Publications (37) View all
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Article: Epithelial Cell Extrusion Leads to Breaches in the Intestinal Epithelium.
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ABSTRACT: BACKGROUND:: Two distinct forms of intestinal epithelial cell (IEC) extrusion are described: 1 with preserved epithelial integrity and 1 that introduced breaches in the epithelial lining. In this study, we sought to determine the mechanism underlying the IEC extrusion that alters the permeability of the gut epithelium. METHODS:: IEC extrusions in polarized T84 monolayer were induced with nigericin. Epithelial permeability was assessed with transepithelial electrical resistance and movements of latex microspheres and green fluorescent protein-transfected Escherichia coli across the monolayer. In vivo IEC extrusion was modulated in wild-type and a colitic (interleukin-10 knock-out) mouse model with caspase-1 activation and inhibition. Luminal aspirates and mucosal biopsies from control patients and patients with inflammatory bowel disease were analyzed for caspase-1 and caspase-3&7 activation. RESULTS:: Caspase-1-induced IEC extrusion in T84 monolayers resulted in dose-dependent and time-dependent barrier dysfunction, reversible with caspase-1 inhibition. Moreover, the movements of microspheres and microbes across the treated epithelial monolayers were observed. Increased caspase-1-mediated IEC extrusion in interleukin-10 knock-out mice corresponded to enhanced permeation of dextran, microspheres, and translocation of E. coli compared with wild type. Caspase-1 inhibition in interleukin-10 knock-out mice resulted in a time-dependent reduction in cell extrusion and normalization of permeability to microspheres. Increased IEC extrusion in wild-type mice was induced with caspase-1 activation. In human luminal aspirates, the ratio of positively stained caspase-1 to caspase-3&7 cells were 1:1 and 2:1 in control patients and patients with inflammatory bowel disease, respectively; these observations were confirmed by cytochemical analysis of mucosal biopsies. CONCLUSIONS:: IEC extrusion mediated by caspase-1 activation contributes to altered intestinal permeability in vitro and in vivo.Inflammatory Bowel Diseases 03/2013; · 4.86 Impact Factor -
Article: Sirolimus drug-eluting, hydrogel-impregnated polypropylene mesh reduces intra-abdominal adhesion formation in a mouse model.
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ABSTRACT: Prosthetic mesh is used frequently in abdominal wall hernia reconstruction but is prone to postoperative adhesion formation. Complications resulting from intra-abdominal adhesions represent a considerable clinical and cost burden. We, herein, investigate the antiproliferative and antiadhesiogenic properties of sirolimus and hydrogel-impregnated, drug-eluting mesh to decrease such complications in a mouse model of abdominal wall hernia repair. A 1 × 1cm(2) polypropylene mesh from 1 of 3 groups (group 1, plain control; group 2, hydrogel [2% agarose]; and group 3, hydrogel + 10 mcg sirolimus) was implanted operatively into the peritoneal cavity of BALB/c mice and followed for up to 4 weeks. Adhesions were scored by percent surface area of mesh (range, 0-100%), severity (range, 0-3), and tenacity (range, 0-4). Representative samples were assessed by scanning electron microscopy. Mesh impregnated with the combination of hydrogel and sirolimus led to a significant decrease in adhesion formation. The percent surface area of adhesional attachment to mesh was decreased from 100.0 ± 0% in the plain mesh control group versus 18 ± 8% (P < .001) in the combined impregnated mesh group. Similarly, adhesion severity scores were decreased from a score of 2.9 ± 0.1 (plain mesh) versus 1.4 ± 0.1 (sirolimus/hydrogel-impregnated mesh) (P < .001). Scores for tenacity were also decreased markedly from 3.5 ± 0.2 (plain mesh) versus 1.5 ± 0.1 (sirolimus/hydrogel-impregnated mesh (P < .001). Creation of a sirolimus drug-eluting and hydrogel-impregnated polypropylene mesh resulted in marked decrease of adhesion formation in this mouse model, was well tolerated without side effects, and has potential for clinical application.Surgery 09/2011; 150(5):907-15. · 3.10 Impact Factor -
Article: Epithelial Gaps in a Rodent Model of Inflammatory Bowel Disease: A Quantitative Validation Study
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ABSTRACT: OBJECTIVES: Confocal laser endomicroscopy (CLE) is a non-invasive imaging modality of the gastrointestinal tract. Epithelial gaps in the small intestine of patients and rodents have been demonstrated using CLE. The goal of this study was to quantitatively validate the findings of epithelial gap density observed with CLE against confocal microscopy (CM) and light microscopy.Clinical and Translational Gastroenterology. 05/2011; 2(6):e3. -
Article: Small Intestinal Transplant Mucosal Necrosis Associated With Enteral Sodium Polystyrene Sulfonate Administration.
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ABSTRACT: Diarrhea is a common manifestation of disease in recipients of intestinal transplants. Sodium Polystyrene Sulfonate administration has been associated with significant bowel injury. Recognizing the diagnosis requires clinical awareness and comprehensive review of intestinal biopsies. We present an illustrative case and discussion. It is the first reported case in a pediatric intestinal transplant patient with serial intestinal biopsies documenting the evolution of disease.American Journal of Transplantation 08/2012; · 6.39 Impact Factor -
Article: Increased epithelial gaps in the small intestines of patients with inflammatory bowel disease: density matters.
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ABSTRACT: Epithelial gaps created by shedding of epithelial cells in the small intestine can be visualized by using confocal laser endomicroscopy (CLE). The density of epithelial gaps in the small bowels of patients with inflammatory bowel disease (IBD) and controls without IBD is unknown. To determine whether the epithelial gap density in patients with IBD is different from that in controls. Prospective, controlled, cohort study. A tertiary-care referral center. This study involved patients with IBD and control patients without IBD undergoing colonoscopy. Probe-based CLE (pCLE) was used to image the terminal ileum. The primary outcome of the study was gap density, defined as the total number of gaps per 1000 cells counted in adequately imaged villi by using pCLE. The pCLE images were blindly reviewed, and the number of epithelial gaps and cells were manually counted. The secondary outcomes were correlation of gap density with disease activity, location, and severity of clinical disease. There were 30 controls and 28 patients with IBD. Of the patients with IBD, 16 had Crohn's disease, and 12 had ulcerative colitis. The median epithelial gap densities for controls and patients with IBD were 18 and 61 gaps/1000 cells, respectively (P < .001). Gap density did not correlate with disease activity. Patients with ulcerative pan-colitis tended toward gap densities lower than those of patients with limited colitis (32 versus 97 gaps/1000 cells, P = .06). Patients with IBD with severe clinical disease also had lower median gap densities (37 vs 90 gaps/1000 cells, P = .04). A single-center study. The epithelial gap density was significantly increased in patients with IBD compared with controls. (Clinical trial registration number: NCT00988273.).Gastrointestinal endoscopy 03/2011; 73(6):1174-80. · 6.71 Impact Factor
