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

Cystic fibrosis results from defects in the gene encoding a cyclic adenosine monophosphate-dependent chloride ion channel known as the cystic fibrosis transmembrane conductance regulator (CFTR). To create an animal model for cystic fibrosis, mice were generated from embryonic stem cells in which the CFTR gene was disrupted by gene targeting. Mice homozygous for the disrupted gene display many features common to young human cystic fibrosis patients, including failure to thrive, meconium ileus, alteration of mucous and serous glands, and obstruction of glandlike structures with inspissated eosinophilic material. Death resulting from intestinal obstruction usually occurs before 40 days of age.
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PMID:An animal model for cystic fibrosis made by gene targeting. 138 Jul 23

Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). A potential animal model of CF, the CFTR-/- mouse, has had limited utility because most mice die from intestinal obstruction during the first month of life. Human CFTR (hCFTR) was expressed in CFTR-/- mice under the control of the rat intestinal fatty acid-binding protein gene promoter. The mice survived and showed functional correction of ileal goblet cell and crypt cell hyperplasia and cyclic adenosine monophosphate-stimulated chloride secretion. These results support the concept that transfer of the hCFTR gene may be a useful strategy for correcting physiologic defects in patients with CF.
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PMID:Correction of lethal intestinal defect in a mouse model of cystic fibrosis by human CFTR. 752 88

Mice that have been made deficient for the cystic fibrosis transmembrane conductance regulator (Cftr) usually die of intestinal obstruction. We have created Cftr-deficient mice and demonstrate prolonged survival among backcross and intercross progeny with different inbred strains, suggesting that modulation of disease severity is genetically determined. A genome scan showed that the major modifier locus maps near the centromere of mouse chromosome 7. Electrophysiological studies on mice with prolonged survival show that the partial rectification of Cl- and Na+ ion transport abnormalities can be explained in part by up-regulation of a calcium-activated Cl- conductance. Identification of modifier genes in our Cftr(m1HSC)/Cftr(m1HSC) mice should provide important insight into the heterogeneous disease presentation observed among CF patients.
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PMID:Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor. 858 19

CFTR, or cystic fibrosis transmembrane conductance regulator, the gene product that is defective in cystic fibrosis, is present in the apical membrane of the epithelial cells from the stomach to the colon. In the foregut, the clinical manifestations are not directly related to the primary defect of the CFTR chloride channel. The most troublesome complaints and symptoms originate from the oesophagus as peptic oesophagitis or oesophageal varices. In the small intestinal wall, the clinical expression of CF depends largely on the decreased secretion of fluid and chloride ions, the increased permeability of the paracellular space between adjacent enterocytes and the sticky mucous cover over the enterocytes. As a rule, the brush border enzyme activities are normal and there is some enhanced active transport as shown for glucose and alanine. The results of continuous enteral feeding of CF patients clearly show that the small intestinal mucosa, in the daily situation, is not functioning at maximal capacity. Although CFTR expression in the colon is lower, the large intestine may be the site of several serious complications such as rectal prolapse, meconium ileus equivalent, intussusception, volvulus and silent appendicitis. In recent years colonic strictures, after the use of high-dose pancreatic enzymes, are being increasingly reported; the condition has recently been called CF fibrosing colonopathy. The CF gastrointestinal content itself differs mainly from the normal condition by the lower acidity in the foregut and the accretion of mucins and proteins, eventually resulting in intestinal obstruction, in the ileum and colon. Better understanding of the CF gastrointestinal phenotype may contribute to improvement of the overall wellbeing of these patients.
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PMID:Gastrointestinal manifestations in cystic fibrosis. 886 67

