Crohn's disease: in defense of a microvascular aetiology

Thornton, Michelle; Solomon, Michael J.

doi:10.1007/s00384-002-0408-5

Cited by 72 publications

(57 citation statements)

References 85 publications

(89 reference statements)

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“…[1][2][3][4]24 In contrast, the role of microvascular endothelial barrier in defense of intestinal homeostasis is less recognized and investigated despite the fact that it: (1) is essential for capillary blood flow, oxygen and nutrient delivery; (2) serves as a 'gatekeeper' preventing the extravasation of circulating leukocytes and other inflammatory cells and proteins into the mucosa; and (3) has a major role in innate immune response, by synthesis and release of pro-inflammatory cytokines. 10,[25][26][27] We found that young Ga-i2 À/À mice in early stages of spontaneously developing UC demonstrate areas of colonic mucosa with perivascular edema in the lamina propria covered by uninterrupted normal layer of surface epithelial cells. Older Ga-i2 À/À mice with advanced stage of UC had focal areas of perivascular edema containing leukocytes and a continuous layer of surface epithelial cells outside the areas of erosions and ulcers.…”

Section: Discussionmentioning

confidence: 69%

“…A number of clinical and experimental studies showed oxygen deprivation of colonic epithelial cells in inflammatory bowel disease (IBD). 5,10,25,36 Moreover, prevention of hypoxia by heparin 37 or endothelin-1 receptor antagonist 38 significantly reduced the degree of mucosal injury and inflammatory response. In addition to endothelial damage and intravascular congestion, our present study demonstrated hypoxia in colonic surface epithelial cells that preceded the enhanced colonic EP.…”

Section: Endothelial Damage In Ulcerative Colitismentioning

confidence: 96%

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Early endothelial damage and increased colonic vascular permeability in the development of experimental ulcerative colitis in rats and mice

Tolstanova

Deng

French

et al. 2012

Laboratory Investigation

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The role of endothelial damage and increased vascular permeability (VP) in the pathogenesis of ulcerative colitis (UC) has not been investigated. We examined using functional, morphologic, and molecular biologic studies whether and to what extent the endothelial barrier dysfunction precedes enhanced epithelial permeability (EP) and the development of mucosal lesions during the early stages of experimental UC. We showed that in rats with iodoacetamide (IA)-induced UC increased colonic VP occurs early (ie, 2.6-fold increase at 15 min, Po0.01) preceding changes in epithelial barrier permeability. EP was unchanged at 15 and 30 min after IA administration and was increased 1.9-fold at 1 h and 6.7-fold at 2 h (both Po0.001) after IA. In the dextran sodium sulfate-induced slowly developing UC, colonic VP was significantly increased in 2 days (Po0.05) and EP only in 4 days (Po0.05). Mucosal endothelial injury led to hypoxia (Po0.05) of colonic surface epithelial cells 30 min after IA administration that was associated with increased expressions of transcription factors hypoxia-inducible factor-1a and early growth response-1. Electron and light microscopy demonstrated areas of colonic mucosa with perivascular edema covered by intact layer of surface epithelial cells in both rat and mouse models of UC. This is the first demonstration in four models of UC that endothelial damage, increased colonic VP, perivascular edema, and epithelial hypoxia precede epithelial barrier dysfunction that is followed by erosions, ulceration, and inflammation in UC. KEYWORDS: endothelial damage; epithelial permeability; hypoxia; inflammatory bowel disease; ulcerative colitis; vascular permeability Ulcerative colitis (UC) is characterized by chronic, recurrent ulcers and inflammation of the colonic mucosa. It has been postulated that impaired epithelial barrier function, resulting in penetration of bacteria and other antigens into the mucosa, is one of the major factors of UC pathogenesis.

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Section: Discussionmentioning

confidence: 69%

Section: Endothelial Damage In Ulcerative Colitismentioning

confidence: 96%

Early endothelial damage and increased colonic vascular permeability in the development of experimental ulcerative colitis in rats and mice

Tolstanova

Deng

French

et al. 2012

Laboratory Investigation

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“…In the present example of colitis, it was proposed that the vasculitis associated with such diseases as Crohn disease contributed significantly to the establishment and maintenance of chronic inflammation (1,4). In addition, there is evidence for a complex system of bidirectional crosstalk between hypoxia and inflammation, since cytokines liberated during inflammation (e.g., IL-1, IFN-β, TNF-α) may regu- vehicle-treated WT), such differences were enhanced in conditional Vhlh mutant animals exposed to TNBS in regard to ITF, MDR1, and CD73 ( † P ≤ 0.05 vs. TNBS-treated WT, ‡ P ≤ 0.05 vs. vehicle-treated Vhlh mutants).…”

