Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021843 (bowel obstruction)
 9,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abnormal epithelial electrolyte transport has been identified in a range of cystic fibrosis (CF) organs and appears to account for the various clinical manifestations of the disease. The aim of this study was to further define the Cl- secretion defect in CF jejunum. Excised jejunum was obtained from 11 CF patients and 12 controls. Transport studies were performed on stripped epithelium in vitro under short-circuited conditions in Ussing Chambers. 3-Isobutyl-1-methylxanthine (IBMX) (300 microM) significantly increased Cl- secretion in control (-2.3 +/- 0.6 to -3.3 +/- 0.7 mueq.cm-2.h-1; P less than 0.01, paired t test; n = 5 subjects) but not in CF jejunum (-0.5 +/- 0.3 to -0.1 +/- 0.4; n = 4). However in contrast to control jejunum, net Na+ absorption in CF jejunum was higher in the IBMX (1.3 +/- 0.5 mueq.cm-2.h-1) compared with basal periods (0.6 +/- 0.3; P less than 0.05, paired t test). IBMX stimulation of tissue adenosine 3',5'-cyclic monophosphate (cAMP) was similar in both control and CF jejunum. A range of secretagogues known to induce secretion in mammalian intestine, including dibutyryl cAMP (DBcAMP), DBcGMP, Ca2+ ionophore A23187, and the protein kinase C activator 4 beta-phorbol 12,13-dibutyrate, failed to induce secretion in CF jejunum. In conclusion, CF jejunum failed to exhibit Cl- secretion and also demonstrated abnormalities of Na+ absorption. These results support the view that the defect lies at a site distal to the intracellular messengers. Moreover, these abnormalities of intestinal electrolyte transport may account for some of the gastrointestinal manifestations of the disease such as meconium ileus and distal intestinal obstruction syndrome.
 ...
PMID:Abnormal epithelial transport in cystic fibrosis jejunum. 170 89

Cystic fibrosis (CF) is the most frequent inheritable disease with a lethal course during childhood. The characteristic high viscosity of the mucoid secretion products in the lungs, pancreas, and gut cause plugging and secondary damage of these organs. In the past 20 years effective treatment of intestinal obstruction in the neonatal period and the infections of the lungs has improved the prognosis significantly. Many patients will reach adulthood in the near future. In the past 10 years new insights into the cause of the disease changed diagnostic procedures and, it is to be hoped, soon also treatment. The first development was the estimation of brush-border enzymes in amniotic fluid. With this method prenatal diagnosis is possible in the 17th-18th week of pregnancy. The recent discovery of the gene on chromosome 7 and its structure is the most important breakthrough. At the same time the process of Cl- transport across the mucosal membrane of many types of epithelium was subject to investigation by several laboratories. We have studied the transport of ions in the small and large intestines of CF patients. The effect of all three types of intracellular signal transfer is abnormal, although the second messengers themselves (cAMP, cGMP, and Ca2+) are present. Evidence is found for K+ instead of Cl- secretion after addition of secretagogues.
 ...
PMID:New insights into the pathogenesis of cystic fibrosis. 227 66

To develop an animal model for cystic fibrosis (CF), targeted gene disruption in embryonic stem (ES) cells was used to generate a duplication of exon 3 (cftrm1Bay allele) of the mouse CF gene. ES cells containing this mutation were used to generate chimeric animals that transmitted the mutant allele through the germline. Homozygous mutant animals display a severe phenotype, with approximately 40% dying within 1 week from intestinal obstruction. RNAase protection analysis of the cftrm1Bay allele did not detect any normal mRNA (< 1-2% of wild-type) in mutant animals. Pathologic changes in the intestines from mutant mice included mucus accumulation in the crypts and intestinal lumen, dilatation of the bases of the crypts, enlargement of goblet cells, and the presence of concretions in the crypts or between the villi. Changes were also present in the mucosal glands of the pharynx and the minor sublingual glands, where dilatation of acini and accumulation of eosinophilic material were evident. Atrophy of acinar cells that may be secondary to nutritional deficiency and mild inflammation in the main pancreatic duct were present in the pancreas of mutant animals. No changes were noted in the lung, trachea, liver, or male reproductive tract of mutant animals, and mutant males were fertile. Homozygous mutant mice showed defects in cAMP-mediated ion transport both in ileum and in cultured fetal tracheal explants. Thus, an additional mouse model for CF has been generated that should prove useful for the understanding of the pathogenesis and the development of treatments for CF.
 ...
PMID:A severe phenotype in mice with a duplication of exon 3 in the cystic fibrosis locus. 750 91