Mouse models of cystic fibrosis that are generated by targeted disruption (knockout) of the cystic fibrosis transmembrane conductance regulator gene, cftr(-/-), typically die shortly after weaning, from intestinal obstruction/rupture caused by an inability to secrete fluid into the bowel lumen. We investigated the use of a commercial osmotic laxative, Colyte, provided continuously in the drinking water, to increase the survival of cftr(-/-) mice. Genotype analysis of 623 offspring surviving at 10 days of age yielded 28.1% cftr(+/+), 59.6% cftr(+/-), and 12.4% cftr(-/-) mice (25% predicted), suggesting that cftr(-/-) mice have a significant perinatal mortality rate. However, of the 77 cftr(-/-) mice alive at 10 days of age, >98% survived weaning and were maintained in apparent health to a minimum of 56 days of age (arbitrary age for experimentation). In intestinal bioelectric studies Colyte-treated drinking water, compared with tap water, had no significant effect on basal short-circuit current, cyclic AMP-stimulated Cl- secretion, Na+-coupled glucose absorption, or electrogenic Na+ absorption across intestinal sections from cftr(+/+ or +/-) mice. Other than a mild dilatation of the distal portion of the colon in the Colyte-treated animals, examination of jejunal and colonic sections revealed no histologic differences between the two treatments. These findings indicate that the chronic use of Colyte osmotic laxative in drinking water is an economical means of greatly increasing the survival of CFTR knockout mice without altering the major electrolyte transport processes or histomorphologic integrity of the intestine.
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PMID:Increased survival of CFTR knockout mice with an oral osmotic laxative. 900 Nov 72

Cystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population. The primary cellular defect, the reduced expression of the cystic fibrosis transmembrane conductance regulator (CFTR), leading to a chloride secretory defect, is present in all epithelial cells of endodermal and mesodermal origin and has been described in sweat glands, the airway epithelium and the small intestine, the colon and rectum, including the pancreas. In the upper GI-tract the most troublesome complaints and symptoms originating from the esophagus are peptic esophagitis or esophageal varices. In the small intestinal wall, the clinical expression of CF largely depends on the decreased secretion of fluid and chloride ions and the sticky mucous covering the enterocytes. Although CFTR expression in the colon is lower, the large intestine may be the site of several serious complications such as rectal prolapse, distal intestinal obstruction (DIOS), and intussusception. In recent years an increase in colonic strictures after the use of high-dose pancreatic enzymes, has been increasingly reported. CF has also been reported to be increasingly associated with a number of hepatic and/or biliary abnormalities, of which chronic cholestatic liver disease is by far the most relevant. Plugging of intrahepatic bile ducts with inspissated secretions is thought to play a major role in the pathogenesis. It has been estimated that about 15% of cystic fibrosis patients reveal serum liver enzyme abnormalities, but prevalence of liver involvement is likely to be higher. Oral bile acid therapy is promising, but its long-term benefits in terms of survival and prevention of major complications by liver cirrhosis remain to be established. Pancreatic dysfunction in cystic fibrosis (CF) is characterized by an insufficient pancreatic exocrine function. However, 10-15% of CF patients have pancreatic sufficiency and this status is genetically determined by one or two "mild" mutations in the CFTR.
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PMID:[Gastrointestinal complications of adult patients with cystic fibrosis]. 1049 10

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.
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PMID:Cellular localization of the cystic fibrosis transmembrane conductance regulator in mouse intestinal tract. 1095 24

Cystic fibrosis is the most common life-limiting recessive genetic disorder in Caucasian. It is caused by mutations of CFTR gene (cystic fibrosis transmembrane conductance regulator); at present over 500 mutations are known. Cystic fibrosis as a cause of respiratory distress in the neonate is quite rare. In neonatal period the most important clinical manifestations are meconium ileum and much rarely cholestatic jaundice. We present two cases of cystic fibrosis in newborns. In the first one, we point out the strict association between meconium ileum and cystic fibrosis. The patient underwent a surgical treatment for meconium ileum and the diagnosis was rapidly confirmed by genetic analysis and sweat test. The second one had intestinal obstruction from birth caused by meconium ileum associated with ileal atresia; besides, he developed cholestatic jaundice, severe and rapidly progressive respiratory disease. He died at 102 degrees day of age for cardiac failure. The diagnosis of cystic fibrosis, supported by typical clinical features and high level of serum trypsin, unfortunately wasn't confirmed by genetic analysis (lambda F508/neg), in addition, the sweat test wasn't reliable because an inadequate quantity of sweat was collected.
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PMID:[Neonatal cystic fibrosis: report of 2 cases]. 1142 48

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.
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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.
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PMID:Generation of a conditional null allele for Cftr in mice. 1880 65


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