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Biomedical subjects

S M Collins

Publications and source records attributed to S M Collins.

At least 73 records · Page 4Linked to original sources
PubMed1999

Stress, inflammation and the irritable bowel syndrome.

Studies in animals have shown that inflammation of the mucosa of the gastrointestinal tract is accompanied by changes in enteric nerve and smooth muscle function, and in gut motility and sensation. In some instances, these changes persist long after resolution of the mucosal inflammation. Some of these observations have been made in human studies of irritable bowel syndrome (IBS) in patients after an enteric infection or in patients in remission from ulcerative colitis. Stress has also been implicated as a modulator of gastrointestinal inflammation in both animal and human studies. In animals, stress causes a reactivation of previous enteric inflammation and induces the attendant physiological changes. Prior stress also enhances the response to subsequent inflammatory stimuli. In humans, postinfectious IBS tends to occur in patients with psychological profiles similar to those observed in IBS patients and in whom there is a higher incidence of stressful life events just before exposure to the infection. Taken together, these observations link stress and inflammation as a putative pathogenetic mechanism in at least a subset of IBS patients.

Animals↗
PubMed1999

Slow wave and spike action potentials recorded in cell cultures from the muscularis externa of the guinea pig small intestine.

Intracellular recordings were obtained to investigate whether slow wave and spike type action potentials are present in cell cultures of the muscularis externa from the guinea pig small intestine. The muscularis externa of the small intestine was dissociated by using specific purified enzymes and gentle mechanical dissociation. Cells were plated on cover slips and maintained in culture for up to 4 weeks. Dissociated cells obtained in this way reorganized themselves in a few days to form small cell clumps showing spontaneous movements. Intracellular recordings of these clumps displayed both spike and slow wave type action potentials. Spikes were observed on top of some slow waves and were abolished by the addition of nifedipine or the removal of extracellular calcium. Slow waves, however, were nifedipine insensitive and temperature sensitive, and were abolished by octanol (a gap junction blocker) and forskolin (an adenyl cyclase activator). Slow waves were never observed in small clumps (<50 microm), suggesting that a critical mass of cells might be required for their generation. These observations demonstrated for the first time the presence of nifedipine-insensitive slow waves in cell cultures of the muscularis externa from the guinea pig small intestine. Cell cultures allow rigorous control of the immediate environment for the cells and this should facilitate future studies on the molecular and cellular mechanisms responsible for the slow waves in the gastrointestinal tract.

Action Potentials↗
PubMed1998

T cell-mediated exocrine pancreatic damage in major histocompatibility complex class II-deficient mice.

BACKGROUND & AIMS: Recent observations suggest a role for lymphocytes in human pancreatitis. However, existing animal models of pancreatitis are not immunologically based. In studies on major histocompatibility complex (MHC) II-deficient mice backcrossed five generations onto a C57BL/6 background, we discovered a progressive wasting disease due to pancreatic damage. The purpose of this study was to characterize this model of immune-based pancreatic injury. METHODS: The pathology was characterized histologically and functionally by assaying for pancreatic enzymes and glucose. RESULTS: By 6 months, a periductal lymphocytic infiltrate was observed that later developed into pancreatic lesions with extensive, but selective, destruction of acinar cells. Mice eventually lost weight, developed a hunched appearance, and began to pass large, pale pellets. Histology of affected mice revealed pancreatic atrophy with almost complete loss of acinar cells, although islets remained intact. Serum levels of amylase, lipase, and glucose confirmed the selective loss of the exocrine pancreas, with both amylase and lipase levels being significantly decreased in affected mice. However, glucose levels remained unaffected. Adoptive transfer of splenic mononuclear cells to athymic mice was found to transfer the disease. CONCLUSIONS: Aged MHC II-deficient mice develop an immune-based pancreatitis with selective loss of exocrine cells and function.

Amylases↗
PubMed1998

Use of combinatorial library screening to identify inhibitors of a bacterial two-component signal transduction kinase.

