Epithelial Barrier Function In Vivo Is Sustained Despite Gaps in Epithelial Layers

Watson, Alastair; Chu, Shaoyou; Sieck, Leah K.; Gerasimenko, Oleg Vsevolodovich; Bullen, Tim F; Campbell, Fiona; McKenna, Michael; Rose, Tracy L.; Montrose, Marshall H.

doi:10.1053/j.gastro.2005.06.015

Cited by 188 publications

(191 citation statements)

References 43 publications

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“…This may be because the villus enterocyte turnover rates in Gn pigs are slower than in conventional pigs of similar ages (30). Moreover, in mouse small intestine, shedding of enterocytes from these zones usually occurs prior to detectable cellular activation of caspase 3 or nuclear condensation (52). Data from a microarray study of mouse gene expression in intestinal epithelial cells along the crypt-villus axis supports these findings (25).…”

Section: Discussionmentioning

confidence: 88%

Pathogenesis of a Genogroup II Human Norovirus in Gnotobiotic Pigs

Cheetham

Souza

Meulia

et al. 2006

J Virol

252

264

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Human noroviruses (HuNoVs) are a major cause of foodborne gastroenteritis worldwide. Because they do not grow in cell culture and there is no animal model for HuNoVs, pathogenesis studies have been hampered. Thus, little is known about their replication strategies or induction of neutralizing antibodies.The limited information on their pathogenesis is from human volunteer studies of HuNoV infections in which villus atrophy in duodenal biopsies and presence of malabsorptive diarrhea were described (1,7,8). No information is available on lesions in other portions of the intestines of these volunteers (9). Intestinal transplant pediatric patients that were diagnosed with HuNoV infection developed secretory or osmotic diarrhea (19,20,31). These patients had prolonged diarrhea (17 to 326 days) due to immunosuppressive therapy. The detection of HuNoV RNA and the clinical symptoms remitted after reduction of the immunosuppressive therapy. Usually in exposed individuals, histologic lesions correlate with diarrhea, but in one report, lesions in volunteers who did not show clinical symptoms were described (42). There are also numerous reports of asymptomatic individuals who were infected with HuNoVs and shed virus in the feces (11, 28).Most past attempts to study these viruses in an animal model may have failed because (i) the human strains that were used were not closely related to the host animal NoV strains, (ii) sensitive detection techniques were lacking, and finally (iii) the role of histo-blood group antigen (HBGA) phenotypes in differential susceptibility of the host was unrecognized. Our goal was to adapt a HuNoV strain to replicate in the gnotobiotic (Gn) pig to develop an animal model for the study of HuNoV pathogenesis. Gnotobiotic pigs are good models for human enteric diseases (40) because pigs resemble humans in their gastrointestinal anatomy, physiology, and immune responses. The Gn pigs are immunocompetent at birth, but they lack maternal antibodies and previous or ongoing exposure to microbial agents, including caliciviruses.Recently, viral RNA genetically similar to that of human NoV GII (65 to 71% amino acid sequence identity in the capsid gene) was detected in pigs in Japan (46, 47) and Europe (22,48). In U.S. swine, our laboratory detected both viral RNA and virus particles similar to GII HuNoV (70% sequence identity in the capsid region) which were infectious for Gn pigs (50). Our approach to infect Gn pigs with a HuNoV was to use a GII strain that is closely related genetically to the identified GII porcine NoVs and that has a broad HBGA binding pattern because little information or reagents are available for pig HBGA. Additionally, we used sensitive assays and reagents including reverse transcription (RT)-PCR to detect fecal shedding, virus-like particles (VLPs) for serological assays, and antisera to these VLPs for antigen enzyme-linked immunosor-

