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PubMed1993

Intestinal ischemia in the newborn: the role of intestinal maturation.

Premature infants are susceptible to intestinal ischemia during the newborn period when their intestinal tracts are functionally and structurally immature. Studies have shown that exogenous glucocorticoids hasten intestinal maturation. We investigated the effects of hydrocortisone on platelet activating factor (PAF)-induced intestinal ischemia in the neonatal rat. On Postnatal Days 7-11, Sprague-Dawley rats were given intraperitoneal (ip) injections of either saline (SAL) or hydrocortisone (HC; 50 mg/kg total). On Day 12, rats were injected with either PAF (2 micrograms/kg) or an equal volume of saline. After 2 hr the rats were sacrificed and sections were taken for histology. The remaining intestine was analyzed for maltase, lactase, myeloperoxidase (MPO), and xanthine oxidase (XO). Experimental groups were as follows: SAL (N = 8), received saline only; SAL+PAF (N = 8), received saline plus PAF; HC (N = 3), received hydrocortisone+saline; and HC+PAF (N = 5), received hydrocortisone plus PAF. XO was significantly decreased (P < 0.001) in the hydrocortisone-treated groups (HC + SAL = 16.36 +/- 18.42 units/g protein, HC + PAF = 17.33 +/- 9.06 units/g protein) vs the controls (SAL only = 108.90 +/- 20.24 units g/protein, SAL + PAF = 145.77 21.28 units/g protein). MPO was not significantly elevated in SAL + PAF (4.60 +/- 0.95 units/g protein) vs HC + PAF (2.18 +/- 0.80 units/g protein) in this study. Maltase was significantly elevated (P < 0.001) in the HC + PAF (241.46 +/- 40.6 mole/min/g protein) and HC + SAL (152.78 +/- 16.35 mole/min/g protein) vs saline only (28.35 +/- 5.77 mole/min/g protein and SAL + PAF (37.29 +/- 8.70 mole/min/g protein. Animals (7/8) in the SAL + PAF group developed ischemia by inspection and histologic exam.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Effects of the benzodiazepine receptor agonist midazolam and antagonist flumazenil on 5-hydroxytryptamine release from guinea-pig intestine in vitro. Indirect support for a "natural" benzodiazepine-like substance in the intestine.

Isolated segments of the guinea-pig small intestine and the guinea-pig stomach were vascularly perfused and the release of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid into the portal venous effluent determined by high pressure liquid chromatography with electrochemical detection. Test substances were applied intraarterially. The benzodiazepine receptor agonist, midazolam, concentration-dependently increased (by 58%, at 1 nmol/l) and decreased (by 32%, at 100 nmol/l) the release of 5-HT from small intestine preparations. Both effects were blocked by the benzodiazepine receptor antagonist flumazenil (10 nmol/l) The stimulatory effect of midazolam was also abolished in the presence of tetrodotoxin (1 mumol/l) or scopolamine (100 nmol/l). In the absence of tetrodotoxin, flumazenil (10 nmol/l) alone decreased the release of 5-HT from the small intestine by 41%, but it increased the release of 5-HT by 50% in the presence of tetrodotoxin. Both effects of flumazenil were abolished in the presence of bicuculline (50 mumol/l). In the absence of tetrodotoxin, flumazenil (10 nmol/l) decreased also the release of 5-HT and its metabolite from the perfused stomach by about 40%, whereas midazolam (1 nmol/l) caused an increase by about 60%. In conclusion, benzodiazepine receptors modulate the previously described intrinsic GABAergic regulation of 5-HT release from enterochromaffin cells in the guinea-pig intestine. It is suggested that an endogenous benzodiazepine-like substance of non-neuronal origin is present in the small intestine and stomach of the guinea-pig.

Animals↗
PubMed2004

Recipient non-hematopoietic bone marrow cells in the intestinal graft after fetal small intestinal transplantation.

We examined whether non-hematopoietic BM cells can migrate into the intestinal graft after fetal small intestinal transplantation (FSITx). Fetal small intestine from donor C57BL/6 mice was transplanted into the rectus abdominis of recipient C57BL/6 mice with only green fluorescent protein (GFP) BM cells (syngeneic FSITx). Intestinal grafts were harvested on days 5, 10, and 30 after FSITx and stained immunohistochemically using anti-CD45 antibody (a marker for hematopoietic BM cells). Although there were no GFP-positive cells identified in the epithelium of the graft intestinal villi, there were a few cells positive for both GFP and CD45 in the lamina propria on day 5 after FSITx, and many present on days 10 and 30. In some grafts there were only cells that were GFP positive/CD45 negative (i.e., non-hematopoietic BM cells) found in the lamina propria on days 10 and 30. These data indicate that non-hematopoietic BM cells as well as hematopoietic BM cells can migrate from the recipient's bone marrow, suggesting that recipient mesenchymal stem cells may be strongly implicated in graft regeneration and development after FSITx.