Bacterial resistance to antibiotics is emerging as a major concern to the medical community. The appearance of several antibiotic-resistant strains, including multidrug-resistant Staphylococcus aureus, raises the prospect that infections by these bacteria could soon become untreatable with currently available antibiotics. In order to address this problem, increased emphasis is being placed on the discovery of novel classes of antibacterial agents that inhibit novel molecular targets using sources of compounds not yet exploited for antibiotic drug discovery. Novel classes of compounds can now be rapidly investigated using combinatorial chemistry approaches. This report describes the identification of novel antibacterial compounds from a combinatorial library of N-acetylated, C-amidated D-amino acid hexapeptides. This library of compounds was screened for inhibitors of CheA, a member of the bacterial two-component signal transduction kinase family. Several peptides with apparent IC50 values in the low micromolar range were identified. In addition to inhibiting CheA, these peptides inhibited mammalian protein kinase C (from rat brain) with comparable potency. Finally, these peptides were also found to have significant antibacterial properties, although the true mechanism by which they exhibited inhibition of bacterial growth remains uncertain.

Amino Acids↗
PubMed1998

The effect of nematode infection upon intestinal smooth muscle function.

Nematode infections are useful in studying both host defence and inflammation induced changes in intestinal physiology, including increased contraction by intestinal muscle. Our initial studies of the heightened muscle function found during T. spiralis infection led to investigations of the role of immune and inflammatory cells and mediators in the immunodulation of intestinal muscle function. By infecting various immunodeficient mouse strains, as well as gene transfer to the intestine, T lymphocytes, and in particular the CD4+ve subset were found to be responsible for altering smooth muscle function. However, eosinophils as well as the cytokine interleukin-4 may also be involved. Investigations also indicate a potential role for increased muscle function and propulsive activity in expelling nematode parasites. Mutant mice which suffer aberrant intestinal propulsion, or based upon an immunodeficiency, undergo reduced changes in muscle function during infection, undergo prolonged infections. While increased muscle function may be an adaptive host response, the changes in muscle function may persist long after the resolution of the infection. Thus understanding the mechanisms behind the immunomodulation of intestinal muscle function may also impact upon clinical gastroenterology, since motility disturbances in man often occur following enteric infections, or other inflammatory conditions of the bowel.

Animals↗
PubMed1998

T lymphocyte-dependent and -independent intestinal smooth muscle dysfunction in the T. spiralis-infected mouse.

We examined the profile of increased intestinal muscle contractility after primary infection with Trichinella spiralis in the mouse, correlating it with parasite expulsion. We also examined the extent to which the changes in muscle contraction were T lymphocyte dependent, by infecting athymic and SCID mice. Infection was accompanied by increased tension development by intestinal muscle. Two components of this response were identified, a rapid peak increase in tension generation observed on day 6 postinfection, and a smaller but sustained increase in tension evident thereafter in euthymic BALB/c mice. The peak muscle response was significantly delayed in infected athymic and SCID mice, along with a corresponding reduction in the magnitude of the sustained component. These changes were accompanied by reduced parasite expulsion in athymic and SCID mice, compared with euthymic mice. Reconstitution of T cell function in athymic mice restored both the acute and sustained profile of muscle contraction seen in euthymic mice, and this was accompanied by faster expulsion of the worms. These results identify T cell-dependent and -independent components of the muscle response to nematode infection in the mouse and suggest that the onset of the peak contractile response, as well as the magnitude of the sustained muscle response, contributes to parasite eviction from the gut.

Animals↗
PubMed1997

Therapeutic effects of interleukin-4 gene transfer in experimental inflammatory bowel disease.

