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P Blennerhassett

Publications and source records attributed to P Blennerhassett.

11 recordsLinked to original sources
PubMed2005

Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice.

BACKGROUND AND AIMS: Abdominal pain and discomfort are common symptoms in functional disorders and are attributed to visceral hypersensitivity. These symptoms fluctuate over time but the basis for this is unknown. Here we examine the impact of changes in gut flora and gut inflammatory cell activity on visceral sensitivity. METHODS: Visceral sensitivity to colorectal distension (CRD) was assessed at intervals in healthy mice for up to 12 weeks, and in mice before and after administration of dexamethasone or non-absorbable antibiotics with or without supplementation with Lactobacillus paracasei (NCC2461). Tissue was obtained for measurement of myeloperoxidase activity (MPO), histology, microbiota analysis, and substance P (SP) immunolabelling. RESULTS: Visceral hypersensitivity developed over time in healthy mice maintained without sterile precautions. This was accompanied by a small increase in MPO activity. Dexamethasone treatment normalised MPO and CRD responses. Antibiotic treatment perturbed gut flora, increased MPO and SP immunoreactivity in the colon, and produced visceral hypersensitivity. Administration of Lactobacillus paracasei in spent culture medium normalised visceral sensitivity and SP immunolabelling, but not intestinal microbiota counts. CONCLUSION: Perturbations in gut flora and in inflammatory cell activity alter sensory neurotransmitter content in the colon, and result in altered visceral perception. Changes in gut flora may be a basis for the variability of abdominal symptoms observed in functional gastrointestinal disorders and may be prevented by specific probiotic administration.

Abdominal Pain↗
PubMed2001

Role of immunologic factors and cyclooxygenase 2 in persistent postinfective enteric muscle dysfunction in mice.

BACKGROUND & AIMS: Chronic abdominal symptoms develop in some patients after acute enteric infection. This study examined mechanisms underlying smooth muscle hypercontractility that persists after acute infection in mice. METHODS: Euthymic and athymic National Institutes of Health (NIH) Swiss mice were infected with Trichinella spiralis and studied 4 weeks postinfection (PI). Isometric tension was assessed in longitudinal muscle. Cytokine and cyclooxygenase (COX)-2 messenger RNA was determined in the muscularis externa by reverse-transcription polymerase chain reaction. COX-2 protein was identified by immunohistochemistry and prostaglandin E(2) was measured by enzymatic immunoassay. Studies were performed in euthymic and athymic NIH Swiss mice 28 days PI and in the presence or absence of treatment with corticosteroid or COX inhibitors. RESULTS: Muscle hypercontractility was evident in euthymic mice but was attenuated in athymic mice or in steroid-treated euthymic mice 28 days PI. Expression of Th2 cytokines interleukins 4, 5, and 13 was increased during the acute infection but not thereafter. COX-2 was localized to muscle and its enzymatic activity remained significantly increased in the muscle on day 28 PI. Selective COX-2 inhibition in vitro reduced the sustained increase in tension generation. CONCLUSIONS: These findings show that COX-2 activation in resident cells of the muscularis externa contributes to the muscle hypercontractility that persists after infection.

Adrenal Cortex Hormones↗
PubMed2001

Intestinal inflammation and activation of sensory nerve pathways: a functional and morphological study in the nematode infected rat.

BACKGROUND: In the rat, gastric distension elicits an intensity dependent pseudoaffective bradycardia mediated via capsaicin sensitive afferent and cholinergic efferent vagal pathways. Inflammation alters visceral perception although the mediators responsible have not been identified. In the nematode infected rat, there is a substantial increase in neuronal substance P (SP) content of the gut. AIMS: To examine the effects of inflammation on perception of a noxious visceral stimulus and on SP and neurokinin 1 (NK-1) receptor immunoreactivity (IR) in visceral afferent pathways. METHODS: Immunohistochemistry was performed on sections from the jejunum, dorsal root ganglia (DRG), and spinal cord (T1-L1) using SP and NK-1 rabbit polyclonal antibodies. In the DRG, the number of SP-IR or NK-1-IR neurones per section was visually quantified. The pseudoaffective cardiac reflex response to gastric stimulation was compared in control and Trichinella spiralis infected rats. RESULTS: Intestinal inflammation induced a rightward shift in the intensity dependent bradycardic response to gastric distension. This was associated with a marked increase in SP-IR not only in the gut wall but also in the DRG and dorsal horn of the spine. In contrast, NK-1-IR was not increased in the gut wall. Moreover, inflammation evoked a decrease in NK-1-IR in the dorsal horn. No NK-1-IR was identified in the DRG of either control or infected animals. CONCLUSIONS: Intestinal inflammation modulates the capsaicin sensitive pseudoaffective autonomic response to gastric distension, increases SP-IR in afferent pathways, and downregulates dorsal horn NK-1-IR. As the pseudoaffective response is capsaicin sensitive, the rightward shift of the response is likely the consequence of the decrease in NK-1 receptors in the sensory pathways.