Animals↗
PubMed2004

The effect of intestinal plication on intestinal transit time in rats.

Short bowel syndrome (SBS) can occur after extensive intestinal resections. In SBS, the aim of surgical techniques is to prolong intestinal transit time (ITT) and to increase the absorptive surface. This experimental study was conducted to research the effect of extramucosal intestinal plication on ITT in rats. Thirty Sprague-Dawley rats were divided into three groups. In the control group, barium solution was administrated by gavage. Forty-five minutes later, the rats were sacrificed, and the total length of their small bowels (SBs) and the distance of the barium in the SBs were measured. The ratio of the distance of the barium to the length of the SB was calculated, and the ITT was found for normal rats. Intestinal plication (made with three seromuscular sutures at the same level: one on the antimesenteric side, and two on the lateral sides of the bowel) and laparotomy and bowel manipulation were carried out in the study and sham groups, respectively, and ITT was measured by the same method after 1 week. A one-way ANOVA test was used to compare the groups in terms of body weight, total length of the SB, distance of the barium in the SB, and the ratio of this distance to the length of the SB. The rats were statistically homogeneous in terms of body weight and total length of the SB ( p>0.05). The distances of the barium in the small bowel in the control, sham, and study groups were 73.4+/-8.5 cm, 77.5+/-6.8 cm, and 56.3+/-3.6 cm, respectively. The distances of barium in the SB in the study group were statistically shorter than in the other groups ( p<0.05). The ratios of the distance of the barium to the length of the SB in the control, sham, and study groups were 65.8+/-7.3, 66.4+/-4.5, and 49.9+/-3.8, respectively. In the study group, this ratio was also statistically lower than in the other groups ( p<0.05). Extramucosal intestinal plication retarded ITT significantly in the study group compared with the other groups. This technique does not entail any risk of morbidity and mortality; therefore, it can be used in the treatment of SBS.

Animals↗
PubMed1999

Is glutamine essential for the maintenance of intestinal function? A study in the isolated perfused rat small intestine.

Glutamine has received considerable interest as a gut-targeted nutrient due to its proposed key role in the maintenance of intestinal structure and function. We used a preparation of isolated vascularly perfused rat small intestine to investigate whether glutamine is essential for the maintenance of intestinal function. When glutamine was available, arterial glutamine was extracted at 15 +/- 2%, and net uptake was -89 +/- 5 nmol min-1 g-1. Nitrogenous metabolites ammonia, alanine, and citrulline (41 +/- 7, 41 +/- 4, and 11 +/- 2 nmol min-1 g-1, respectively) were released into the venous perfusate, but only ammonia was also excreted into the lumen (36 +/- 3 nmol min-1 g-1). In the absence of exogenous glutamine alanine release was halved and that of citrulline and ammonia nullified. Additional inhibition of glutamine synthetase yielded the same results. In all cases variables of tissue function were fully maintained also in the absence of exogenous and/or endogenous glutamine. The inhibition of glutaminase/amidotransferase reactions, however, was accompanied by a reduction in glutamine consumption and a graded deterioration in tissue function. In conclusion, glutamine seems to be dispensable as a metabolic fuel to be fully oxidized by the mucosa. However, the inhibition of major glutamine consuming pathways was associated with impaired tissue function and viability. Therefore the role of intestinal glutamine metabolism seems to be threefold: (a) providing affluent amounts of nitrogen precursors for mucosal anabolic pathways to maintain intestinal structure and function, (b) feeding the liver with an optimal substrate mix, and (c) providing citrulline and thereby arginine for the whole organism.

Alanine↗
PubMed2005

Expression of small intestinal and colonic phenotypes in complete intestinal metaplasia of the human stomach.

