PubMed Health⌕ Search

Biomedical subjects

Stephen M Collins

Publications and source records attributed to Stephen M Collins.

29 records · Page 2Linked to original sources
PubMed2004

Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome.

BACKGROUND & AIMS: The mechanisms underlying abdominal pain perception in irritable bowel syndrome (IBS) are poorly understood. Intestinal mast cell infiltration may perturb nerve function leading to symptom perception. We assessed colonic mast cell infiltration, mediator release, and spatial interactions with mucosal innervation and their correlation with abdominal pain in IBS patients. METHODS: IBS patients were diagnosed according to Rome II criteria and abdominal pain quantified according to a validated questionnaire. Colonic mucosal mast cells were identified immunohistochemically and quantified with a computer-assisted counting method. Mast cell tryptase and histamine release were analyzed immunoenzymatically. Intestinal nerve to mast cell distance was assessed with electron microscopy. RESULTS: Thirty-four out of 44 IBS patients (77%) showed an increased area of mucosa occupied by mast cells as compared with controls (9.2% +/- 2.5% vs. 3.3 +/- 0.8%, respectively; P < 0.001). There was a 150% increase in the number of degranulating mast cells (4.76 +/- 3.18/field vs. 2.42 +/- 2.26/field, respectively; P = 0.026). Mucosal content of tryptase was increased in IBS and mast cells spontaneously released more tryptase (3.22 +/- 3.48 pmol/min/mg vs. 0.87 +/- 0.65 pmol/min/mg, respectively; P = 0.015) and histamine (339.7 +/- 59.0 ng/g vs. 169.3 +/- 130.6 ng/g, respectively; P = 0.015). Mast cells located within 5 microm of nerve fibers were 7.14 +/- 3.87/field vs. 2.27 +/- 1.63/field in IBS vs. controls (P < 0.001). Only mast cells in close proximity to nerves were significantly correlated with severity and frequency of abdominal pain/discomfort (P < 0.001 and P = 0.003, respectively). CONCLUSIONS: Colonic mast cell infiltration and mediator release in proximity to mucosal innervation may contribute to abdominal pain perception in IBS patients.

Abdominal Pain↗
PubMed2004

Visceral hyperalgesia and intestinal dysmotility in a mouse model of postinfective gut dysfunction.

BACKGROUND & AIMS: We established the concept that transient enteric infection may lead to persistent gut dysfunction, evident in vitro, in nematode-infected mice. The present study determined whether gut dysfunction in this model involves motor and sensory changes reminiscent of changes found in patients with postinfective irritable bowel syndrome (PI-IBS) and investigated underlying mechanisms. METHODS: Mice infected up to 70 days previously with Trichinella spiralis (Tsp) underwent videofluoroscopy with image analysis to assess upper gastrointestinal motility. Pseudoaffective responses to colorectal distention (CRD) were assessed using a barostat and validated by single fiber recordings from spinal nerves during CRD. Tissues were examined at different time points for histology, immunohistochemistry, and cytokine analysis. Some mice received dexamethasone intraperitoneally on days 23-25 PI or Tsp antigen orally on days 29, 43, and 57 PI. RESULTS: From day 28 PI, no discernible inflammation was present in the gut. Frequency and propagation velocity of intestinal contractions decreased, and retroperistalsis increased at days 28 to 42 PI. CRD induced an allodynic and hyperalgesic response in PI mice, which was accompanied by increased single unit discharge. Gavage of Tsp antigen induced T-cell responses and sustained gut dysfunction for 70 days PI. Administration of dexamethasone postinfection normalized dysmotility and visceral hyperalgesia. CONCLUSIONS: Long-lasting gut dysmotility and hyperalgesia develop in mice after transient intestinal inflammation. These changes are maintained by luminal exposure to antigen and reversed by corticosteroid treatment. The findings prompt consideration of this as a model of PI-IBS.

Animals↗
PubMed2004

Lactobacillus paracasei normalizes muscle hypercontractility in a murine model of postinfective gut dysfunction.