Inflammatory bowel disease (IBD) is characterized by altered immunoregulation and augmented intestinal synthesis of nitric oxide. The purpose of this study was to determine the effects of exogenous IL-4, introduced by a recombinant human type 5 adenovirus (Ad5) vector, on the tissue injury associated with an experimental model of colonic immune activation and inflammation. Colitis was induced in rats by the intrarectal administration of trinitrobenzene sulfonic acid (TNB) dissolved in 50% ethanol, and control rats received saline via the same route. 1 h later, all rats were randomized into two groups. The first group was injected intraperitoneally (ip) with 3.0 x 10(6) plaque forming units (PFUs) of Ad5 transfected with murine interleukin-4 (Ad5IL-4) and the second group was injected ip with the same amount of Ad5 expressing the Escherichia coli Lac Z gene (Ad5LacZ). One-half of the colitic and control rats were injected again with 3.0 x 10(6) PFUs of Ad5IL-4 or Ad5LacZ on day 3 of the 6-d study. When introduced once or twice via the peritoneal route into control rats, Ad5LacZ was localized to the serosal lining of the peritoneal cavity, the diaphragm and the liver on day 6. One or two injections of Ad5IL-4 into rats also produced measurable levels of circulating IL-4. TNB-colitis in both Ad5LacZ-treated groups was associated with pronounced elevations in serum IFN-gamma, and mucosal ulceration of the distal colon. Myeloperoxidase and inducible nitric oxide synthase II (NOS II) synthetic activity were also increased by 30- and fivefold, respectively, above control levels in the distal colon. However, two injections of Ad5IL-4 into colitic rats caused the overexpression of IL-4, and significantly inhibited tissue damage, serum and colon IFN-gamma levels and myeloperoxidase activity in the distal colon. In addition, NOS II gene expression and NOS II nitric oxide synthesis was significantly inhibited. No therapeutic effect was observed in rats injected once with Ad5IL-4. Thus, IL-4, introduced by Ad5, is therapeutic during acute inflammation in the rat colon. The therapeutic effect of IL-4 was associated with an inhibition of inducible nitric oxide expression and a reduction in nitric oxide synthesis.

Adenoviruses, Human↗
PubMed1997

The mechanism of altered neural function in a rat model of acute colitis.

BACKGROUND & AIMS: Distal colitis induced in rats by trinitrobenzene sulfonic acid (TNBS) causes a suppression of [3H]noradrenaline release from the myenteric plexus, of inflamed distal colon, as well as in noninflamed regions of colon and ileum. The aim of this study was to explore the mechanisms underlying these neural changes in TNBS colitis. METHODS: Colitis was induced by intrarectal administration of TNBS, and the animals were killed on day 5. Inflammation was assessed by measuring myeloperoxidase (MPO) activity, and noradrenaline release was measured as 3H release from rats myenteric plexus preparations preloaded with [3H]noradrenaline. These end points were examined: (1) after administration of the locally active steroid budesonide; (2) in congenitally athymic rats; and (3) in rats treated with the interleukin 1 receptor antagonist (IL-1ra) to interleukin 1 beta. RESULTS: In colitis, both topical budesonide and systemic IL-1ra treatments attenuated the suppression of KCl-evoked 3H release from longitudinal muscle myenteric plexus in both inflamed and noninflamed segments. However, neither of these treatments altered MPO activity. A similar suppression of [3H]noradrenaline release was observed in athymic rats after TNBS, although there was a substantially greater increase in MPO activity compared with euthymic rats with colitis. CONCLUSIONS: TNBS-induced colitis alters myenteric nerve function at inflamed and noninflamed sites via a steroid-sensitive and interleukin 1-mediated process that does not require T lymphocytes.

Acute Disease↗
PubMed1997

Neuromuscular regulation of T-cell activation.

Recent investigations in our laboratory have shown that murine intestinal smooth muscle cells (ISMCs) can exert an immunomodulatory effect on T-cells. Therefore, we examined the effects of substance P, calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) on the ability of ISMCs to modulate T-cell proliferation and lymphokine generation. T-cell proliferation was observed when these cells were co-cultured with IFN-pretreated C57/BL6 ISMCs which expressed major histocompatibility complex II (MHC II), but not during T-cell co-culture with C2D (MHC II -/-) ISMCs pretreated in the same manner. T-cell proliferation during co-culture with C57/BL6 ISMCs was also associated with significantly enhanced T-cell synthesis of IFN. When CGRP (at 10(-9) M), but not substance P or VIP, was added to C57/BL6 ISMCs during the IFN-pretreatment period. T-cell proliferation was significantly increased. However, increased T-cell proliferation was not observed if the concentration of CGRP was increased to 10(-6) M. At the higher concentration, addition of substance P or VIP during the pretreatment period significantly inhibited the subsequent T-cell proliferation. Pretreatment of C57/BL6 ISMCs with any of the three neuropeptides and IFN resulted in the diminished production of IL-4 and IFN by co-cultured T-cells. A similar pattern of cytokine secretion was observed during T-cell co-culture with IFN- and neuropeptide-pretreated C2D ISMCs except when 10(-6) M substance P was added; IFN secretion by co-cultured T-cells was increased 4-fold under these conditions. Taken together, these data show a direct modulatory role for neuropeptides in the interaction between ISMCs and T-cells and suggest that, in general, neuropeptides may dampen immune responses in the neuromuscular layers of the inflamed intestine.