The incomplete intestinal metaplasia (IM) that is reported to be a risk factor for gastric carcinogenesis in man usually features sulfomucin production and thus is considered of colonic type. To cast light on the underlying mechanisms, we here examined the proportions of colonic and small intestinal phenotypes in IM by immunohistochemistry and real-time reverse transcription-polymerase chain reaction at the single isolated gland level. Carbonic anhydrase 1 (CA1) is a specific marker of colonic epithelial cells, whereas sucrase is specific to absorptive cells of the small intestine. Totals of 139 (23.5%) and 452 (76.5%) IM glands were judged to be CA1 positive and CA1 negative, respectively, in resected pyloric mucosa from cancer patients. The average score for MUC5AC in CA1-positive IMs was significantly lower than in CA1-negative counterpart tissue (P<0.0001), whereas the opposite was the case for sucrase (P<0.0001). High iron diamine-Alcian blue staining revealed CA1 expression to coincide with type I complete IM. The expression of CA1 mRNA strongly correlated with that of sucrase-isomaltase, and inversely with that of MUC5AC in isolated IM glands. In conclusion, CA1 could be colocalized with small intestinal proteins such as sucrase, but only rarely with the gastric mucin, MUC5AC. Its expression warrants further study, with the focus on stimulation and/or suppression mechanisms by gastric and intestinal transcription factors.

Biomarkers↗
PubMed2003

Expression of the intestine-specific transcription factors, Cdx1 and Cdx2, correlates shift to an intestinal phenotype in gastric cancer cells.

PURPOSE: It is well known that gastric cancers (GCs) at early stages, independent of the histological type, mainly consist of gastric phenotype malignant cells, while those at advanced stage tend to have a more intestinal phenotype with progression. However, the connection between this shift and expression of homeobox genes, which are important factors to maintain tissue character, has remained unclear. We therefore evaluated the expression of Cdx1/2 in relation to the phenotype of GCs. METHODS: We analyzed the expression of Cdx1/2 mRNAs by Northern blotting and Cdx2 protein by immunohistochemistry in seventy advanced GCs, and evaluated phenotypically using mucin- and immunohistochemistry. RESULTS: Seventy GCs were divided phenotypically into 16 gastric (G type), 18 gastric and intestinal mixed (GI type), 18 intestinal (I type), and 18 null (N type) phenotypes, independent of the histological classification. Cdx1 and Cdx2 mRNAs statistically demonstrated an increase with shift from G to I ( P=0.042 and P=0.0082, respectively). Cdx2 nuclear staining was observed immunohistochemically in the intestinal phenotypic cancer cells, but could not be detected in those with only the gastric phenotype. CONCLUSIONS: These results show that Cdx1 and Cdx2 might be indispensable for intestinal phenotypic expression even in gastric cancer cells.

Biomarkers, Tumor↗
PubMed2004

Effects of intestinal surgery on pulmonary, glomerular, and intestinal permeability, and its relation to the hemodynamics and oxidative stress.

PURPOSE: To investigate the pattern of changes of gut mucosal, glomerular, and pulmonary permeability in response to major resectional intestinal surgery, and to evaluate whether these changes are related to oxidative stress. METHODS: Eight patients undergoing elective intestinal surgery. Lactulose/mannitol ratio (LMR), urinary albumin/creatinine ratio (MACR), and extravascular lung water and its ratio to intrathoracic blood volume (EVLW/ITBV) were measured preoperatively and at different time points postsurgery. The oxidant/antioxidant balance was assessed by measuring thiobarbituric acid-reactive species, reduced glutathione, plasma total antioxidant capacity, superoxide dismutase, and glutathione peroxidase. RESULTS: Uncomplicated intestinal surgery was associated with early increase in LMR and MACR. The EVLW/ITBV ratio increased, but still remained within the normal range. The amount of EVLW was not affected. While renal permeability changes resolved rapidly, increased intestinal permeability persisted longer postoperatively. There was no evidence for any marked disturbances in the oxidant/antioxidant balance. CONCLUSIONS: This pilot study indicated that a moderate increase in gut and renal permeability, even in the absence of clinical sequelae, is an early feature of uncomplicated intestinal surgical trauma. These alterations are not accompanied by any clinically detectable changes in pulmonary permeability.

Adult↗
PubMed2006

In vitro studies of intestinal permeability and hepatic and intestinal metabolism of 8-prenylnaringenin, a potent phytoestrogen from hops (Humulus lupulus L.).