BACKGROUND & AIMS: The effects of probiotics on gut dysfunction in postinfective irritable bowel syndrome are unknown. We tested whether probiotics influence persistent muscle hypercontractility in mice after recovery from infection with Trichinella spiralis and analyzed the underlying mechanisms. METHODS: Mice were gavaged with Lactobacillus paracasei, Lactobacillus johnsonii, Bifidobacterium longum, or Bifidobacterium lactis in spent culture medium from days 10 to 21 after infection. Additional mice received heat-inactivated Lactobacillus paracasei, Lactobacillus paracasei -free spent culture medium, or heat-inactivated Lactobacillus paracasei -free spent culture medium. Lactobacilli enumeration, immunohistochemistry, and cytokine detection (enzyme-linked immunosorbent assay) were performed. Mice were also treated with Lactobacillus paracasei or Lactobacillus paracasei -free spent culture medium from days 18 to 28 after infection. Contractility was measured on days 21 and 28 after infection. RESULTS: Lactobacillus paracasei, but not Lactobacillus johnsonii, Bifidobacterium lactis, or Bifidobacterium longum, attenuated muscle hypercontractility. This was associated with a reduction in the Trichinella spiralis -associated T-helper 2 response and a reduction in transforming growth factor-beta1, cyclooxygenase-2, and prostaglandin E 2 levels in muscle. Attenuation of muscle hypercontractility by Lactobacillus paracasei -free spent culture medium was abolished after heat treatment. Improvement of muscle hypercontractility at day 28 after infection was also observed after the administration of Lactobacillus paracasei or Lactobacillus paracasei -free spent culture medium from day 18 after infection. CONCLUSIONS: Probiotics show strain-dependent attenuation of muscle hypercontractility in an animal model of postinfective irritable bowel syndrome. This likely occurs via both a modulation of the immunologic response to infection and a direct effect of Lactobacillus paracasei or a heat-labile metabolite on postinfective muscle hypercontractility. Lactobacillus paracasei may be useful in the treatment of postinfective irritable bowel syndrome.

Animals↗
PubMed2003

The establishment of a national tissue bank for inflammatory bowel disease research in Canada.

The Crohn's and Colitis Foundation of Canada (CCFC) has established a national bank for tissue, serum and blood from patients with inflammatory bowel disease (IBD). Investigators from across the country submit material to the bank together with clinical data. Investigators may access their own patient information from the bank for their own study purposes, but the distribution of tissue is restricted to specific CCFC-funded projects. Currently, tissues are being collected from newly diagnosed, untreated IBD patients to support a recent initiative aimed at characterizing microbes in colonic and ileal biopsies from such patients. In the future, criteria for the submission of tissue will be tailored to specific research questions. This bank is believed to be the first national bank of its kind dedicated to research in Crohn's disease and ulcerative colitis

Canada↗
PubMed2002

Pathology of interstitial cells of Cajal in relation to inflammation revealed by ultrastructure but not immunohistochemistry.

The role of interstitial cells of Cajal associated with Auerbach's plexus (ICC-AP) in the pathophysiology of inflammation-induced abnormalities in gut motor activity is poorly understood. Therefore we applied a well-described model of inflammation (infection by Trichinella spiralis) to the mouse small intestine where the structure and function of ICC-AP are best known. Electron microscopic evaluation revealed that 1 to 3 days after infection, selective and patchy damage to the ICC processes occurred, thereby disrupting contacts between these ICC and smooth muscle cells as well as ICC and nerves, which was associated with disordered electrical activity and abnormal peristalsis. Ten to 15 days after infection, damage to ICC-AP was maximal and now involving the cell body and major processes. Marked synthetic activity and regrowth of their processes occurred from day 3 onward and recovery was completed at day 40 after infection. No changes to the network of ICC-AP were seen with c-Kit immunohistochemistry. From day 1 after infection, macrophages infiltrated the AP area, making close contact including peg-and-socket-like junctions with smooth muscle cells and ICC-AP but up to day 6 after infection without any sign of phagocytosis. By day 6 after infection, lymphocytes entered the musculature forming close contacts with ICC-AP. This was not associated with damage to ICC-AP but with proliferation of rough endoplasmic reticulum. From day 23 onward, immune cells withdrew from the musculature except macrophages, resulting in a markedly increased population of macrophages in the AP area at day 60 after infection.

Animals↗
PubMed2002

Evolving pathophysiologic models of functional gastrointestinal disorders.

In contrast to most other disorders of the digestive system, functional disorders of the gut continue to be defined by symptom criteria rather than by biological markers. At the same time, animal models of functional gastrointestinal disorders in which to test pathophysiologic hypotheses are lacking. The aim of this report is to critically review recently proposed conceptual as well as animal models of functional gastrointestinal disorders. Converging disease models have been proposed that postulate an enhanced responsiveness of neural, immune, or neuroimmune circuits in the central nervous system or in the gut to exteroceptive (psychosocial) or interoceptive (tissue irritation, inflammation, infection) perturbations of the organism's homeostasis. The enhanced responsiveness results in dysregulation of gut motility, epithelial function (immune, permeability), and visceral hypersensitivity, which in turn produce irritable bowel syndrome symptoms. These conceptual models provide plausible mechanisms for irritable bowel syndrome symptom generation and are consistent with extensive epidemiologic and pathophysiologic data. Several animal models have recently been proposed that mimic key features of these conceptual disease models. They fall into models triggered by centrally targeted stimuli (neonatal stress, post-traumatic stress disorder) or those triggered by peripherally targeted stimuli (infection, inflammation). Depending on the timing of the trigger (neonatal vs. adult), the changes induced in the animal may be permanent or transient. Future development of existing and novel models involves the use of transgenic and knockout animals, as well as the demonstration of predictive validity in terms of responsiveness to candidate drugs.

