Hymenolepis diminuta-associated alterations in rat intestinal myoelectric patterns are abolished following therapeutic administration of the anthelmintic praziquantel (PZQ). Host intestinal smooth ...muscle myoelectric patterns, reflecting smooth muscle contractility and intestinal phasic motility, were recorded using in vivo serosal electrodes, surgically implanted on the duodenum, jejunum, and ileum. Repeated electromyographic recording from unrestrained and unanesthetized rats began 5 days after electrode implantation surgery. Three initial control recordings from each rat confirmed the appearance of normal intestinal myoelectric patterns, characterized by the interdigestive migrating myoelectric complex (MMC). All animals were subsequently infected with H. diminuta and myoelectric recordings beginning after day 8 postinfection confirmed the appearance of diminished frequency of the MMC and 2 nonmigrating myoelectric patterns, i.e., repetitive bursts of action potentials and sustained spike potentials. PZQ was used to remove the tapeworms from rats 12 days after Hymenolepis diminuta infection, as intestinal myoelectric changes become maximal at this time in tapeworm-infected rats. PZQ administered to uninfected rats at either of 2 dose levels did not affect host interdigestive myoelectric activity. After removal of the parasite with PZQ, electromyographic recordings indicated a return to normal uninfected electrical patterns within 24 hr of drug treatment. We have demonstrated that the presence of Hymenolepis diminuta is necessary to induce and maintain abnormal intestinal myoelectric patterns. The altered motor properties of tapeworm-infected rat intestine and the rapid reconversion to preinfection myoelectric patterns provides a new and unique model to examine the regulatory mechanisms of intestinal motility and its control by luminal parasites.
The intestinal epithelium produces and responds to cytokines and lipid mediators that play a key role in the induction and regulation of mucosal inflammation. The lipid mediator platelet-activating ...factor (PAF) can be produced and degraded by the human intestinal epithelium and is known to mediate a range of proinflammatory and other biological effects in the intestinal mucosa. In the studies herein, we assessed whether or not human intestinal epithelial cells express cell surface or intracellular PAF receptors (PAF-R), whether expression of these receptors can be regulated, and whether human intestinal epithelial cells respond to PAF. Several human colon epithelial cell lines (HT-29, Caco-2, T84, HCT-8, HCA-7, I407, and LS-174T) were shown by RT-PCR to constitutively express mRNA for PAF-R. In addition, PAF-R expression was demonstrated by immunoblot analysis and PAF-R was shown to be constitutively expressed on the cell surface of several of these cell lines, as assessed by flow cytometry. PAF-R expression by human colon epithelial cells was upregulated by stimulation with retinoic acid but not by stimulation with PAF, proinflammatory agonists (tumor necrosis factor-alpha, interleukin-1, interferon-gamma), or transforming growth factor-alpha. PAF-R on intestinal epithelial cells were functional, as PAF stimulation of the cells increased tyrosine phosphorylation of several cellular proteins, including proteins of 75 and 125 kDa, and this response was blocked by a PAF-R antagonist. Consistent with the findings using cell lines, PAF-R were also constitutively expressed by normal human colon and small intestinal epithelium in vivo, as shown by immunohistology. The constitutive and regulated expression of functional PAF-R by human intestinal epithelium suggests PAF produced by the intestinal epithelial cells or cells underlying the epithelium has autocrine or paracrine effects on intestinal epithelial cells.
Intestinal epithelial cell migration plays a key role in gastrointestinal mucosal barrier formation, enterocyte development, differentiation, turnover, wound healing, and adenocarcinoma metastasis. ...Chemokines, through engagement of their corresponding receptors, are potent mediators of directed cell migration and are critical in the establishment and regulation of innate and adaptive immune responses. The aim of this study was to define the role for the chemokine CXCL12 and its sole cognate receptor CXCR4 in regulating intestinal epithelial cell migration and to determine its impact on barrier integrity. CXCL12 stimulated the dose-dependent chemotactic migration of human T84 colonic epithelial cells. Epithelial cell migration was inhibited by CXCR4 neutralizing antibody, pertussis toxin, LY-294002, and PD-98059, thereby implicating Galpha(i), phosphatidylinositol 3-kinase (PI3-kinase), and the ERK1/2 MAP kinase pathways in CXCR4-specific signaling. CXCL12 was also shown to increase barrier integrity, as defined by transepithelial resistance and paracellular flux across differentiating T84 monolayers. To determine whether CXCL12 regulated epithelial restitution, we used the normal nontransformed intestinal epithelial cell-6 (IEC-6) wound healing model. By using RT-PCR, immunoblot analysis, and immunofluorescence microscopy, we first showed expression of both CXCR4 and its ligand by IEC-6 cells. We then demonstrated that CXCL12 activated comparable signaling mechanisms to stimulate epithelial migration in the absence of proliferation in wounded IEC-6 monolayers. Taken together, these data indicate that CXCL12 signaling via CXCR4 directs intestinal epithelial cell migration, barrier maturation, and restitution, consistent with an important mechanistic role for these molecules in mucosal barrier integrity and innate host defense.
The Rat Genome Database pathway portal Petri, Victoria; Shimoyama, Mary; Hayman, G Thomas ...
Database : the journal of biological databases and curation,
2011, Letnik:
2011
Journal Article
Recenzirano
Odprti dostop
The set of interacting molecules collectively referred to as a pathway or network represents a fundamental structural unit, the building block of the larger, highly integrated networks of biological ...systems. The scientific community's interest in understanding the fine details of how pathways work, communicate with each other and synergize, and how alterations in one or several pathways may converge into a disease phenotype, places heightened demands on pathway data and information providers. To meet such demands, the Rat Genome Database (RGD) http://rgd.mcw.edu has adopted a multitiered approach to pathway data acquisition and presentation. Resources and tools are continuously added or expanded to offer more comprehensive pathway data sets as well as enhanced pathway data manipulation, exploration and visualization capabilities. At RGD, users can easily identify genes in pathways, see how pathways relate to each other and visualize pathways in a dynamic and integrated manner. They can access these and other components from several entry points and effortlessly navigate between them and they can download the data of interest. The Pathway Portal resources at RGD are presented, and future directions are discussed. Database URL: http://rgd.mcw.edu.