Animals↗
PubMed1995

Mucosal permeability after subclinical intestinal ischemia-reperfusion injury: an exploration of possible mechanisms.

Changes in mucosal permeability may be important in the etiology of necrotizing enterocolitis. The authors have previously shown that subclinical ischemia-reperfusion injury results in increased permeability in the rat intestine, and have partially characterized this phenomenon. In the present study the authors attempt to determine the mechanism by which these changes occur. Six-week-old rats underwent 10-minute superior mesenteric artery occlusion (SMAO) or sham, and mucosal permeability to 51CrEDTA was measured after 30 minutes. Rats were pretreated with saline, inhibitors of oxygen free radicals (superoxide dismutase+catalase, vitamin E, allopurinol, alpha-phenyl-N-tert butyl-nitrone), inhibitors of eicosanoids (indomethacin, quinacrine, diethylcarbamazine, 13-azaprostanoic acid), the putative cytoprotective agent prostaglandin E2, or the inhibitor of neutrophil free radical production fructose 1-6 diphosphate. None of the agents significantly attenuated the increase in mucosal permeability caused by SMAO, although indomethacin and prostaglandin E2 significantly exacerbated the permeability changes. To further explore the role of neutrophils, tissue myeloperoxidase was measured 30 minutes after SMAO. There was no significant difference in myeloperoxidase levels between sham and SMAO animals. These data suggest that the early increase in mucosal permeability after subclinical ischemia-reperfusion injury is not mediated by oxygen free radicals, eicosanoids, or neutrophils. The deleterious effect of indomethacin and prostaglandin E2 suggests a possible protective role for the cyclooxygenase system, but further studies are necessary to elucidate this possibility.

Animals↗
PubMed1993

Human recombinant interleukin 1 beta suppresses acetylcholine release from rat myenteric plexus.

BACKGROUND: A marked suppression of acetylcholine (ACh) release from myenteric nerves in the inflamed intestine of rats infected by Trichinella spiralis has been shown. In this model, there is increased expression of interleukin 1 beta (IL-1 beta) in the myenteric plexus. Therefore, the ability of IL-1 beta to alter ACh release in longitudinal muscle-myenteric plexus (LMMP) preparations from noninfected rats was examined. METHODS: LMMP preparations were loaded with [3H]choline before stimulation by KCl or electrical field stimulation. ACh release was recorded by measuring 3H in the superfusate. Experiments were performed in the presence or absence of human recombinant IL-1 beta. RESULTS: IL-1 beta had no immediate effect on the basal or stimulated release of ACh. A marked suppression of ACh release was observed in tissues that had been preincubated with IL-1 beta for 60 minutes or more. The effect of IL-1 beta was concentration and time dependent with maximum suppression occurring with 10 ng/mL of the cytokine after a 90-minute incubation. The action of human recombinant (hr) IL-1 beta was abolished by boiling the cytokine for 20 minutes and was prevented by preincubating the cytokine with neutralizing antibody. The IL-1 beta effect was also blocked by cycloheximide and was spontaneously reversible after 60 minutes. CONCLUSION: It was concluded that IL-1 beta suppresses ACh release via the formation and release of a protein mediator that could be another cytokine, including IL-1. Based on these findings, we consider IL-1 beta a putative mediator of the changes in cholinergic nerve function observed in the inflamed rat intestine.

Acetylcholine↗
PubMed1992

Increased levels of substance P in the myenteric plexus of Trichinella-infected rats.

Changes in immunoreactive substance P concentrations were investigated in longitudinal muscle-myenteric plexus preparations from the inflamed jejunum of Trichinella spiralis-infected rats. The substance P concentration increased within 2 days of infection and increased fivefold by day 6; in contrast, there was no significant increase in substance P in the noninflamed ileum. In vitro exposure of preparations from infected rats to scorpion venom reduced substance P levels by 88%. In addition, no increase in substance P was observed in rats that had been treated with capsaicin as neonates or as adults before infection. Treatment of infected rats with betamethasone attenuated the inflammatory response to the infection and prevented the increase in substance P. Furthermore, no significant increase in substance P concentration was seen in congenitally athymic rats infected with T. spiralis. This study is consistent with the hypothesis that inflammation increases substance P in myenteric nerves by a process that involves T lymphocytes.

Animals↗
PubMed1992

Effect of inflammation of enteric nerves. Cytokine-induced changes in neurotransmitter content and release.

