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Carbon Monoxide-Releasing Molecule-2 Reduces Intestinal Epithelial Tight-Junction Damage and Mortality in Septic Rats.

Zhang S, Zheng S, Wang X, Shi Q, Wang X, Yuan S, Wang G, Ji Z - PLoS ONE (2015)

Bottom Line: CORM-2, but not iCORM-2, significantly reduced sepsis-induced damage of intestinal mucosa (including TJ disruption), TJ protein reduction (including zonula occludens-l (ZO-1), claudin-1 and occludin), MLC phosphorylation and proinflammatory cytokine release.The overall outcomes showed that CORM-2 suppressed sepsis-induced intestinal epithelial permeability changes and reduced mortality rate of those septic rats.Our data strongly suggest that CORM-2 could be a potential therapeutic reagent for sepsis by suppressing inflammation, restoring intestinal epithelial barrier and reducing mortality.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Zhongda Hospital, Southeast University Medical School, Nanjing, Jiangsu 210009, China.

ABSTRACT

Objective: Damage to intestinal epithelial tight junctions plays an important role in sepsis. Recently we found that Carbon Monoxide-Releasing Molecule-2 (CORM-2) is able to protect LPS-induced intestinal epithelial tight junction damage and in this study we will investigate if CORM-2 could protect intestinal epithelial tight junctions in the rat cecal ligation and puncture (CLP) model.

Materials and methods: The CLP model was generated using male Sprague-Dawley (SD) rats according to standard procedure and treated with CORM-2 or inactive CORM-2 (iCORM-2), 8 mg/kg, i.v. immediately after CLP induction and euthanized after 24h or 72h (for mortality rate only). Morphological changes were investigated using both transmission electron and confocal microscopy. The levels of important TJ proteins and phosphorylation of myosin light chain (MLC) were examined using Western blotting. Cytokines, IL-1β and TNF-α were measured using ELISA kits. The overall intestinal epithelial permeability was evaluated using FD-4 as a marker.

Results: CORM-2, but not iCORM-2, significantly reduced sepsis-induced damage of intestinal mucosa (including TJ disruption), TJ protein reduction (including zonula occludens-l (ZO-1), claudin-1 and occludin), MLC phosphorylation and proinflammatory cytokine release. The overall outcomes showed that CORM-2 suppressed sepsis-induced intestinal epithelial permeability changes and reduced mortality rate of those septic rats.

Conclusions: Our data strongly suggest that CORM-2 could be a potential therapeutic reagent for sepsis by suppressing inflammation, restoring intestinal epithelial barrier and reducing mortality.

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Related in: MedlinePlus

Tight junctions of intestinal epithelium were revealed by transmission electronic microscopy.Typical images from Sham rats (A), CLP rats (B), CLP rats treated with CORM-2 (C) or iCORM-2 (D). Black arrows indicate epithelial cell surface microvilli and white arrows indicate tight junctions. Magnification × 60000.
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pone.0145988.g002: Tight junctions of intestinal epithelium were revealed by transmission electronic microscopy.Typical images from Sham rats (A), CLP rats (B), CLP rats treated with CORM-2 (C) or iCORM-2 (D). Black arrows indicate epithelial cell surface microvilli and white arrows indicate tight junctions. Magnification × 60000.

Mentions: Since TJs play critical roles in the maintaining intestinal mucosa barrier permeability, the ultrastructural changes of intercellular TJs were examined by transmission electron microscopy. The TJs of 20 out of 40 rats, i.e. 5 rats per group were examined due to the extensive labor required for processing and examining each sample. In the sham group, the rows of epithelial cells were arranged closely, and epithelial cell surface microvilli were arranged in neat rows (Fig 2A). The TJ stand and desmosome were clear and complete, and the paracellular spaces were narrow (Fig 2A). In the CLP group, the microvilli were sparse with irregular length and arrangement (Fig 2B). The TJ stand and desmosome were obscured or had disappeared, and the paracellular spaces were wider (Fig 2B). CORM-2 treatment obviously improved CLP-induced TJ disruption (Fig 2C) with respect to structural integration and increased the closeness of intercellular connection. In contrast, no obvious improvement by iCORM-2 treatment was observed (Fig 2D). These results demonstrated that CORM-2 could reduce the TJ ultrastructure distortion induced by sepsis.