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Section: Discussionmentioning

confidence: 88%

Pathogenesis of a Genogroup II Human Norovirus in Gnotobiotic Pigs

Cheetham

Souza

Meulia

et al. 2006

J Virol

252

264

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“…1 During normal gut homeostasis, only superficial epithelial cells undergo apoptosis, and carefully coordinated mechanisms close the gaps that are formed without impairing barrier function. 2,3 Uncontrolled excessive apoptosis of colonocytes permits the influx of antigens from the intestinal lumen, which trigger antigen-presenting cells residing in the lamina propria. Such dysregulated apoptosis throughout the complete crypt-villus axis has been observed in active lesions of patients with UC.…”

mentioning

confidence: 99%

Tauroursodeoxycholic acid inhibits experimental colitis by preventing early intestinal epithelial cell death

Laukens

Devisscher

Bossche

et al. 2014

Laboratory Investigation

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Ulcerative colitis (UC) is characterized by increased epithelial cell death and subsequent breakdown of the intestinal epithelial barrier, which perpetuates chronic intestinal inflammation. Since fecal bile acid dysmetabolism is associated with UC and tauroursodeoxycholic acid (TUDCA) has been shown to improve murine colitis, we evaluated the effect of TUDCA on intestinal epithelial cell death in a mouse model of UC-like barrier dysfunction elicited by dextran sulfate sodium (DSS). We identified the prevention of colonic caspase-3 induction, a key proapoptotic marker which was also over-activated in UC, as the earliest event resulting in a clear clinical benefit. Whereas vehicle-treated mice showed a cumulative mortality of 40%, all TUDCA-treated mice survived the DSS experiment during a 14-day follow-up period. In line with a barrier protective effect, TUDCA decreased bacterial translocation to the spleen and stimulated mucin production. Similarly, TUDCA inhibited lipopolysaccharide-induced intestinal permeability and associated enterocyte apoptosis. The anti-apoptotic effect was confirmed in vitro by a dose-dependent inhibition of both receptor-dependent (using tumor necrosis factor and Fas ligand) and receptor-independent (staurosporine) caspase-3 induction in HT29 colonic epithelial cells. These data imply that caspase-3 activation is an early marker of colitis that is prevented by TUDCA treatment. These data, together with the previously reported beneficial effect in colitis, suggest that TUDCA could be an add-on strategy to current immunosuppressive treatment of UC patients.

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“…Such gap formation seems to be part of normal epithelial regeneration, and gaps smaller or just the size of a single epithelial cell seem to be present in a large number but sealed by a yet unidentified substance to preserve epithelial barrier function [93]. In a further step, the characteristics of such gaps have been defined in healthy mice in vivo and after the induction of colitis, and subsequently have been visualized with eCLE in healthy patients [94].…”

Section: Functional Imagingmentioning

confidence: 99%

Confocal Laser Endomicroscopy: Applications in Clinical and Translational Science—A Comprehensive Review

Goetz

2012

ISRN Pathology

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Confocal laser endomicroscopy (CLE) is a novel tool in the endoscopist's armamentarium. It allows on-site histological information. The ability of gastroenterologists to interpret such microscopic information has been demonstrated in multiple studies from the upper and lower gastrointestinal tract. Recently, the field of application has expanded to provide hepatobiliary and intra-abdominal CLE imaging. CLE allows "smart," targeted biopsies and is able to guide endoscopic interventions. But CLE is also translational in its approach and permits functional imaging that significantly impacts on our understanding of gastrointestinal diseases. Molecular imaging with CLE allows detection and characterization of lesions and may even be used for prediction of response to targeted therapy. This paper provides a comprehensive review over current applications of CLE in clinical applications and translational science.

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Epithelial Barrier Function In Vivo Is Sustained Despite Gaps in Epithelial Layers

Cited by 188 publications

References 43 publications

Pathogenesis of a Genogroup II Human Norovirus in Gnotobiotic Pigs

Pathogenesis of a Genogroup II Human Norovirus in Gnotobiotic Pigs

Tauroursodeoxycholic acid inhibits experimental colitis by preventing early intestinal epithelial cell death

Confocal Laser Endomicroscopy: Applications in Clinical and Translational Science—A Comprehensive Review

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