SDF-1/CXCR4 signalling is involved in blood vessel growth and remodelling by intussusception.

The precise mechanisms of SDF-1 (CXCL12) in angiogenesis are not fully elucidated. Recently, we showed that Notch inhibition induces extensive intussusceptive angiogenesis by recruitment of mononuclear cells and it was associated with increased levels of SDF-1 and CXCR4. In the current study, we demonstrated SDF-1 expression in liver sinusoidal vessels of Notch1 knockout mice with regenerative hyperplasia by means of intussusception, but we did not detect any SDF-1 expression in wild-type mice with normal liver vessel structure. In addition, pharmacological inhibition of SDF-1/CXCR4 signalling by AMD3100 perturbs intussusceptive vascular growth and abolishes mononuclear cell recruitment in the chicken area vasculosa. In contrast, treatment with recombinant SDF-1 protein increased microvascular density by 34% through augmentation of pillar number compared to controls. The number of extravasating mononuclear cells was four times higher after SDF-1 application and two times less after blocking this pathway. Bone marrow-derived mononuclear cells (BMDC) were recruited to vessels in response to elevated expression of SDF-1 in endothelial cells. They participated in formation and stabilization of pillars. The current study is the first report to implicate SDF-1/CXCR4 signalling in intussusceptive angiogenesis and further highlights the stabilizing role of BMDC in the formation of pillars during vascular remodelling.

Invaginación intestinal como presentación atípica de enfermedad celiaca / Intestinal intussusception as an atypical presentation of celiac disease

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Role of innate immunity and altered intestinal motility in LPS- and MnCl2-induced intestinal intussusception in mice.

Intestinal intussusception (ISS) commonly causes intestinal obstruction in children. One mechanism that has been proposed to cause ISS is inflammation-induced alteration of intestinal motility. We investigated whether innate inflammatory factors or altered motility is required for induction of ISS by LPS. We compared rates of ISS among BALB/c and C57BL/6 mice, mice lacking lymphocytes or depleted of phagocytes, or mice with defects in the Toll-like receptor 4 (TLR4) signaling pathway following administration of LPS or the Ca(2+) analog MnCl2. At 6 or 2 h after administration of LPS or MnCl2, respectively, mice underwent image analysis to assess intestinal contraction rate or laparotomy to identify ISS. LPS-induced ISS (LPS-ISS) was observed in BALB/c mice, but not in C57BL/6 mice or any BALB/c mice with disruptions of TLR4 signaling. LPS-induced serum TNF-α, IL-6, and nitric oxide (NO) and intestinal NO levels were similar in BALB/c and C57BL/6 mice. The rate of LPS-ISS was significantly reduced in phagocyte-depleted, but not lymphocyte-deficient, mice. Intestinal contraction rates were reduced in LPS-ISS-susceptible BALB/c mice, but not in LPS-ISS-resistant C57BL/6 or TLR4 mutant mice, suggesting a role for reduced intestinal contraction rate in LPS-ISS susceptibility. This was tested with MnCl2, a Ca(2+) antagonist that reduced intestinal contraction rates and induced ISS, irrespective of mouse strain. Therefore, LPS-ISS is initiated by innate immune signaling that requires TLR4 and phagocytes but may be independent of TNF-α, IL-6, and NO levels. Furthermore, alteration of intestinal motility, specifically, reduced intestinal contraction rate, is a key factor in the development of ISS.

VEGF over-expression in skeletal muscle induces angiogenesis by intussusception rather than sprouting.

Therapeutic over-expression of vascular endothelial growth factor (VEGF) can be used to treat ischemic conditions. However, VEGF can induce either normal or aberrant angiogenesis depending on its dose in the microenvironment around each producing cell in vivo, which limits its clinical usefulness. The goal herein was to determine the cellular mechanisms by which physiologic and aberrant vessels are induced by over-expression of different VEGF doses in adult skeletal muscle. We took advantage of a well-characterized cell-based platform for controlled gene expression in skeletal muscle. Clonal populations of retrovirally transduced myoblasts were implanted in limb muscles of immunodeficient mice to homogeneously over-express two specific VEGF(164) levels, previously shown to induce physiologic and therapeutic or aberrant angiogenesis, respectively. Three independent and complementary methods (confocal microscopy, vascular casting and 3D-reconstruction of serial semi-thin sections) showed that, at both VEGF doses, angiogenesis took place without sprouting, but rather by intussusception, or vascular splitting. VEGF-induced endothelial proliferation without tip-cell formation caused an initial homogeneous enlargement of pre-existing microvessels, followed by the formation of intravascular transluminal pillars, hallmarks of intussusception. This was associated with increased flow and shear stress, which are potent triggers of intussusception. A similar process of enlargement without sprouting, followed by intussusception, was also induced by VEGF over-expression through a clinically relevant adenoviral gene therapy vector, without the use of transduced cells. Our findings indicate that VEGF over-expression, at doses that have been shown to induce functional benefit, induces vascular growth in skeletal muscle by intussusception rather than sprouting.