Animals↗
PubMed2002

Immune-mediated neural dysfunction in a murine model of chronic Helicobacter pylori infection.

BACKGROUND & AIMS: Neuromuscular changes producing dysmotility and hyperalgesia may underlie symptom generation in functional gastrointestinal disorders. We investigated whether chronic Helicobacter pylori-induced gastritis causes neuromuscular dysfunction. METHODS: In vitro muscle contractility and acetylcholine release were evaluated in mice before and after H. pylori eradication. H. pylori colonization and gastritis were graded histologically. Substance P (SP)-, vasoactive intestinal polypeptide (VIP)-, and calcitonin gene-related peptide (CGRP) immunoreactivity (IR) and macrophages were studied by immunohistochemistry. RESULTS: In Balb/c mice, chronic H. pylori infection did not affect muscle function but augmented antral relaxation after nerve electric field stimulation. Infected mice had lower acetylcholine release by electric field stimulation and had higher density of SP-, CGRP-, and VIP-IR nerves in the stomach and of SP- and CGRP-IR in the spinal cord. Cholinergic nerve dysfunction worsened progressively and was associated with increasing macrophage and mononuclear but not polymorphonuclear infiltrate or bacterial colonization. SCID mice had unchanged acetylcholine release despite high H. pylori colonization and macrophage infiltration. Eradication of H. pylori normalized functional and morphologic abnormalities except for increased density of gastric SP- and CGRP-IR nerves. CONCLUSIONS: H. pylori infection induces functional and morphologic changes in the gastric neural circuitry that are progressive and lymphocyte dependent, and some persist after H. pylori eradication. The data have direct implications regarding the role of H. pylori infection in functional dyspepsia.

Acetylcholine↗
PubMed2002

Modulatory effects of estrogen in two murine models of experimental colitis.

The association between oral contraceptives or pregnancy and inflammatory bowel disease is unclear. We investigated whether 17beta-estradiol modulates intestinal inflammation in two models of colitis. Female mice were treated with 17beta-estradiol alone or with tamoxifen, tamoxifen alone, 17 alpha-estradiol, or placebo. Dinitrobenzene sulfonic acid (DNB)- or dextran sodium sulfate (DSS)-induced colitis were assessed macroscopically, histologically, and by myeloperoxidase (MPO) activity. Malondialdehyde and mRNA levels of intercellular adhesion molecule-1 (ICAM-1), interferon-gamma (IFN-gamma), and interleukin-13 (IL-13) were determined. In DNB colitis, 17beta-estradiol alone, but not 17beta-estradiol plus tamoxifen, or 17 alpha-estradiol reduced macroscopic and histological scores, MPO activity and malondialdehyde levels. 17beta-Estradiol also decreased the expression of ICAM-1, IFN-gamma, and IL-13 mRNA levels compared with placebo. In contrast, 17beta-Estradiol increased the macroscopic and histological scores compared with placebo in mice with DSS colitis. These results demonstrate anti-inflammatory and proinflammatory effects of 17beta-estradiol in two different models of experimental colitis. The net modulatory effect most likely reflects a combination of estrogen receptor-mediated effects and antioxidant activity and may explain, in part, conflicting results from clinical trials.

Animals↗
PubMed2002

Role of IL-4, IL-13, and STAT6 in inflammation-induced hypercontractility of murine smooth muscle cells.

T helper 2 (Th2) cytokines interleukin (IL)-4 and IL-13, which activate signal transducer and activator of transcription 6 (STAT6) are expressed in the muscularis externa during nematode infection and are candidate mediators of the associated hypercontractility. To determine the locus of action of these cytokines, we examined the IL-4- and IL-13-induced hypercontractility of the isolated muscle cells from STAT6 +/+ and STAT6 -/- mice. We compared the results with cells isolated from Trichinella spiralis-infected STAT6 +/+ and STAT6 -/- mice. Carbamylcholine chloride (Carbachol) induced the contraction of jejunal muscle cells in a concentration-dependent manner maximal contraction (R(max) 26.7 +/- 1.9%). Cells from T. spiralis-infected STAT6 -/- mice showed the hypertrophy (cell lengths 41.4 +/- 0.8 to 89.0 +/- 8.7 microm) and hypercontractility (R(max) 37.5 +/- 1.3%) induced by infection. IL-4Ralpha mRNA was detected in dispersed smooth muscle cells. Incubation of longitudinal muscle-myenteric plexus (LMMP) with IL-4 and IL-13 enhanced Carbachol-induced muscle contraction (R(max) 35.5 +/- 1.9 and 32.4 +/- 2.9%, respectively). Incubation of LMMP from STAT6 -/- mice with IL-4 did not enhance the contraction. The hypercontractility in T. spiralis-infected mice was attenuated in STAT6 -/- mice (P < 0.02). These results indicate both IL-4 and IL-13 induce hypercontractility of muscle cells via the STAT6 pathway, and this is the basis for hypercontractility observed in T. spiralis-infected mice.

Animals↗