PURPOSE: The absorption potential and metabolism of 8-prenylnaringenin (8-PN) from hops (Humulus lupulus L.) were investigated. 8-PN is a potent estrogen with the potential to be used for the relief of menopausal symptoms in women. METHODS: Monolayers of the human intestinal epithelial cancer cell line Caco-2 and human hepatocytes were incubated with 8-PN to model its intestinal absorption and hepatic metabolism, respectively. RESULTS: The apparent permeability coefficients for 8-PN in the apical-to-basolateral and basolateral-to-apical directions of a Caco-2 monolayer were 5.2 +/- 0.7 x 10(-5) and 4.9 +/- 0.5 x 10(-5) cm/s, respectively, indicating good intestinal absorption via passive diffusion. Both glucuronide and sulfate conjugates of 8-PN were detected in the Caco-2 cell incubations. The 4'-O-glucuronide was the predominant Caco-2 cell metabolite, followed by 7-O-sulfate and 4'-O-sulfate. Both phase I and phase II metabolites of 8-PN were formed by human hepatocytes. The 7-O-glucuronide was the most abundant hepatocyte metabolite, and no sulfate conjugates were detected. Incubations with various cDNA-expressed UDP-glucuronosyltransferases indicated that the isozymes UGT1A1, UGT1A6, UGT1A8, and UGT1A9 were responsible for glucuronidation of 8-PN. CONCLUSIONS: Although orally administered 8-PN should be readily absorbed from the intestine, its bioavailability should be reduced significantly by intestinal and hepatic metabolism.

Caco-2 Cells↗
PubMed1986

Ontogenic and phylogenic studies of intestinal, hepatic, and placental alkaline phosphatases. Evidence that intestinal alkaline phosphatase is a late evolutionary development.

We have studied the intrauterine development of guinea pig and rat organ phosphatases using biochemical, immunologic, and histologic techniques. In all organs tested the features of the adult phosphatase activity were achieved during the second or third gestational phases. In the rat, the tissue-unspecific phosphatase activity was found by immunoprecipitation with antiserum to rat liver phosphatase in all gestational phases in liver and placenta. The high liver activity in the first phase of gestation corresponded to hematopoietic cells. Hepatocyte phosphatase did not appear until the second gestational phase. The tissue-unspecific phosphatase activity was found in the first and second gestational phase in surface intestinal epithelial cells, even after crypt formation occurred. Once phosphatase appeared in enterocytes on villi, only the intestinal-type enzyme was detected. Alkaline phosphatase was measured in the liver and intestine from animals in various phyla. In fish and reptiles, the intestinal activity had the enzymatic characteristics of the tissue-unspecific enzyme. The appearance of intestinal alkaline phosphatase with unique properties and high specific activity is a characteristic of mammals.

Alkaline Phosphatase↗
PubMed1991

In vivo intestinal metabolism of 7-ethoxycoumarin in the rat: production and distribution of phase I and II metabolites in the isolated, perfused intestinal loop.

These studies describe the phase I and II metabolism of 7-ethoxycoumarin (7-EC) in the isolated, perfused intestinal loop. Following cytochrome P450-dependent oxidative deethylation of 7-EC by intestinal epithelial cells, the product, 7-hydroxycoumarin (7-HC), undergoes phase II conjugation to form both the glucuronide and sulfate conjugates. The capacity for conjugation of 7-HC within the intestinal epithelium exceeds that of phase I oxidative deethylation, as demonstrated by the absence of increased release of unconjugated 7-HC upon saturation of the conjugation pathways. The formation of both glucuronide (53-62%) and sulfate (41-43%) conjugates contributed to a comparable extent to the overall phase II metabolism of 7-HC within the intestine. This is in contrast to the liver, where sulfate conjugation has been shown to be the predominant phase II metabolic pathway. Furthermore, it was found that unconjugated and sulfate conjugated 7-HC were evenly distributed between the lumenal perfusate and blood compartments, whereas the glucuronide conjugates of 7-HC were preferentially transported at a 4:1 ratio toward the blood. These results indicate that the epithelial cells of the small intestine have the capacity to biotransform orally administered xenobiotics, and the ultimate profile of metabolites generated may influence the biodisposition of these compounds.

Animals↗
PubMed2005

Intestinal uptake of nateglinide by an intestinal fluorescein transporter.

Nateglinide, a novel oral hypoglycemic agent, rapidly reaches its maximum serum concentration after oral administration, suggesting that it is rapidly absorbed in the intestine. However, nateglinide itself is not transported by MCT1 or PEPT1. The aim of this study was to characterize the transporters on the apical side of the small intestine that are responsible for the rapid absorption of nateglinide. It has been reported that the uptake of fluorescein by Caco-2 cells occurs via an H+-driven transporter and that the intestinal fluorescein transporter is probably not MCT1. We examined the contribution of the fluorescein transporter to the uptake of nateglinide by Caco-2 cells. Fluorescein competitively inhibited H+-dependent nateglinide uptake. All of fluorescein transporter inhibitors examined reduced the uptake of nateglinide. Furthermore, nateglinide inhibited fluorescein uptake. We conclude that the intestinal nateglinide/H+ cotransport system is identical to the intestinal fluorescein/H+ cotransport system.