Animals↗
PubMed1997

Role of nitric oxide in norepinephrine release from myenteric plexus in vitro and in Trichinella spiralis-infected rats.

Nitric oxide (NO) has been implicated as modulator of neural function and inflammatory mediator. Previously, we have demonstrated suppression of norepinephrine (NE) release from myenteric nerves following Trichinella spiralis infection implicating interleukin-1 beta (IL-1 beta) as a mediator of these changes. In the present study, we have examined the role of NO in NE release from the myenteric plexus and in the suppression of NE release induced by IL-1 beta in vitro, and we have determined whether NO is involved in the suppression of NE release from the myenteric plexus observed in T. spiralis-infected rats. Electrically evoked NE release from jejunal longitudinal muscle-myenteric plexus preparations (LMMP) was measured following (a) in vitro exposure of the tissue to the NO donor 3-morpholinosydnonimine (SIN-1), L-arginine, or IL-1 beta, in the presence or absence of NOS inhibitors, and (b) in vivo treatment of control or T. spiralis-infected rats with N6-nitro-L-arginine-methyl-ester (L-NAME), NG-nitro-D-arginine-methyl-ester (D-NAME) or vehicle for 6 days. In vitro inhibition of NO synthesis had no effect on NE release from the myenteric plexus. Treatment with SIN-1 or L-arginine suppressed NE release in a manner similar to that observed with IL-1 beta. Moreover, the effect of IL-1 beta was attenuated by L-NAME. In contrast, treatment of T. spiralis-infected rats with L-NAME had no effect on the suppression of NE release. These results indicate that in the absence of inflammation, the myenteric plexus can generate sufficient NO to inhibit NE release and that NO mediates the action of IL-1 beta on NE release in vitro. However, we have no evidence for the involvement of NO in the suppression of NE release in nematode-infected rats.

Animals↗
PubMed1997

Cytokine modulation of T-lymphocyte activation by intestinal smooth muscle cells.

BACKGROUND & AIMS: Interleukin 1beta (IL-beta) and tumor necrosis factor alpha (TNF-alpha) are present in the neuromuscular layers during intestinal inflammation and directly affect intestinal smooth muscle function. We investigated whether IL-1beta and TNF-alpha modulate T-cell activation by murine intestinal smooth muscle cells (ISMCs). METHODS: alpha- and gamma- actin expression in ISMCs was confirmed using reverse-transcription polymerase chain reaction (RT-PCR). ISMCs were analyzed for class II major histocompatibility complex (MHC), intercellular adhesion molecule 1 (ICAM-1), and B7 before and after exposure to interferon gamma (IFN-gamma; 100 or 1000 U/ mL) in the presence or absence of IL-1beta (10 ng/mL) or TNF-alpha (5 ng/mL) for 72 hours. T-cell proliferation on cytokine-pretreated ISMCs was measured in the absence or presence of anti-B7 antibodies. RESULTS: In a dose-dependent fashion, IFN-gamma-pretreated ISMCs expressed MHC class II, ICAM-1, and B7-2, and stimulated T-cell proliferation. Pretreatment of ISMCs with IL-1beta and IFN-gamma reduced MHC class II and ICAM-1 expression and inhibited T-cell proliferation. When added with 100 U/mL IFN-gamma, TNF-alpha enhanced MHC class II and ICAM-1 expression on ISMCs and T-cell proliferation. However, TNF-alpha and 1000 U/mL IFN-gamma significantly decreased MHC class II expression and T-cell proliferation. Anti-B7-2 monoclonal antibody but not anti-B7-1 inhibited T-cell proliferative responses by >50%. CONCLUSIONS: Because IL-1beta, TNF-alpha, and T cells are present in the intestinal muscle layers during inflammation, these cytokines may serve to modulate the activation of T cells in this site.