Ileocolic intussusception due to a cecal endometriosis: case report and review of literature.

UNLABELLED: Cecal endometriosis and ileocolic intussusception due to a cecal endometriosis is extremely rare. We report a case of a woman who presented an ileocecal intussusception due to a cecal endometriosis. The patient gave two months history of chronic periombilical pain requiring regular hospital admission and analgesia. The symptoms were not related to menses. A laparotomy was performed and revealed an ileocolic intussusception. The abdominal exploration did not find any endometriosis lesion. Ileocaecal resection was performed. Microscopic examination showed a cystic component, lined by a regular cylindric epithelium. Foci of endometrial tissue were observed in the cecal subserosa and muscularis mucosal, with irregular endometrial glands lined by cylindric epithelium without atypia immunostained with CK7, and characteristic endometrial stroma immunostained with CD10. Cecal endometriosis and ileocolic intussusception due to a cecal endometriosis is extremely rare. Diagnose of etiology remains challenging due to the absence of clinical and radiological specific characteristics. VIRTUAL SLIDE: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2975867306869166.

Histologic and immunohistochemical evaluation of intestinal innervation in dogs with and without intussusception.

OBJECTIVE: To assess viability of innervation in bowel segments appearing macroscopically viable from dogs with intussusception. ANIMALS: 7 dogs without gastrointestinal dysfunction that had been euthanized for reasons unrelated to the study (control dogs) and 13 dogs with intussusception that underwent enterectomy and intestinal anastomosis (affected dogs). PROCEDURES: A total of 31 samples of intestinal tissue were obtained from the control dogs; 28 samples were obtained from affected dogs during surgery. Samples were histologically and immunohistochemically prepared and subjectively scored for degree of vacuolization and staining, respectively. Other data collected included mean muscle cell density of circular and longitudinal muscular layers, ratio between areas of muscular layers, mean number of myenteric plexuses, mean ganglion cell density of myenteric plexuses, and degree of degeneration in neuronal plexuses as estimated through synaptophysin and neuron-specific enolase (NSE) immunoreactivity. RESULTS: Mean muscle cell density of longitudinal muscular layers, ratio between areas of muscular layers, and synaptophysin immunoreactivity did not differ significantly between affected and control dogs; values of all other variables did. Correlations were evident between mean ganglion cell density in myenteric plexuses and mean muscle cell density in circular muscular layers, degree of neuronal degeneration in myenteric plexuses and NSE immunoreactivity, and degree of neuronal degeneration in myenteric plexuses and mean ganglion cell density of myenteric plexuses. CONCLUSIONS AND CLINICAL RELEVANCE: Innervation may be impaired in bowel segments that appear macroscopically viable. Therefore, careful evaluation of preserved surgical margins during enterectomy and enteroanastomosis and monitoring of digestive function after surgery are important.

Association of tumor necrosis factor, interleukin-6 and cyclooxygenase pathway with lipopolysaccharide-induced intussusception.

INTRODUCTION: Many factors and mechanisms have been proposed as causes for intussusception (IN); however, the etiology remains unclear. Inflammatory mediators such as tumor necrosis factor (TNF) and interleukin-6 (IL-6), which are elevated during infectious diseases, can significantly affect gastrointestinal motility. Motility changes caused by these agents might contribute to the development of IN. The aim of this experimental study was to determine the preventive effects of indomethacin on lipopolysaccharide (LPS)-induced IN in mice and to investigate the role of TNF and IL-6 on intussusception. MATERIALS AND METHODS: Seventy-eight mice were divided into five groups. In the Control group (n=6), no procedure was done. In the Sham group (n=6), 1 ml saline, in the Indomethacin group (n=6), 10 mg/kg of indomethacin, in the LPS group (n=30), 12 mg/kg of LPS was administered intraperitoneally (IP). In the Treatment group (n=30), 10 mg/kg of indomethacin was administered IP following 12 mg/kg of LPS. All animals were laparotomized 6 hours following IP injections. The existence of IN was noted and blood specimens were obtained. TNFalpha and IL-6 plasma level measurements were performed by standard ELISA for mice. The results were compared using the Mann-Whitney U test and one-way ANOVA test. A value of p<0.05 was considered significant. RESULTS: Five mice (1 in the control, 2 in the LPS, 2 in the Treatment group) were excluded from the study. IN was observed in 6 (20%) mice in the LPS group, whereas it was not found in any mice in the Treatment group. Mean TNFalpha and IL-6 levels were statistically higher in the LPS group (394.72+/-403.79; 195.18+/-218.37 pg/ml, respectively) compared to all other groups, including the Treatment group (p<0.05 for each comparison). Within the LPS group of mice, the levels were higher in animals with IN compared to the mice without IN. CONCLUSION: Increased TNFalpha and IL-6 levels induced by LPS correlated well with the occurrence of IN, and a decrease in these levels via cyclooxygenase (COX) inhibition by indomethacin prevented IN from forming in this experimental model.

Florid vascular proliferation of the colon related to intussusception and mucosal prolapse: potential diagnostic confusion with angiosarcoma.