Section: Discussionmentioning

confidence: 90%

“…A number of studies suggest a close association of inflammation and hypoxia at the tissue level. In Crohn disease, a chronic intestinal inflammatory process that is, at least in part, characterized by marked abnormalities of gut barrier function, microvascular disturbances have been consistently demonstrated (1)(2)(3). Consequently, observations from both human disease (4,5) and experimental colitis (6,7) suggest the presence of colonic hypoxia and its significance in the disease process.…”

Section: Introductionmentioning

confidence: 99%

Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis

Karhausen¹,

Furuta²,

Tomaszewski³

et al. 2004

J. Clin. Invest.

517

475

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Mucosal epithelial cells are uniquely equipped to maintain barrier function even under adverse conditions. Previous studies have implicated hypoxia in mucosal tissue damage resulting from both acute and chronic inflammation. Given the importance of the transcriptional regulator hypoxia-inducible factor-1 (HIF-1) for adaptive hypoxia responses, we hypothesized that HIF-1 may serve as a barrier-protective element during mucosal inflammation. Initial studies of hapten-based murine colitis revealed extensive mucosal hypoxia and concomitant HIF-1 activation during colitis. To study this in more detail, we generated 2 mouse lines with intestinal epithelium-targeted expression of either mutant Hif1a (inability to form HIF-1) or mutant von Hippel-Lindau gene (Vhlh; constitutively active HIF-1). Studies of colitis in these mice revealed that decreased HIF-1 expression correlated with more severe clinical symptoms (mortality, weight loss, colon length), while increased HIF levels were protective in these parameters. Furthermore, colons with constitutive activation of HIF displayed increased expression levels of HIF-1-regulated barrier-protective genes (multidrug resistance gene-1, intestinal trefoil factor, CD73), resulting in attenuated loss of barrier during colitis in vivo. Taken together, these studies provide insight into tissue microenvironmental changes during model inflammatory bowel disease and identify HIF-1 as a critical factor for barrier protection during mucosal insult.

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“…Doenças intestinais inflamatórias frequentemente podem levar a episódios de isquemia, como a Doença de Crohn e isquemia aguda mesentérica (HAGLUND; BERGQVIST, 1999;THORNTON;SOLOMON, 2002). Além disso, I/R-i de vasos intestinais são recorrentes em pacientes hospitalizados, especialmente aqueles que estão nas unidades de terapias intensivas (OLDENBURG et al, 2004).…”

Section: Isquemia E Reperfusão Intestinal (I/r-i)unclassified

Estudo das células gliais entéricas imunorreativas aos receptores P2x2 e P2x7 do íleo de ratos submetidos à isquemia e reperfusão intestinal.

Mendes¹

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The enteric nervous system response to various injuries involves the activation of enteric glial cells. This activation has been suggested as an early signaling mechanism precise, responsible for the subsequent neuronal degeneration. The aim of the work was to analyze the effect of ischemia and reperfusion (I/R-i) on enteric glial cells, neurons and purinergic P2X 2 and P2X 7 receptors. Intestinal ischemia was obtained by the obstruction of blood flow in the vessels ileal period of 35 minutes followed by reperfusion periods of 0 hour (h), 24 h and 14 days.Tissues were prepared by immunohistochemical methods of double labeling of P2X 2 and P2X 7 with Hu (pan-neuronal) and S100 (glial marker); and Hu with glial fibrillary acidic protein (GFAP glial marker) / DAPI (nuclear marker) and S100 with GFAP / DAPI. The qualitative and quantitative analyzes of colocalization, density, profiles area and cell proliferation were obtained from fluorescence microscopes and the Confocal Scanning Laser. Quantitative results have shown: a) neurons and glial cells were immunoreactive to P2X 2 and P2X 7 ; b) a decrease in density of cells immunoreactive (-IR) P2X 2 and P2X 7 receptors, as well as Hu-IR neurons in the Groups I/R-i 0 h, 24 h and 14 days; c) an increase in the density of enteric glial cell S100-IR and GFAP-IR; d) in the profile area of Hu-IR neurons showed no significant differences, however the area profile glial cells S100-IR showed a decrease in Groups I/R-I; e) detected enteric glial cell proliferation S100-IR and GFAP-IR in Groups I/R-i 0 h and 24 h. This study showed that I/R-i is associated with significant loss of neurons, alteration of the expression of purinergic receptors and increased enteric glial cells and these changes may contribute to intestinal motility disorders.

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Crohn's disease: in defense of a microvascular aetiology

Cited by 72 publications

References 85 publications

Early endothelial damage and increased colonic vascular permeability in the development of experimental ulcerative colitis in rats and mice

Early endothelial damage and increased colonic vascular permeability in the development of experimental ulcerative colitis in rats and mice

Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis

Estudo das células gliais entéricas imunorreativas aos receptores P2x2 e P2x7 do íleo de ratos submetidos à isquemia e reperfusão intestinal.

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