Animals↗
PubMed1997

Persistent intestinal neuromuscular dysfunction after acute nematode infection in mice.

BACKGROUND & AIMS: Although most acute enteric infections in humans resolve, some herald the onset of chronic symptomatology and persistent gastrointestinal dysfunction--so-called postinfectious irritable bowel syndrome. This entity is poorly understood, and there are no animal models for testing hypotheses. The aim of this study was to investigate changes in intestinal neuromuscular function during and after recovery from acute intestinal inflammation due to primary Trichinella spiralis infections in NIH Swiss mice. METHODS: Morphometric scores and myeloperoxidase activity were used to monitor mucosal inflammation. Neuromuscular function was assessed in vitro by pharmacological or electrical stimulation of longitudinal muscle. RESULTS: Acute inflammation resulted in an approximately 50% reduction of villus height, an approximately 50% increase in crypt depth, and a threefold increase in myeloperoxidase activity. Carbachol- and KCl-induced contractions of longitudinal muscle were also increased threefold, whereas contraction induced by electrical field stimulation of intramural nerves was decreased by 60%. Mucosal morphology and myeloperoxidase activity rapidly returned to control values, but the increased muscle contractility and the decreased excitatory neurotransmission persisted as long as 42 and 28 days after infection, respectively. CONCLUSIONS: These findings show that transient mucosal inflammation alters enteric neuromuscular function; this alteration persists after recovery from the infection and mucosal restitution.

Animals↗
PubMed1997

Adaptive approach to accurate analysis of small-diameter vessels in cineangiograms.

In coronary vessels smaller than 1 mm in diameter, it is difficult to accurately identify lumen borders using existing border detection techniques. Computer-detected diameters of small coronary vessels are often severely overestimated due to the influence of the imaging system point spread function and the use of an edge operator designed for a broad range of vessel sizes, Computer-detected diameters may be corrected if a calibration curve for the X-ray system is available. Unfortunately, the performance of this postprocessing diameter correction approach is severely limited by the presence of image noise. We report here a new approach that uses a two-stage adaption of edge operator parameters to optimally match the edge operator to the local lumen diameter. In the first stage, approximate lumen diameters are detected using a single edge operator in a half-resolution image. Depending on the approximate lumen size, one of three edge operators is selected for the second full-resolution stage in which left and right coronary borders are simultaneously identified. The method was tested in a set of 72 segments of nine angiographic phantom vessels with diameters ranging from 0.46 to 4.14 mm and in 82 clinical coronary angiograms. Performance of the adaptive simultaneous border detection method was compared to that of a conventional border detection method and to that of a postprocessing diameter correction border detection method. Adaptive border detection yielded significantly improved accuracy in small phantom vessels and across all vessel sizes in comparison to the conventional and postprocessing diameter correction methods (p < 0.001 in all cases). Adaptive simultaneous coronary border detection provides both accurate and robust quantitative analysis of coronary vessels of all sizes.

Algorithms↗
PubMed1997

Increased intestinal muscle contractility and worm expulsion in nematode-infected mice.

Intestinal nematode infections are accompanied by mucosal inflammation and an increase in propulsive motor activity that may contribute to parasite eviction from the gut. To examine whether differences in worm expulsion correspond to the increased intestinal muscle contractility that accompanies nematode infection, we studied mice with genetically determined differences in their ability to expel the nematode parasite Trichinella spiralis. Specifically, we examined isometric contraction of longitudinal muscle, worm counts, and inflammation, as measured by myeloperoxidase activity, in two strains of mice infected with T. spiralis. The strong responder strain, NIH Swiss, expelled the parasites by day 16 postinfection, whereas the poorer responding B10.BR strain was still heavily infected by day 21 postinfection. However, both strains developed similar increases in jejunal myeloperoxidase activity. Both strains demonstrated increased isometric tension development after infection, but peak tension occurred earlier in NIH Swiss mice (day 8 vs. day 12 postinfection) and was of significantly greater magnitude than in B10.BR mice. We conclude that the ability to expel T. spiralis from the small bowel is not related to the degree of granulocyte-dependent mucosal inflammation but is reflected in the magnitude of the accompanying increase in force generation by intestinal smooth muscle.

