Targeting α-7 Nicotinic Acetylcholine Receptor in the Enteric Nervous System

Costantini, Todd W.; Krzyżaniak, Michael; Cheadle, Gerald; Putnam, James G.; Hageny, A.; Lopez, Nicole; Eliceiri, Brian P.; Bansal, Vishal; Coimbra, Raúl

doi:10.1016/j.ajpath.2012.04.005

Cited by 101 publications

(44 citation statements)

References 62 publications

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“…Borovikova, et al demonstrated that cholinergic agonists such as acetylcholine, nicotine, and muscarine all were able to replicate the anti-inflammatory effects of VNS [30][31][32][33]. Finally, studies in our laboratory revealed that stimulation of the α-7 nicotinic cholinergic receptor by nicotine also replicated the intestinal barrier protective effects of VNS [28]. Thus, mounting evidence suggests EGCs are a logical candidate to propagate the antiinflammatory effects of VNS in the intestine through a nicotinic cholinergic signaling mechanism.…”

Section: Discussionmentioning

confidence: 59%

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: 59%

Enteric Glia Cells Attenuate Cytomix-Induced Intestinal Epithelial Barrier Breakdown

Cheadle

Costantini

Hageny

et al. 2012

Journal of Surgical Research

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“…Further researches have documented that α7nAchR could benefit ALI models by lowering alveoli-artery gradient, reducing neutrophils accumulation and pulmonary apoptosis 61-63. Additionally, maintaining the integrity of pulmonary endothelium also appeared to be the effects of α7nAchR activation 36, 64.…”

Section: The Protective Effect Of α7 Nicotinic Acetylcholine Receptormentioning

confidence: 97%

“…It has been reported that nicotine or GTS-21 utilization could significantly attenuate cognitive dysfunction following experimental TBI and improve burned mice survival by attenuating local and systemic inflammation 33, 48. And treatment with nicotine could also protect gut barrier through up-regulating the expression of occludin and ZO-1 which were proteins contributing to cellular tight junctions 36.…”

Section: The Protective Effect Of α7 Nicotinic Acetylcholine Receptormentioning

confidence: 99%

The Protective Effect of Alpha 7 Nicotinic Acetylcholine Receptor Activation on Critical Illness and Its Mechanism

Ren

Tong

et al. 2017

Int. J. Biol. Sci.

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Critical illnesses and injuries are recognized as major threats to human health, and they are usually accompanied by uncontrolled inflammation and dysfunction of immune response. The alpha 7 nicotinic acetylcholine receptor (α7nAchR), which is a primary receptor of cholinergic anti-inflammatory pathway (CAP), exhibits great benefits for critical ill conditions. It is composed of 5 identical α7 subunits that form a central pore with high permeability for calcium. This putative structure is closely associated with its functional states. Activated α7nAChR exhibits extensive anti-inflammatory and immune modulatory reactions, including lowered pro-inflammatory cytokines levels, decreased expressions of chemokines as well as adhesion molecules, and altered differentiation and activation of immune cells, which are important in maintaining immune homeostasis. Well understanding of the effects and mechanisms of α7nAChR will be of great value in exploring effective targets for treating critical diseases.

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“…Intestinal injury is thought to serve as the source of this SIRS reaction after injury, with the spread of pro-inflammatory mediators through the mesenteric lymph that drive the inflammatory response [13,14]. We have focused on the effects of severe burn injury on intestinal barrier integrity and intestinal inflammation in a murine model of 30% total body surface area burn, finding that severe burn increases intestinal permeability, causes histologic gut injury, alters the expression of intestinal tight junction proteins, and increases gut cytokine levels [4,6,7,9]. We have demonstrated that intestinal epithelial injury occurs at early time points following injury, which would require prompt intervention to alter these burn-induced changes [8].…”

Section: Introductionmentioning

confidence: 99%

Intravenous phage display identifies peptide sequences that target the burn-injured intestine

et al. 2012

Self Cite

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The injured intestine is responsible for significant morbidity and mortality after severe trauma and burn; however, targeting the intestine with therapeutics aimed at decreasing injury has proven difficult. We hypothesized that we could use intravenous phage display technology to identify peptide sequences that target the injured intestinal mucosa in a murine model, and then confirm the cross-reactivity of this peptide sequence with ex vivo human gut. Four hours following 30% TBSA burn we performed an in vivo, intravenous systemic administration of phage library containing 1012 phage in balb/c mice to biopan for gut-targeting peptides. In vivo assessment of the candidate peptide sequences identified after 4 rounds of internalization was performed by injecting 1 × 1012 copies of each selected phage clone into sham or burned animals. Internalization into the gut was assessed using quantitative polymerase chain reaction. We then incubated this gut-targeting peptide sequence with human intestine and visualized fluorescence using confocal microscopy. We identified 3 gut-targeting peptide sequences which caused collapse of the phage library (4–1: SGHQLLLNKMP, 4–5: ILANDLTAPGPR, 4–11: SFKPSGLPAQSL). Sequence 4–5 was internalized into the intestinal mucosa of burned animals 9.3-fold higher than sham animals injected with the same sequence (2.9 × 105 vs. 3.1 × 104 particles per mg tissue). Sequences 4–1 and 4–11 were both internalized into the gut, but did not demonstrate specificity for the injured mucosa. Phage sequence 4–11 demonstrated cross-reactivity with human intestine. In the future, this gut-targeting peptide sequence could serve as a platform for the delivery of biotherapeutics.

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Targeting α-7 Nicotinic Acetylcholine Receptor in the Enteric Nervous System

Cited by 101 publications

References 62 publications

Enteric Glia Cells Attenuate Cytomix-Induced Intestinal Epithelial Barrier Breakdown

Enteric Glia Cells Attenuate Cytomix-Induced Intestinal Epithelial Barrier Breakdown

The Protective Effect of Alpha 7 Nicotinic Acetylcholine Receptor Activation on Critical Illness and Its Mechanism

Intravenous phage display identifies peptide sequences that target the burn-injured intestine

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