Mouse models for cystic fibrosis (CF) with no CFTR function (Cftr-/-) have the disadvantage that most animals die of intestinal obstruction shortly after weaning. The objective of this research was to extend the lifespan of CF mice and characterize their phenotype. Weanlings were placed on a nutrient liquid diet, and histologic and functional aspects of organs implicated in the disease were subsequently examined. Approximately 90% of Cftr-/- mice survived to 60 d, the majority beyond 100 d. Cftr-/- mice were underweight and had markedly abnormal intestinal histology. The intestinal epithelia did not respond to challenges with agents that raised intracellular cAMP, consistent with the absence of functional CFTR. No lesions or functional abnormalities were evident in the lungs. Liquid-fed Cftr-/- mice were infertile, although some males weaned to a solid diet were fertile before they died. Thus, we have succeeded in using dietary means to prolong the lives of Cftr-/- mice.
 ...
PMID:Phenotypic abnormalities in long-term surviving cystic fibrosis mice. 882 71

From 1988 to 1992 the serum gastrin levels of 124 patients with intussusception and 20 normal infants and 15 patients with intestinal obstruction under 3 years of age were measured. Serum cAMP levels of 10 normal infants and 10 patients with intussusception were determined. In animal experiment study, the pressures of ileum cavity and ileoceal valve were determined before and after injectting pentagastrin into the veins of 8 young dogs. The levels of gastrin (219.9 +/- 100.6 pg/ml) and cAMP (32.4 +/- 7.6 pmol/ml) were higher in patient group than in the control group. (89 +/- 3 pg/ml, P < 0.05 and 22.2 +/- 7.5 pmol/ml P < 0.05). The result of animal experiment showed that the effect of gastrin and etiology of intussusception are identical. The main physiological funcitons of gastrin is to increase the intestinal peristalsis and relax the ileocecal sphincter. Our study showed that hypergastrinemia may be the basis etiologic factor of intussusception. Main clinical feactures were explained by this new theory.
 ...
PMID:[The role of hypergastrinemia in the pathogenesis of intussusception in infants]. 938 31

Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR). Mutations in the CFTR gene may result in a defective processing of its protein and alter the function and regulation of this channel. Mutations are associated with different symptoms, including pancreatic insufficiency, bile duct obstruction, infertility in males, high sweat Cl-, intestinal obstruction, nasal polyp formation, chronic sinusitis, mucus dehydration, and chronic Pseudomonas aeruginosa and Staphylococcus aureus lung infection, responsible for 90% of the mortality of CF patients. The gene responsible for the cellular defect in CF was cloned in 1989 and its protein product CFTR is activated by an increase of intracellular cAMP. The CFTR contains two membrane domains, each with six transmembrane domain segments, two nucleotide-binding domains (NBDs), and a cytoplasmic domain. In this review we discuss the studies that have correlated the role of each CFTR domain in the protein function as a chloride channel and as a regulator of the outwardly rectifying Cl- channels (ORCCs).
 ...
PMID:Structure and function of the cystic fibrosis transmembrane conductance regulator. 1045 65

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP and cGMP-regulated chloride channel critical to the regulation of intestinal fluid, chloride, and bicarbonate secretion. In cystic fibrosis (CF), mutations in CFTR result in downregulation of CFTR function and small intestinal obstruction. Unlike the human CF intestine, severe gastrointestinal disease and lethal obstruction is common in transgenic mice deficient in CFTR. The relevance of the physiology of CFTR and pathophysiology of CF in genetically altered mice to that of human CF disease remains incompletely understood. We hypothesized that the expression and distribution of CFTR in mouse intestine may differ from that of human and may contribute to the variation in disease expression between the two species. Using immunocytochemical and immunoblot techniques and well-characterized anti-rodent anti-CFTR antibodies, we examined the cellular distribution of CFTR in the mouse intestinal tract. We identified significant differences in villus distribution for CFTR in the mouse proximal small intestine compared to those previously reported for human and rat. These observations are important to the understanding of CFTR pathophysiology in transgenic CF mouse model systems and bear relevance to the different phenotypic expression of disease in mice compared to human.
 ...
PMID:Cellular localization of the cystic fibrosis transmembrane conductance regulator in mouse intestinal tract. 1095 24