Human intestinal epithelial cells secrete an array of chemokines known to signal the trafficking of neutrophils and monocytes important in innate mucosal immunity. We hypothesized that intestinal ...epithelium may also have the capacity to play a role in signaling host adaptive immunity. The CC chemokine macrophage inflammatory protein (MIP)-3α/CCL20 is chemotactic for immature dendritic cells and CD45RO
+
T cells that are important components of the host adaptive immune system. In these studies, we demonstrate the widespread production and regulated expression of MIP-3α by human intestinal epithelium. Several intestinal epithelial cell lines were shown to constitutively express MIP-3α mRNA. Moreover, MIP-3α mRNA expression and protein production were upregulated by stimulation of intestinal epithelial cells with the proinflammatory cytokines tumor necrosis factor-α or interleukin-1α or in response to infection with the enteric bacterial pathogens Salmonella or enteroinvasive Escherichia coli. In addition, MIP-3α was shown to function as a nuclear factor-κB target gene. In vitro findings were paralleled in vivo by increased expression of MIP-3α in the epithelium of cytokine-stimulated or bacteria-infected human intestinal xenografts and in the epithelium of inflamed human colon. Mucosal T cells, other mucosal mononuclear cells, and intestinal epithelial cells expressed CCR6, the cognate receptor for MIP-3α. The constitutive and regulated expression of MIP-3α by human intestinal epithelium is consistent with a role for epithelial cell-produced MIP-3α in modulating mucosal adaptive immune responses.
Ventilatory sensitivity to CO^sub 2^ in awake adult Brown Norway (BN) rats is 50-75% lower than in adult Sprague-Dawley (SD) and salt-sensitive Dahl S (SS) rats. The purpose of the present study was ...to test the hypothesis that this difference would be apparent during the development of CO^sub 2^ sensitivity. Four litters of each strain were divided into four groups such that rats were exposed to 7% inspired CO^sub 2^ for 5 min in a plethysmograph every third day from postnatal day (P) 0 to P21 and again on P29 and P30. From P0 to P14, CO^sub 2^ exposure increased pulmonary ventilation (VE) by 25-50% in the BN and SD strains and between 25 to over 200% in the SS strain. In all strains beginning around P15, the response to CO^sub 2^ increased progressively reaching a peak at P19-21 when VE during hypercapnia was 175-225% above eucapnia. There were minimal changes in CO^sub 2^ sensitivity between P21 and P30, and at both ages there were minimal between-strain differences. At P30, the response to CO^sub 2^ in the SS and SD strains was near the adult response, but the response in the BN rats was 100% greater at P30 than in adults. We conclude that 1) CO^sub 2^-sensing mechanisms, and/or mechanisms downstream from the chemoreceptors, change dramatically at the age in rats when other physiological systems are also maturing (~P15), and 2) there is a high degree of age-dependent plasticity in CO^sub 2^ sensitivity in rats, which differs between strains. PUBLICATION ABSTRACT
1 University of Wisconsin-Milwaukee, Milwaukee, Wisconsin
2 Medical College of Wisconsin, Milwaukee, Wisconsin
Chromosomal substitution strains afford the opportunity to discover regions of the rat ...genome that contain genes related to cardiovascular traits with the long-range goal of linking these genes to physiological function. PhysGen (Programs for Genomic Applications) created a consomic panel of rats derived from the introgression of a single chromosome ( 95% of the BN chromosome, one at a time) of the Brown Norway (BN/NHsdMcwi) rat onto the homogeneous genetic background of the Dahl salt-sensitive rat (SS/JrHsdMcwi). For 3 wk before the experiment, the rats were maintained on a low-salt diet (0.4% NaCl). The dose response of aortic rings from each strain of rat to phenylephrine, acetylcholine, sodium nitroprusside, and three different levels of tissue bath hypoxia (10, 5, and 0% O 2 ) was measured and compared with the parental SS rat. To maximize the possibility that differences among the strains would become apparent, each strain of rat including the parental SS and BN was also studied after being maintained on a high-salt diet (4.0% NaCl) for 3 wk. If the response of the aortic ring from a consomic strain to these vasoactive substances was different from that of the SS parental strain, it was concluded that the introgressed chromosome contained a gene or genes that contributed to that difference. Because the BN chromosome is removed from its native background and the SS rat loses a native chromosome, it is also necessary to consider the contribution of changes in gene-to-gene interaction.
aortic ring; high-salt diet; chromosomal substitution
The Rat Genome Database (RGD) is the premier repository of rat genomic and genetic data and currently houses over 40,000 rat gene records as well as human and mouse orthologs, 1771 rat and 1911 human ...quantitative trait loci (QTLs) and 2209 rat strains. Biological information curated for these data objects includes disease associations, phenotypes, pathways, molecular functions, biological processes and cellular components. A suite of tools has been developed to aid curators in acquiring and validating data objects, assigning nomenclature, attaching biological information to objects and making connections among data types. The software used to assign nomenclature, to create and edit objects and to make annotations to the data objects has been specifically designed to make the curation process as fast and efficient as possible. The user interfaces have been adapted to the work routines of the curators, creating a suite of tools that is intuitive and powerful. Database URL: http://rgd.mcw.edu.
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