The Intestinal Microvasculature as a Therapeutic Target in Inflammatory Bowel Disease

Hatoum, Ossama A.; Heidemann, Jan; Binion, David G.

doi:10.1196/annals.1326.003

Cited by 77 publications

(63 citation statements)

References 145 publications

(233 reference statements)

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“…Although the effects of CB-01-05 on cytokines production are in agreement with the known ability of dalteparin and other heparin derivatives to influence cytokines production and to arrest immune inflammation in rodents [16,17,25], we cannot exclude the involvement of additional mechanisms. Among these putative mechanisms increase of expression of some growth factors [26], decrease of nitric oxide synthesis [18,20,27], as well as effects on intestinal microcirculation [12,28], and leucocyte-endothelial interactions [19] could be involved in the activity of CB-01-05. On the other hand, the observation that macroscopic mucosal haemorrhages were not severer in CB-01-05 group than in the control groups suggests that the local activity of CB-01-05 is not mediated by a direct anticoagulant mechanism.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Intracolonic Administration of Low-Molecular-Weight Heparin CB-01-05, Compared to Other Low-Molecular-Weight Heparins and Unfractionated Heparin, in Experimentally Induced Colitis in Rat

et al. 2008

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Purpose Parenteral administration of lowmolecular-weight heparins (LMWHs) and unfractionated heparin (UFH) resulted effective in improving the symptoms of experimental colitis in rat. Today, there is little information about their activity by intracolonic instillation. The scope of this study was to evaluate the ability of CB-01-05 (a LMWH with a mean molecular weight of about 5,700), compared to a series of other LMWHs and to UFH, directly instilled into the distal colon of the rat, to ameliorate dinitrobenzene (DNB)-induced experimental colitis. Method Adult male Wistar rats underwent colitis induction by intracolonic instillation of DNB. Starting 24 h after colitis induction, CB-01-05 (0.005-0.9 mg), other LMWHs (0.3-0.6 mg), and UFH (0.6 mg) were instilled, by rectal route, into the distal colon once a day for three consecutive days. On the day following the last administration, the animals were sacrificed and the distal colon was isolated, weighed, macroscopically examined, and processed for histology. Additional experiments in rat splenocytes, performed in order to elucidate the anti-inflammatory mechanisms of CB-01-05, were performed. Results Among the tested items, only CB-01-05 at doses ranging from 0.2 to 0.9 mg was significantly effective in reducing colon weight increase and in improving both the mucosal damaged area and the histological score. The other LMWHs resulted far less effective, showing decreasing activity closely related with the decrease of their molecular weight, thus demonstrating their biological nonequivalence. CB-01-05 resulted also more active than UFH. CB-01-05 was shown to interfere with cytokines production by rat splenocytes, mainly inhibiting interferon (IFN)-c expression. Conclusions CB-01-05 instilled into the colon is well tolerated, has strong anti-inflammatory effect on DNBinduced colitis in rat, and is the most effective agent among other LMWHs and UFH. These results suggest that the anti-inflammatory activity of CB-01-05, together with its topical administration, could represent a new approach in the management of ulcerative colitis.

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Section: Discussionmentioning

confidence: 99%

Efficacy of Intracolonic Administration of Low-Molecular-Weight Heparin CB-01-05, Compared to Other Low-Molecular-Weight Heparins and Unfractionated Heparin, in Experimentally Induced Colitis in Rat

et al. 2008

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“…Biological agents targeting adhesion molecules and chemokines to reduce leukocyte infiltration and inflammatory responses, modulation of coagulation pathways, angiogenesis inhibition, and reversal of microvascular dysfunction are all currently areas of intense study with the goal to rapidly expand our therapeutic armamentarium for IBD therapy and to translate bench research and conquests to the patient bedside. 105 …”

Section: Discussionmentioning

confidence: 99%

Multiple Pathogenic Roles of Microvasculature in Inflammatory Bowel Disease: A Jack of All Trades

