Postinjury Vagal Nerve Stimulation Protects Against Intestinal Epithelial Barrier Breakdown

Krzyżaniak, Michael; Peterson, Carrie Y.; Loomis, William; Hageny, A.; Wolf, Paul L.; Reys, Luiz G.; Putnam, James G.; Eliceiri, Brian P.; Baird, Andrew; Bansal, Vishal; Coimbra, Raúl

doi:10.1097/ta.0b013e318216f754

Cited by 45 publications

(41 citation statements)

References 19 publications

(23 reference statements)

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“…Breakdown of the gut barrier is associated with increases in systemic inflammation, distant organ injury, and death [4,6,7,14,20]. Studies have shown that modulation of intestinal epithelial tight junction proteins, through VNS, may be a potential strategy for attenuating gut barrier failure after injury [5,6,[13][14][15].…”

Section: Discussionmentioning

confidence: 99%

“…Other studies have shown similar correlations between intestinal permeability and tight junction breakdown in vivo. In a murine model of traumatic brain injury (TBI) [20] or severe burn injury [6,7,14], Enteric Glia Protect the Intestinal Barrier PLOS ONE | www.plosone.orgincreases in intestinal barrier failure, as evidenced by increased paracellular permeability and histologic gut injury, were associated with decreased expression or altered localization of both occludin and ZO-1.…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidence suggests Vagus nerve stimulation (VNS) may modulate intestinal barrier integrity [13], through improved expression of occludin [6] and ZO-1 [14] and a reduction in phosphorylated MLC (P-MLC) [15]. However, the signaling mechanism that links the central nervous system and the intestinal epithelium remains elusive.…”

Section: Introductionmentioning

confidence: 99%

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Enteric Glia Cells Attenuate Cytomix-Induced Intestinal Epithelial Barrier Breakdown

Cheadle

Costantini

Hageny

et al. 2012

Journal of Surgical Research

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Background: Intestinal barrier failure may lead to systemic inflammation and distant organ injury in patients following severe injury. Enteric glia cells (EGCs) have been shown to play an important role in maintaining gut barrier integrity through secretion of S-Nitrosoglutathione (GSNO). We have recently shown than Vagal Nerve Stimulation (VNS) increases EGC activation, which was associated with improved gut barrier integrity. Thus, we sought to further study the mechanism by which EGCs prevent intestinal barrier breakdown utilizing an in vitro model. We postulated that EGCs, through the secretion of GSNO, would improve intestinal barrier function through improved expression and localization of intestinal tight junction proteins.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Enteric Glia Cells Attenuate Cytomix-Induced Intestinal Epithelial Barrier Breakdown

Cheadle

Costantini

Hageny

et al. 2012

Journal of Surgical Research

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“…Leaky gut syndrome is leading to the translocation of microbial products in the systemic circulation further aggravating the prognostic outcome 87. In several experimental settings, mimicking the loss of intestinal barrier activation of the cholinergic anti-inflammatory pathway has been reported to efficiently reduce both systemic inflammation, to limit loss of barrier function, and to reduce intestinal damage 88 89. Interestingly, as described above, enteral feeding with high-fat diet resulted in the activation of the cholinergic anti-inflammatory pathway reducing systemic inflammation and supporting gut barrier function in a rat model of haemorrhagic shock 21.…”

Section: Other Gi Disordersmentioning

confidence: 99%

The vagal innervation of the gut and immune homeostasis

Matteoli

Boeckxstaens

2012

Gut

214

196

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The central nervous system interacts dynamically with the immune system to modulate inflammation through humoral and neural pathways. Recently, in animal models of sepsis, the vagus nerve (VN) has been proposed to play a crucial role in the regulation of the immune response, also referred to as the cholinergic anti-inflammatory pathway. The VN, through release of acetylcholine, dampens immune cell activation by interacting with α-7 nicotinic acetylcholine receptors. Recent evidence suggests that the vagal innervation of the gastrointestinal tract also plays a major role controlling intestinal immune activation. Indeed, VN electrical stimulation potently reduces intestinal inflammation restoring intestinal homeostasis, whereas vagotomy has the reverse effect. In this review, we will discuss the current understanding concerning the mechanisms and effects involved in the cholinergic anti-inflammatory pathway in the gastrointestinal tract. Deeper investigation on this counter-regulatory neuroimmune mechanism will provide new insights in the cross-talk between the nervous and immune system leading to the identification of new therapeutic targets to treat intestinal immune disease.

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“…10,11 The ultimate target of protection is tight junction protein expression in epithelial cells and preservation of their function in the intestinal mucosal barrier.…”

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confidence: 99%

CPSI-121 pharmacologically prevents intestinal barrier dysfunction after cutaneous burn through a vagus nerve-dependent mechanism

Krzyżaniak

Ortiz-Pomales

Lopez

et al. 2012

Journal of Trauma and Acute Care Surgery

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BACKGROUND We have recently demonstrated the protective effects of electrical stimulation of the vagus nerve in prevention of gut injury after severe burn. Here we evaluate the potential for a pharmacologic agonist of the vagus nerve as an approach to regulate outcomes in preclinical models. We tested a new generation of guanylhydrazone-derived compounds, CPSI-121; a compound that may activate the parasympathetic nervous system through poorly understood mechanisms to determine whether we could prevent intestinal mucosal barrier breakdown. METHODS Male balb/c mice were subjected to a full-thickness, 30% total body surface area steam burn, and the efficacy of CPSI-121 was tested against vagus nerve stimulation (VNS) postburn at 4 hours. Surgical vagotomy was used to disrupt the neuroenteric axis and gut injury prevention was assessed. Gut barrier dysfunction was quantified by permeability to 4-kDa fluorescein isothiocyanatedextran. Gut injury was assessed by histologic evaluation. Tight junction protein expression (ZO-1 and occludin) was characterized by immunofluorescence and immunoblot. RESULTS VNS and CPSI-121 administration significantly reduced the permeability to 4-kDa fluorescein isothiocyanate-dextran and maintained normal histology compared with burn. However, abdominal vagotomy eliminated the protective effects of both VNS and CPSI-121. ZO-1 and occludin expression was similar to sham in VNS and CPSI-121-treated burn animals, but significantly altered in burn-vagotomized animals. Splenectomy did not alter the effect of CPSI-121. CONCLUSION Similar to direct electrical VNS, CPSI-121 effectively protects the intestinal mucosal barrier from breakdown after severe burn. We suggest that this could represent a noninvasive therapy to prevent end-organ dysfunction after trauma that would be administered during resuscitation.

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Postinjury Vagal Nerve Stimulation Protects Against Intestinal Epithelial Barrier Breakdown

Cited by 45 publications

References 19 publications

Enteric Glia Cells Attenuate Cytomix-Induced Intestinal Epithelial Barrier Breakdown

Enteric Glia Cells Attenuate Cytomix-Induced Intestinal Epithelial Barrier Breakdown

The vagal innervation of the gut and immune homeostasis

CPSI-121 pharmacologically prevents intestinal barrier dysfunction after cutaneous burn through a vagus nerve-dependent mechanism

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