Carbon Monoxide-Releasing Molecule-2 Reduces Intestinal Epithelial Tight-Junction Damage and Mortality in Septic Rats.

Zhang S, Zheng S, Wang X, Shi Q, Wang X, Yuan S, Wang G, Ji Z - PLoS ONE (2015)

Tight junctions of intestinal epithelium were revealed by transmission electronic microscopy.Typical images from Sham rats (A), CLP rats (B), CLP rats treated with CORM-2 (C) or iCORM-2 (D). Black arrows indicate epithelial cell surface microvilli and white arrows indicate tight junctions. Magnification × 60000.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4697838&req=5

pone.0145988.g002: Tight junctions of intestinal epithelium were revealed by transmission electronic microscopy.Typical images from Sham rats (A), CLP rats (B), CLP rats treated with CORM-2 (C) or iCORM-2 (D). Black arrows indicate epithelial cell surface microvilli and white arrows indicate tight junctions. Magnification × 60000.
Mentions: Since TJs play critical roles in the maintaining intestinal mucosa barrier permeability, the ultrastructural changes of intercellular TJs were examined by transmission electron microscopy. The TJs of 20 out of 40 rats, i.e. 5 rats per group were examined due to the extensive labor required for processing and examining each sample. In the sham group, the rows of epithelial cells were arranged closely, and epithelial cell surface microvilli were arranged in neat rows (Fig 2A). The TJ stand and desmosome were clear and complete, and the paracellular spaces were narrow (Fig 2A). In the CLP group, the microvilli were sparse with irregular length and arrangement (Fig 2B). The TJ stand and desmosome were obscured or had disappeared, and the paracellular spaces were wider (Fig 2B). CORM-2 treatment obviously improved CLP-induced TJ disruption (Fig 2C) with respect to structural integration and increased the closeness of intercellular connection. In contrast, no obvious improvement by iCORM-2 treatment was observed (Fig 2D). These results demonstrated that CORM-2 could reduce the TJ ultrastructure distortion induced by sepsis.

Bottom Line: CORM-2, but not iCORM-2, significantly reduced sepsis-induced damage of intestinal mucosa (including TJ disruption), TJ protein reduction (including zonula occludens-l (ZO-1), claudin-1 and occludin), MLC phosphorylation and proinflammatory cytokine release.The overall outcomes showed that CORM-2 suppressed sepsis-induced intestinal epithelial permeability changes and reduced mortality rate of those septic rats.Our data strongly suggest that CORM-2 could be a potential therapeutic reagent for sepsis by suppressing inflammation, restoring intestinal epithelial barrier and reducing mortality.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Zhongda Hospital, Southeast University Medical School, Nanjing, Jiangsu 210009, China.

ABSTRACT

Objective: Damage to intestinal epithelial tight junctions plays an important role in sepsis. Recently we found that Carbon Monoxide-Releasing Molecule-2 (CORM-2) is able to protect LPS-induced intestinal epithelial tight junction damage and in this study we will investigate if CORM-2 could protect intestinal epithelial tight junctions in the rat cecal ligation and puncture (CLP) model.

Materials and methods: The CLP model was generated using male Sprague-Dawley (SD) rats according to standard procedure and treated with CORM-2 or inactive CORM-2 (iCORM-2), 8 mg/kg, i.v. immediately after CLP induction and euthanized after 24h or 72h (for mortality rate only). Morphological changes were investigated using both transmission electron and confocal microscopy. The levels of important TJ proteins and phosphorylation of myosin light chain (MLC) were examined using Western blotting. Cytokines, IL-1β and TNF-α were measured using ELISA kits. The overall intestinal epithelial permeability was evaluated using FD-4 as a marker.

Results: CORM-2, but not iCORM-2, significantly reduced sepsis-induced damage of intestinal mucosa (including TJ disruption), TJ protein reduction (including zonula occludens-l (ZO-1), claudin-1 and occludin), MLC phosphorylation and proinflammatory cytokine release. The overall outcomes showed that CORM-2 suppressed sepsis-induced intestinal epithelial permeability changes and reduced mortality rate of those septic rats.

Conclusions: Our data strongly suggest that CORM-2 could be a potential therapeutic reagent for sepsis by suppressing inflammation, restoring intestinal epithelial barrier and reducing mortality.

Show MeSH
Related in: MedlinePlus