatory Bowel Disease (Ibd)mentioning

confidence: 99%

“…The RNA was reprecipitated using LiCl precipitation solution (Ambion). Subsequently, cDNA was reverse transcribed from 1 g of total RNA using SuperScript III (Invitrogen) and oligo(dT) [12][13][14][15][16][17][18] primers (Invitrogen). Real-time PCR was performed using the primers listed in Table 2 with a Roche Lightcycler and the Quantitech SYBR Green PCR kit (Qiagen).…”

Section: Animals and Materialsmentioning

confidence: 99%

“…These data implicate upregulation of CD39 in impaired sympathetic regulation of gastrointestinal blood flow during colitis. purinergic neurotransmission; ectonucleotidase; inflammation; sympathetic; vasoconstriction STUDIES OF PATIENTS WITH INFLAMMATORY bowel disease (IBD) and animal models of IBD have revealed alterations in gastrointestinal (GI) blood flow (2,15,22,26) and angiogenesis (4 -6). These changes may contribute to disease pathogenesis, inasmuch as defects in mucosal perfusion render the mucosal barrier susceptible to breakdown.…”

mentioning

confidence: 99%

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Loss of purinergic vascular regulation in the colon during colitis is associated with upregulation of CD39

Neshat¹,

deVries²,

Barajas-Espinosa³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Neshat S, deVries M, Barajas-Espinosa AR, Skeith L, Chisholm SP, Lomax AE. Loss of purinergic vascular regulation in the colon during colitis is associated with upregulation of CD39. Am J Physiol Gastrointest Liver Physiol 296: G399 -G405, 2009. First published December 12, 2008 doi:10.1152/ajpgi.90450.2008.-Evidence from patients with inflammatory bowel disease (IBD) and animal models suggests that inflammation alters blood flow to the mucosa, which precipitates mucosal barrier dysfunction. Impaired purinergic sympathetic regulation of submucosal arterioles, the resistance vessels of the splanchnic vasculature, is one of the defects identified during IBD and in mouse models of IBD. We hypothesized that this may be a consequence of upregulated catabolism of ATP during colitis. In vivo and in vitro video microscopy techniques were employed to measure the effects of purinergic agonists and inhibitors of CD39, an enzyme responsible for extracellular ATP catabolism, on the diameter of colonic submucosal arterioles from control mice and mice with dextran sodium sulfate [DSS, 5% (wt/vol)] colitis. Using a luciferase-based ATP assay, we examined the degradation of ATP and utilized real-time PCR, Western blotting, and immunohistochemistry to examine the expression and localization of CD39 during colitis. Arterioles from mice with DSS colitis did not constrict in response to ATP (10 M) but did constrict in the presence of its nonhydrolyzable analog ␣,␤-methylene ATP (1 M). ␣,␤-Methylene ADP (100 M), an inhibitor of CD39, restored ATP-induced vasoconstriction in arterioles from mice with DSS-induced colitis. CD39 protein and mRNA expression was markedly increased during colitis. Immunohistochemical analysis demonstrated that, in addition to vascular CD39, F4/80-immunoreactive macrophages accounted for a large proportion of submucosal CD39 staining during colitis. These data implicate upregulation of CD39 in impaired sympathetic regulation of gastrointestinal blood flow during colitis. purinergic neurotransmission; ectonucleotidase; inflammation; sympathetic; vasoconstriction STUDIES OF PATIENTS WITH INFLAMMATORY bowel disease (IBD) and animal models of IBD have revealed alterations in gastrointestinal (GI) blood flow (2,15,22,26) and angiogenesis (4 -6). These changes may contribute to disease pathogenesis, inasmuch as defects in mucosal perfusion render the mucosal barrier susceptible to breakdown. One potential mechanism of altered mucosal blood flow is defective neural regulation of GI blood vessels during inflammation.Submucosal arterioles are the resistance vessels of the splanchnic vasculature and thus regulate mucosal perfusion (13,23,31). We previously identified a defect in sympathetic vasoconstrictor regulation of colonic submucosal arterioles in the 2,4,6-trinitrobenzene sulfonic acid (TNBS) mouse model of IBD (22). Neurally evoked vasoconstrictions in control mice were sensitive to ␣ 1 -adrenoceptor and purinergic receptor antagonism, and superfusion of ATP and phenylephrine caused robust vasoconstrictions. I...

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“…Recently, researchers have focused on cardiovascular risk and on the possibility of early onset and rapid progression of the atherosclerotic process, with conflicting results [4][5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Increased expression of markers of early atherosclerosis in patients with inflammatory bowel disease

Cappello

Licata

Calvaruso

et al. 2017

European Journal of Internal Medicine

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Background & Aims:Recent studies documented an increased cardiovascular risk in patients with inflammatory bowel disease (IBD). Our study aimed at investigating the prevalence of intima-media thickness (IMT) of the carotid arteries and the arterial stiffness indices as markers of early atherosclerosis in young IBD patients. Methods: We recruited 68 consecutive IBD patients, and 38 matched healthy controls less than 45 years old (median age 31.6 ± 8.1 years). Clinical and demographic features, cardiovascular risk factors, history of cardiovascular events, concomitant therapies were registered on a dedicate database. Carotid IMT was evaluated by using high resolution B-mode ultrasonography. Arterial stiffness was assessed by measurement of carotidfemoral Pulse Wave Velocity (PWV) and Augmentation Index (AIx). Results: Total cholesterol (P b 0.013) and LDL-cholesterol (P b 0.019) levels were significantly lower in IBD patients compared to controls. Carotid IMT was higher in IBD than in controls (P b 0.047), but there was no statistically significant difference among Crohn's Disease (CD) and Ulcerative Colitis (UC) patients. Moreover, PWV and AIx were significantly higher in patients as compared to controls (P b 0.006 and P b 0.004 respectively). No medication seemed to affect vascular measurements, though stiffness parameters were significantly higher in patients treated with 5-ASA (11.9 (9.7) vs 18.2 (10.2), P b 0.021), suggesting a lack of efficacy of 5-ASA in protecting IBD patients from early atherogenesis. Conclusions: Young IBD patients show an increase in subclinical markers of atherosclerosis. Future studies need to address whether these markers result in an increased risk of cardiovascular events in these patient.

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the Vasculature and Inflammatory Bowel Disease. Contribution to Pathogenesis and Clinical Pathology

Cited by 127 publications

References 146 publications

TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

Loss of purinergic vascular regulation in the colon during colitis is associated with upregulation of CD39

Increased expression of markers of early atherosclerosis in patients with inflammatory bowel disease

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