Deban

Correale

Vetrano

et al. 2008

The American Journal of Pathology

124

100

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The etiology of Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD), is still largely unknown. However, it is now clear that the abnormalities underlying pathogenesis of intestinal inflammation are not restricted to those mediated by classic immune cells but also involve nonimmune cells. In particular, advances in vascular biology have outlined a central and multifaceted pathogenic role for the microcirculation in the initiation and perpetuation of IBD. The microcirculation and its endothelial lining play a crucial role in mucosal immune homeostasis through tight regulation of the nature and magnitude of leukocyte migration from the intravascular to the interstitial space. Chronically inflamed IBD microvessels display significant alterations in microvascular physiology and function compared with vessels from healthy and uninvolved IBD intestine. The investigation into human IBD has demonstrated how endothelial activation present in chronically inflamed IBD microvessels results in a functional phenotype that also includes leakiness, chemokine and cytokine expression, procoagulant activity, and angiogenesis. This review contemplates the newly uncovered contribution of intestinal microcirculation to pathogenesis and maintenance of chronic intestinal inflammation. In particular, we assess the multiple roles of the microvascular endothelium in innate immunity, leukocyte recruitment, coagulation and perfusion, and immune-driven angiogenesis in IBD.

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“…This process likely results in an excessive cytotoxic response (15,16), increased permeability of the epithelial barrier (17,18), continuous epithelial erosion, and reduced production of defensins (19). In turn, commensal bacteria cross the epithelial cell layer (20), leading to an accelerated activation of effector T cells (21) and increased recruitment of inflammatory cells into the intestinal mucosa (22).…”

mentioning

confidence: 99%

Endoplasmic Reticulum Stress Response Promotes Cytotoxic Phenotype of CD8αβ+ Intraepithelial Lymphocytes in a Mouse Model for Crohn’s Disease-like Ileitis

Chang

Ocvirk

Berger

et al. 2012

The Journal of Immunology

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Endoplasmic reticulum (ER) unfolded protein responses (UPR) are implicated in the pathogenesis of inflammatory bowel disease. Cytotoxic CD8αβ+ intraepithelial lymphocytes (IEL) contribute to the development of Crohn’s disease-like ileitis in TNFΔARE/+ mice. In this study, we characterized the role of ER-UPR mechanisms in contributing to the disease-associated phenotype of cytotoxic IEL under conditions of chronic inflammation. Inflamed TNFΔARE/+ mice exhibited increased expression of Grp78, ATF6, ATF4, and spliced XBP1 in CD8αβ+ IEL but not in CD8αα+ IEL or in lamina propria lymphocytes. Chromatin immunoprecipitation analysis in CD8αβ+ T cells showed selective recruitment of ER-UPR transducers to the granzyme B gene promoter. Heterozygous Grp78−/+ mice exhibited an attenuated granzyme B-dependent cytotoxicity of CD8αβ+ T cells against intestinal epithelial cells, suggesting a critical activity of this ER-associated chaperone in maintaining a cytotoxic T cell phenotype. Granzyme B-deficient CD8αβ+ T cells showed a defect in IL-2–mediated proliferation in Grp78−/+ mice. Adoptively transferred Grp78−/+ CD8αβ+ T cells had a decreased frequency of accumulation in the intestine of RAG2−/− recipient mice. The tissue pathology in TNFΔARE/+ × Grp78−/+ mice was similar to TNFΔARE/+ mice, even though the cytotoxic effector functions of CD8αβ+ T cells were significantly reduced. In conclusion, ER stress-associated UPR mechanisms promote the development and maintenance of the pathogenic cytotoxic CD8αβ+ IEL phenotype in the mouse model of Crohn’s disease-like ileitis.

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The Intestinal Microvasculature as a Therapeutic Target in Inflammatory Bowel Disease

Cited by 77 publications

References 145 publications

Efficacy of Intracolonic Administration of Low-Molecular-Weight Heparin CB-01-05, Compared to Other Low-Molecular-Weight Heparins and Unfractionated Heparin, in Experimentally Induced Colitis in Rat

Efficacy of Intracolonic Administration of Low-Molecular-Weight Heparin CB-01-05, Compared to Other Low-Molecular-Weight Heparins and Unfractionated Heparin, in Experimentally Induced Colitis in Rat

Multiple Pathogenic Roles of Microvasculature in Inflammatory Bowel Disease: A Jack of All Trades

Endoplasmic Reticulum Stress Response Promotes Cytotoxic Phenotype of CD8αβ+ Intraepithelial Lymphocytes in a Mouse Model for Crohn’s Disease-like Ileitis

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