While most cystic fibrosis (CF) transmembrane conductance regulator (CFTR)-knockout animals die due to intestinal obstruction before or at the time of weaning, a subpopulation of these animals are long living and exhibit a milder phenotype. The decreased severity of intestinal disease in these mildly affected CF mice is related to the expression of non-CFTR genetic modifiers. The identity of these genetic modifiers is not known, but we hypothesize that they may complement CFTR function as a chloride channel in this tissue. To assess the contribution of non-CFTR chloride channels to chloride secretion across the small intestine of CF mice with mild disease, we measured the basal transepithelial potential difference across this tissue as well as the secretory response to agonists of the cAMP and the calcium-mediated signaling pathways. Chloride secretion across the small intestine of mildly affected CF mice was not stimulated by forskolin or by carbachol. The absence of CFTR is thus not compensated by the activity of a distinct, cAMP- or calcium-activated chloride channel at the apical surface of the intestinal epithelium. On the other hand, a basal chloride secretion across the intestinal epithelium was present in these animals, and we hypothesize that this activity may be linked to improved survival of these animals.
 ...
PMID:Non-CFTR chloride channels likely contribute to secretion in the murine small intestine. 1184 13

In cholangiocytes, bile salt (BS) uptake via the apical sodium-dependent bile acid transporter (ASBT) may evoke ductular flow by enhancing cAMP-mediated signaling to the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. We considered that ASBT-mediated BS uptake in the distal ileum might also modulate intestinal fluid secretion. Taurocholate (TC) induced a biphasic rise in the short circuit current across ileal tissue, reflecting transepithelial electrogenic ion transport. This response was sensitive to bumetanide and largely abrogated in Cftr-null mice, indicating that it predominantly reflects CFTR-mediated Cl- secretion. The residual response in Cftr-null mice could be attributed to electrogenic ASBT activity, as it matched the TC-coupled absorptive Na+ flux. TC-evoked Cl- secretion required ASBT-mediated TC uptake, because it was blocked by a selective ASBT inhibitor and was restricted to the distal ileum. Suppression of neurotransmitter or prostaglandin release, blocking of the histamine H1 receptor, or pretreatment with 5-hydroxytryptamine did not abrogate the TC response, suggesting that neurocrine or immune mediators of Cl- secretion are not involved. Responses to TC were retained after carbachol treatment and after permeabilization of the basolateral membrane with nystatin, indicating that BS modulate CFTR channel gating rather than the driving force for Cl- exit. TC-induced Cl- secretion was maintained in cGMP-dependent protein kinase II-deficient mice and only partially inhibited by the cAMP-dependent protein kinase inhibitor H89, suggesting a mechanism of CFTR activation different from cAMP or cGMP signaling. We conclude that active BS absorption in the ileum triggers CFTR activation and, consequently, local salt and water secretion, which may serve to prevent intestinal obstruction in the postprandial state.
 ...
PMID:Activation of CFTR by ASBT-mediated bile salt absorption. 1603 45

The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes a cAMP-regulated chloride channel that is important in controlling the exchange of fluid and electrolytes across epithelial cells. Mutation of CFTR can lead to cystic fibrosis (CF), the most common lethal genetic disease in Caucasians. CF is a systemic illness with multiple organ systems affected including pulmonary, gastrointestinal, pancreatic, immune, endocrine, and reproductive systems. To understand the role of CFTR in the various tissues in which it is expressed, we generated a murine conditional null allele of Cftr (Cftr(fl10)) in which loxP sites were inserted around exon 10 of the Cftr gene. The Cftr(fl10) allele was validated by generating constitutive Cftr null (Cftr(Delta10)) mice using the protamine-cre system. The Cftr(Delta10/Delta10) mice displayed almost identical phenotypes to previously published CF mouse models, including poor growth, decreased survival, intestinal obstruction, and loss of Cftr function as assessed by electrophysiology measurements on gut and nasal epithelium. Mice containing the conditional null Cftr allele will be useful in future studies to understand the role of Cftr in specific tissues and developmental time points and lead to a better understanding of CF disease.
 ...
PMID:Generation of a conditional null allele for Cftr in mice. 1880 65


1 2 Next >>