Animals↗
PubMed1996

An orally active non-selective endothelin receptor antagonist, bosentan, markedly reduces injury in a rat model of colitis.

Activation of endothelial cells by vasoactive mediators, such as endothelins, may be an early, strategically important step in the initiation of inflammation in the intestine. In view of recent evidence that inflammatory bowel disease is associated with elevated intestinal concentrations of endothelins and upregulated expression of endothelin receptors on vascular endothelium in intestine, endothelins may become therapeutic targets in inflammatory bowel disease. The recent availability of an orally active, mixed endothelin receptor antagonist, bosentan, allowed us to examine the role of endothelins in a rat model of colitis. Colitis was induced by intra-rectal administration of trinitrobenzene sulphonic acid. In each treatment group, rats were treated with bosentan (10-60 mg/kg p.o.) 24 and 2 h prior to (pre-dose) or 1 h after the induction (post-induction) of colitis and all animals were treated every 24 h thereafter for 5 days. On day 6, stool consistency and the presence of adhesions in the peritoneal cavity were accessed. Colonic tissue samples were removed for determination of macroscopic and microscopic tissue injury, and myeloperoxidase activity. Colitis was typified by tissue ulceration in the distal colon and a corresponding 35-fold increase in myeloperoxidase activity compared to non-inflamed controls. Daily treatment with bosentan dose-dependently reduced colonic damage and myeloperoxidase activity when bosentan was given prior to induction of colitis. In the pre-dose group, the greatest beneficial effect of bosentan was observed at 60 mg/kg; colonic damage and granulocyte infiltration were attenuated by > 80%. A partial therapeutic effect of bosentan was also observed at 60 mg/kg when the pre-treatment regimen was excluded. These findings demonstrate that an orally active, mixed endothelin receptor antagonist has marked protective and therapeutic effects in an animal model of colitis.

Administration, Oral↗
PubMed1996

Psychometric scores and persistence of irritable bowel after infectious diarrhoea.

BACKGROUND: Although previous studies have shown that psychological disturbances are frequently associated with the irritable bowel syndrome (IBS), the relation was not necessarily cause and effect. The development of chronic bowel symptoms resembling IBS after an episode of acute gastroenteritis has allowed us to examine prospectively the role of psychological factors. METHODS: 75 patients with acute gastroenteritis completed a series of psychometric tests soon after admission to hospital. Of these, 22 had persistent symptoms compatible with IBS after the acute illness, and in 20 of these the symptoms were still present at six months. FINDINGS: At the time of their initial illness, patients who subsequently developed IBS symptoms had higher scores for anxiety, depression, somatisation, and neurotic trait than those who returned to normal bowel function. The psychometric scores had not changed when remeasured three months after the acute illness. Lactose malabsorption was not an important factor. INTERPRETATION: These results support the hypothesis that psychological factors are important in IBS.

Acute Disease↗
PubMed1996

Previous inflammation alters the response of the rat colon to stress.

BACKGROUND & AIMS: Patients with inflammatory bowel disease have symptoms of irritable bowel syndrome (IBS) with a higher than expected prevalence. Stress is an important factor in the pathogenesis of IBS. Thus, previous inflammation may predispose to IBS by rendering the bowel more susceptible to the impact of stress. The aim of this study was to examine the effect of previous colitis on stress-induced responses in rats. METHODS: Acute colitis was induced in rats by intrarectal administration of trinitrobenzene sulfonic acid (TNBS), and the rats were allowed to recover for 6 weeks before application of mild restraint stress for 3 consecutive days. In vitro measurements included myeloperoxidase activity, plasma corticosterone levels, interleukin 1 beta messenger RNA expression, and [3H]noradrenaline release from the myenteric plexus. RESULTS: Six weeks after administration of TNBS, stress caused a significant increase in myeloperoxidase activity in TNBS-treated rats but not in stressed controls; plasma corticosterone responses were similar. Stress also caused an exaggerated and significant suppression of [3H]noradrenaline release in TNBS-treated stressed rats compared with stressed controls. This was accompanied by a significant decrease in interleukin 1 beta messenger RNA expression in the colon. CONCLUSIONS: Previous colitis rendered the colon more susceptible to effects of stress on enteric nerve function and also increased some parameters of inflammation in response to stress.

Animals↗