With the exception of angiodysplasia, vascular abnormalities of the intestines are unusual. We describe a florid benign vascular proliferation of the colon in five adult patients, three of whom presented with idiopathic intussusception. In all cases, the proliferation was sufficiently exuberant to raise the possibility of angiosarcoma as a diagnostic consideration. The group included 2 males and 3 females with a median age of 43 years. Two patients were HIV positive. Four patients presented with a colonic mass; other symptoms at presentation included abdominal pain, diarrhea, bleeding, and bowel obstruction. In all cases, a florid lobular proliferation of small vascular channels lined by plump endothelial cells extended from the submucosa through the entire thickness of the bowel wall. The endothelial cells showed minimal nuclear atypia, and mitotic figures were infrequent. The overlying mucosa showed ulceration with ischemic-type changes, and had features of mucosal prolapse. A possible underlying arteriovenous malformation was identified in two cases. All patients were alive and well at last follow-up (interval, 6 months to 5 years). The presence of intussusception or mucosal prolapse in all of the cases suggests repeated mechanical forces applied to the bowel wall as a possible etiologic factor. The role of HIV infection in the pathogenesis of these lesions remains to be determined.

Endogenous heme oxygenase/carbon monoxide system mediates lipopolysaccharide-induced intussusception in rats.

OBJECTIVES: To investigate the role of endogenous heme oxygenase (HO)/carbon monoxide (CO) system in regulating the process of intussusception (IN) induced by administration of lipopolysaccharide (LPS) in rats. METHODS: IN model of rats were induced by lipopolysaccharide. HO activity was determined by the amount of bilirubin formation which was measured with a double-beam spectrophotometer, and HbCO formation was measured by CO-oximeter. RESULTS: The results showed that LPS (10 mg/kg) caused IN in up to 40% of the rats at 6 h after each treatment of LPS. The incidence of IN were significantly increased by 50% (P < 0.05) and by 83.2% (P < 0.01) in HO substrate (heme-L-lysinate)-treated rats and in exogenous CO-treated rats, respectively; but it was sigificantly decreased by 41.8% (P < 0.05) after administration of ZnDPBG, an inhibitor of heme oxygense (HO) activity. Furthermore, LPS increased HO activity, HbCO formation cGMP content within colic smooth muscle and the plasma level of cGMP, and these parameters were significantly elevated by 62.6% (P < 0.01), 40.0% (P < 0.01), 49.3% (P < 0.05) and 38.9% (P<0.05), respectively, compared with LPS-non-IN rats. CONCLUSION: It is suggested that endogenous HO/CO system plays an important role in the process of IN induced by LPS, and inhibition of HO activity may decrease the formation of IN.

Nitric oxide synthase/nitric oxide pathway mediates intussusception pathogenesis in rats.

OBJECTIVE: To study the role of nitric oxide synthase/nitric oxide pathway in the pathophysiological process of intussusception (IN). METHODS: The IN model of rat was induced by lipopolysaccharide (LPS). The content of NOx in plasma and the NOS activity in colic smooth muscle tissues were measured. The content of cGMP was determined by radioimmunoassay. RESULTS: LPS (10 mg/kg, i.p.) induced IN in up to 40% of the rats 6 hours after treatment with LPS. The incidence of IN was significantly increased by 58.3% (P < 0.05) and by 66.8% (P < 0.01) in L-arginine (L-Arg)-treated rats (2% in drinking water) and in sodium nitroprusside (NSP)-treated rats (1 mg/kg, i.p.), respectively, but it is significantly decreased by 66.8% (P < 0.01) after administration of M-omega-nitro-L-arginine methyl ester (L-NAME, 15 mg/kg, i.p.), an inhibitor of nitric oxide synthase (NOS) activity. Furthermore, LPS increased total NOS activity, NOx production and cGMP levels in plasma or in colic smooth muscle tissues. These parameters in LPS-IN rats were significantly elevated by 38.8%, 50.7%, and 48.7% respectively (P < 0.01) compared with LPS-non-IN rats. CONCLUSION: NOS/NO pathway plays an important role in the process of IN, and inhibition of NO production may serve as a possible approach to prevent IN.

[Adenovirus and intranuclear inclusions in the appendix in children with acute intussusception]. / Adénovirus et inclusions intranucléaires dans les appendices au cours des invaginations intestinales aiguës de l'enfant.

One hundred and five appendices removed at the time of surgical reduction of intussusception in children were studied by light microscopy after routine procedures to search for aetiological factors involved in intussusception. Normal pediatric appendix specimens served as controls (n = 30). Light microscopic examination showed viral inclusions in epithelial cells in 48 of 105 appendices (45%) from the cases of intussusception. No viral inclusion was observed in controls. Immunohistochemistry performed on 21 appendices from intussusception with a monoclonal antibody against adenovirus showed intranuclear positivity in all appendices with viral inclusions. Viral inclusions seen in epithelial cells of appendices from cases of intussusception are caused by virus and in particularly by adenovirus. The etiological factors involved in intussusception without viral inclusion in appendix remain unknown.