Disruption of tight junctions during polymicrobial sepsis <i>in vivo</i>

Li, Qiurong; Zhang, Qiang; Wang, Chenyang; Liu, Xiaoxiang; Li, Ning; Li, Jieshou

doi:10.1002/path.2525

Cited by 95 publications

(77 citation statements)

References 28 publications

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“…Our results are in line with studies in mouse sepsis models, which also show marked reductions in occludin and claudin 5 levels (36,37). Studies in septic mice have also shown decreased ZO-1 expression and disorganized patterning with greater fragmentation, similar to our findings in the zebrafish sepsis model (38).…”

Section: Discussionsupporting

confidence: 82%

“…Studies in septic mice have also shown decreased ZO-1 expression and disorganized patterning with greater fragmentation, similar to our findings in the zebrafish sepsis model (38). We also saw upregulation of claudin 2 expression, pore forming tight junction protein, known to be markedly upregulated in mouse polymicrobial sepsis models (37). Interestingly, we did not detect any significant differences in VE cadherin expression, though this AJ protein is widely implicated in regulating endothelial integrity and permeability.…”

Section: Discussionsupporting

confidence: 77%

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Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Philip

Wang

Mauro

et al. 2017

Mol Med

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Sepsis is a leading cause of death worldwide. Current treatment modalities remain largely supportive. Intervention strategies focused on inhibiting specific mediators of the inflammatory host response have been largely unsuccessful, a consequence of an inadequate understanding of the complexity and heterogeneity of the innate immune response. Moreover, the conventional drug-development pipeline is time-consuming and expensive, and the low success rates associated with cell-based screens underline the need for whole-organism screening strategies, especially for complex pathological processes. Here, we established a lipopolysaccharide (LPS)-induced zebrafish endotoxemia model, which exhibits the major hallmarks of human sepsis, including edema and tissue/organ damage, increased vascular permeability and vascular leakage accompanied by altered expression of cellular junction proteins, increased cytokine expression, immune cell activation and reactive oxygen species (ROS) production, reduced circulation and increased platelet aggregation. We tested the suitability of the model for phenotype-based drug screening using three primary readouts: mortality, vascular leakage and ROS production. Preliminary screening identified fasudil, a drug known to protect against vascular leakage in murine models, as a lead hit, thereby validating the utility of our model for sepsis drug screens. This zebrafish sepsis model has the potential to rapidly analyze sepsis-associated pathologies and cellular processes in the whole organism, as well as to screen and validate many compounds that can modify sepsis pathology in vivo.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 77%

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Philip

Wang

Mauro

et al. 2017

Mol Med

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“…A decrease in TER may be induced by claudin-1 disruption or downregulation (44). Claudin-1 has been shown to be aberrantly localized in response to infection by a variety of pathogens (13,21,44). We observed that monolayers infected with EAEC 042 or JM221 caused a dissociation of claudin-1 from the tight junctions (Fig.…”

Section: Vol 78 2010 Eaec Disrupts Epithelial Cell Tight Junctions mentioning

confidence: 59%

Enteroaggregative Escherichia coli Disrupts Epithelial Cell Tight Junctions

et al. 2010

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Enteroaggregative Escherichia coli (EAEC) is responsible for inflammatory diarrhea in diverse populations, but its mechanisms of pathogenesis have not been fully elucidated. We have used a previously characterized polarized intestinal T84 cell model to investigate the effects of infection with EAEC strain 042 on tight junction integrity. We find that infection with strain 042 induces a decrease in transepithelial electrical resistance (TER) compared to uninfected controls and to cells infected with commensal E. coli strain HS. When the infection was limited after 3 h by washing and application of gentamicin, we observed that the TER of EAEC-infected monolayers continued to decline, and they remained low even as long as 48 h after the infection. Cells infected with the afimbrial mutant strain 042aafA exhibited TER measurements similar to those seen in uninfected monolayers, implicating the aggregative adherence fimbriae II (AAF/II) as necessary for barrier dysfunction. Infection with wild-type strain 042 induced aberrant localization of the tight junction proteins claudin-1 and, to a lesser degree, occludin. EAEC-infected T84 cells exhibited irregular shapes, and some cells became elongated and/or enlarged; these effects were not observed after infection with commensal E. coli strain HS or 042aafA. The effects on tight junctions were also observed with AAF/I-producing strain JM221, and an afimbrial mutant was similarly deficient in inducing barrier dysfunction. Our results show that EAEC induces epithelial barrier dysfunction in vitro and implicates the AAF adhesins in this phenotype.

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“…Tight junctions are part of specialized lipid raft-like membrane microdomains (Nusrat et al, 2000). It was recently shown that sepsis causes redistribution of tight junctions in membrane microdomains and that this redistribution is responsible for increased permeability (Li et al, 2009). Mucosal scrapings from the ileum were homogenized and separated by ultracentrifugation.…”

Section: Mmp13 Contributes To Tight Junction Destabilizationmentioning

confidence: 99%

Bacteroides uniformis CECT 7771 Ameliorates Metabolic and Immunological Dysfunction in Mice with High-Fat-Diet Induced Obesity

2014

Health and the Gut

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Several pathological processes, such as sepsis and inflammatory bowel disease (IBD), are associated with impairment of intestinal epithelial barrier. Here, we investigated the role of matrix metalloproteinase MMP13 in these diseases. We observed that MMP13 À/À mice display a strong protection in LPS-and caecal ligation and puncture-induced sepsis. We could attribute this protection to reduced LPS-induced goblet cell depletion, endoplasmic reticulum stress, permeability and tight junction destabilization in the gut of MMP13 À/À mice compared to MMP13 þ/þ mice. Both in vitro and in vivo, we found that MMP13 is able to cleave pro-TNF into bioactive TNF. By LC-MS/MS, we identified three MMP13 cleavage sites, which proves that MMP13 is an alternative TNF sheddase next to the TNF converting enzyme TACE. Similarly, we found that the same mechanism was responsible for the observed protection of the MMP13mice in a mouse model of DSS-induced colitis. We identified MMP13 as an important mediator in sepsis and IBD via the shedding of TNF. Hence, we propose MMP13 as a novel drug target for diseases in which damage to the gut is essential.

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Disruption of tight junctions during polymicrobial sepsis in vivo

Cited by 95 publications

References 28 publications

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Enteroaggregative Escherichia coli Disrupts Epithelial Cell Tight Junctions

Bacteroides uniformis CECT 7771 Ameliorates Metabolic and Immunological Dysfunction in Mice with High-Fat-Diet Induced Obesity

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