The results of our previously published work provide evidence of inflammation-induced functional disturbances in the enteric nervous system. Data presented in this paper describe our preliminary results indicating that the altered function in enteric nerves in the nematode-infected rat model of intestinal inflammation is mediated by interleukin-1. This is based on the ability of the exogenous cytokine to mimic changes observed in the model, and on the ability of a specific IL-1 antagonist to attenuate these changes. In addition, we have identified mechanisms underlying the actions of IL-1 in the myenteric plexus. Our data are consistent with a direct interaction between the cytokine and neural membranes. In addition, the delayed effect of IL-1 beta on neurotransmitter release appears to be due to the release of endogenous IL-1, most likely from macrophage-like cells in the myenteric plexus (Fig. 3). If such cells possess receptors for neuropeptides, as has been found with macrophages elsewhere in the gut, a neuroimmune axis would exist in the myenteric plexus. Thus, the finding of a source of IL-1 in the plexus of the noninflamed intestine invites speculation on a neuromodulatory role of the cytokine within the enteric nervous system.

Animals↗
PubMed1992

Distribution of mast cells in intestinal muscle of nematode-sensitized rats.

We examined the distribution and functional integrity of mast cells in intestinal longitudinal muscle in rats sensitized by two previous infections with Trichinella spiralis. A segment of jejunum was excluded from the gut before infection, and the remainder of the gut was anastomosed. Few mast cells were seen in muscle of noninfected control rats except in the region of the jejunal anastomosis. In rats sensitized by T. spiralis infection, mast cells were increased in number in the jejunum and the number of mast cells followed an aboral gradient down the entire length of the gut in continuity. In addition, mast cells were present in muscle of the excluded segment of sensitized rats. All mast cells were stained red with safranin. Functional integrity was assessed by the ability of mast cells to induce contraction after degranulation by antigen. In muscle from sensitized rats, contraction was induced in each region after exposure to T. spiralis antigen but not Nippostrongylus brasiliensis antigen. Contraction was inhibited by the mast cell stabilizer doxantrazole and the 5-hydroxytryptamine (5-HT) antagonist cyproheptadine. When antigen-induced contraction was expressed as a percentage of the maximum response of the tissue to exogenous 5-HT, the magnitude of contraction decreased along an aboral gradient down the intestine and correlated well (r2 = 0.878) with mast cell numbers. These results suggest that the increase in connective tissue mast cells in gut muscle after T. spiralis infection involves both local and systemic mechanisms.

Animals↗
PubMed1992

Impaired acetylcholine release in the inflamed rat intestine is T cell independent.

We investigated mechanisms underlying the suppression of [3H]acetylcholine ([3H]ACh) release from myenteric plexus-longitudinal muscle preparations of rats infected 6 days previously with Trichinella spiralis. There was a 73% suppression of KCl-evoked release of [3H]ACh in the jejunum, and a 76% suppression was observed in the worm-free ileum, indicating that the local presence of the parasite in the lumen is not prerequisite for the suppression of ACh release from the myenteric plexus. Treatment of rats with betamethasone (3 mg.kg-1.day-1 ip) during the infection prevented the acute inflammatory response and attenuated the suppression of [3H]-ACh release (from 73 to 22%) in the jejunum of infected rats. This finding is consistent with the hypothesis that the suppression of ACh release occurs as a result of the inflammatory process. Marked suppression of [3H]ACh release was also seen in T. spiralis-infected nude athymic rats, which were shown to lack functioning T lymphocytes. Thus changes in ACh release are not dependent on T lymphocytes. Taken in conjunction with our previously published study showing that altered muscle function in this model is T cell dependent, the results of the present study indicate that different components of the inflammatory response mediate changes in smooth muscle and myenteric nerves in the T.spiralis infected rat.

Acetylcholine↗
PubMed1990

Altered smooth muscle function in worm-free gut regions of Trichinella-infected rats.

We have extended a recent study demonstrating increased contractility of jejunal smooth muscle of rats infected with the nematode parasite Trichinella spiralis, the primary habitat of which is the jejunum. In this study, muscle from the worm-free ileum of infected rats showed decreased contractility compared with control, illustrating regional differences in muscle responses to the infection. However, in jejunal muscle from worm-free segments that had been excluded from the rest of the gut before the infection, we observed increased tension generation, suggesting a systemic mechanism. To evaluate whether the changes in jejunal muscle were due to the host's inflammatory reaction, the effect of beta-methasone was examined. In a dose of 3.0 mg/kg sc daily, the steroid abolished the increase in myeloperoxidase activity associated with the infection and attenuated the increased tension generation in jejunal muscle from Trichinella-infected rats. These results support the hypothesis that alterations in intestinal smooth muscle function in this model do not require the presence of the parasite in the lumen and are mediated by the host's inflammatory reaction.

Animals↗