Absorption↗
PubMed2005

Changes in chicken intestinal zinc exporter mRNA expression and small intestinal functionality following intra-amniotic zinc-methionine administration.

A 303-bp cDNA of intestinal zinc exporter (ZnT1) was isolated from chicken jejunum by reverse transcriptase-polymerase chain reaction and sequenced, and showed 42% homology to Homo sapiens and Rattus novergicus intestinal ZnT1 genes. This specific probe was used to examine the effect of zinc-methionine (ZnMet) administration on the mRNA expression of ZnT1 and on small intestinal development and functionality. In this study, ZnMet was injected into the naturally consumed amniotic fluid of 17-day-old chicken embryos. The ZnT1 gene showed an approximately 200% increase in its mRNA levels from 48 h post-ZnMet injection, as compared to the control. An analysis of the gene expression of the brush-border enzymes and transporters showed increased mRNA expression of sucrase isomaltase, leucine-aminopeptidase, sodium-glucose cotransporter and Na+K+ATPase transporter (Na+K+ATPase) from 48 h post-ZnMet injection, in comparison to controls. Significant increases (P<.05) in the biochemical activity of the brush-border enzymes and transporters, and in jejunal villus surface area were detected from day of hatch (96 h post-ZnMet injection) as compared to controls. These results suggest that ZnMet administration into prenatal intestine via injection into the amniotic fluid enhances intestinal development and improves its functionality.

Amino Acid Sequence↗
PubMed2005

Evaluation of intestinal absorption after longitudinal intestinal lengthening for short bowel syndrome.

PURPOSE: The aim of this study was to answer if the longitudinal intestinal lengthening and tailoring (LILT) by Bianchi, modified by Aigrain, can allow the child to be weaned from parenteral nutrition (PN) and if the length of the bowel after the procedure can influence the results of the absorption test such as Schilling or D-xylose test. PATIENTS AND METHODS: We reviewed the files of 7 children who have had LILT from 1980 to 2003. We performed to explore 2 intestinal function tests: the D-xylose and the Schilling tests. Both were performed early (during the first year after the procedure) and late (during the second year) after the LILT. We used the chi2 and Bartlett's correlation tests for statistical analysis. RESULTS: There were 6 boys and 1 girl. The surgical indication was short bowel syndrome with parenteral nutrition owing to multiple intestinal atresia (2 cases), severe necrotizing enterocolitis with volvulus (1 case), necrotizing enterocolitis (1 case), intestinal atresia with gastroschisis (2 cases), and volvulus owing to malrotation (1 case). The length of the bowel was significantly different before and after LILT (P < .0001). After LILT, the length of the bowel was significantly correlated with the percentage of PN on energy at 6 months (P = .02) and at 12 months (P = .001). Moreover, the length of the bowel after the procedure was significantly correlated with the results of the D-xylose test during the first year (P = .002) but not with the results after the second year. The length after lengthening influenced neither the results of the Schilling test during the first nor those of the second year after. Four patients were weaned from the PN 21 months in average after the LILT (57%); 1 was not because we had only a 2-month follow-up. The average follow-up was 111 (5 months; range, 4-206). CONCLUSION: Longitudinal intestinal lengthening and tailoring for short bowel syndrome is a good option to allow children to be weaned from the PN. The length of the bowel after the procedure can influence the absorption test such as D-xylose during the first postoperative year but not during the second and does not influence the Schilling test. We think it is not necessary to perform these tests during the follow-up of these patients.

Child, Preschool↗
PubMed2004

Adenomatous polyposis coli truncation mutations in 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced intestinal tumours of multiple intestinal neoplasia mice.

The heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces intestinal tumours in C57BL/6J-multiple intestinal neoplasia (Min)/+ mice. The main mechanism for PhIP-induced tumour induction in Min/+ mice is loss of the wild-type adenomatous polyposis coli (Apc) allele, i.e. loss of heterozygosity (LOH). In this study, single injections of either 10, 17.5 or 25 mg/kg PhIP on days 3-6 after birth all increased the mean number of small intestinal tumours two to three-fold, from 37.7 in controls to 124.8 in the PhIP-treated Min/+ mice. In total, we analysed 292 small intestinal tumours and 253 of these had LOH. The frequency of LOH in the Apc gene was 88, 93, 83 and 84% in tumours of 0, 10, 17.5 and 25 mg/kg PhIP-treated mice, respectively. Therefore, these lower doses of PhIP did not reduce the frequency of LOH, as found in our previous study with a single injection of 50 mg/kg PhIP (Mutat. Res. 1-2 (2002) 157). In the second part of this study, we wanted to characterise Apc truncation mutations from tumour samples apparently retaining the Apc wild-type allele from this and two previous experiments with PhIP-exposed Min/+ mice. In the first half of exon 15 in Apc, we verified 25 mutations from 804 tumour samples of PhIP-treated mice. Of these were 60% G-->T transversions, and 16% G deletions, indicating that these are the predominant types of PhIP-induced truncation mutations in the Apc gene in Min/+ mice. Most of the mutations were located between codon 989 and 1156 corresponding to the first part of the beta-catenin binding region. We also identified two Apc truncation mutations from 606 spontaneously formed intestinal tumours from untreated Min/+ mice, one C-->T transition and one T insertion, which were different from those induced by PhIP.

Animals↗
PubMed2000

Inhibitory effect of metformin on intestinal glucose absorption in the perfused rat intestine.

To investigate the effect of metformin on intestinal glucose absorption, a perfusion study of the intestine was performed in the rat. Male Wistar albino rats (8 weeks old) were used in the present study. The glucose absorption by the perfused intestine (788.1+/-81.9 micromol/30 min) was not changed significantly by the direct addition of metformin (90 microg/mL) to the perfusing medium (737.0+/-118.2 micromol/30 min) or by intraduodenal metformin (250 mg/kg in saline solution) infusion (772.8+/-106.3 micromol/30 min). In rats orally administered metformin (250 mg/kg) for 5 days, glucose absorption by the perfused intestine (375.0+/-164.3 micromol/30 min) was significantly (P<0.001) lower than that in control rats (811.0+/-83.1 micromol/30 min). These results indicate that metformin had a significant effect on the digestive tract, and that metformin treatment exerted an inhibitory effect on intestinal glucose absorption in the rat.

Animals↗
PubMed2000

Effects of mu-opioid receptor agonists on intestinal secretion and permeability during acute intestinal inflammation in mice.

We evaluated and compared the effects of mu-opioid receptor agonists on mucosal fluid transport and permeability, during acute intestinal inflammation. We hypothesized that inflammation would sensitize mu-opioid receptors in the submucosal plexus and/or enterocytes enhancing the effects of mu-opioid receptor agonists. Inflammation was induced by intragastric administration of croton oil, whereas controls received saline. Fluid transport was assessed by enteropooling, and intestinal permeability by blood-to-lumen passage of [51Cr] etylenediaminetetraacetate ([51Cr] EDTA). Intestinal inflammation induced a significant increase in enteropooling (1.9 times) and permeability (2.5 times). In saline- and croton oil-treated animals, mu-opioid receptor agonists produced dose-related inhibitions of enteropooling and intestinal permeability. During inflammation, the potency of morphine increased 4.8 and 3.7 times, inhibiting enteropooling and intestinal permeability, respectively; the potencies of fentanyl and PL017 similarly increased by approximately three (enteropooling) and two times (permeability) in croton oil animals. All effects were reversed by naloxone and naloxone methiodide. The results show that inflammation increases the inhibitory potency of mu-opioid receptor agonists on secretion and permeability, suggesting a sensitization of peripheral mu-opioid receptors.

Acute Disease↗
PubMed2000

Intestinal inflammation observed in IL-2R/IL-2 mutant mice is associated with impaired intestinal T lymphopoiesis.

BACKGROUND & AIMS: Although interleukin (IL)-2(-/-) and IL-2Ralpha(-/-) mice develop inflammatory bowel disease, IL-2Rbeta(-/-) animals are apparently free of gut pathology. Intraintestinal T lymphopoiesis is reported to be impaired in IL-2Rbeta(-/-) mice; we have determined whether this characteristic correlated with the apparent resistance of this mutant strain to intestinal inflammation. This led us to reassess intraintestinal T lymphopoiesis in these 3 mutant strains. METHODS: Intestinal histology and intraintestinal T lymphopoiesis were analyzed in unmanipulated mutant mice and in athymic and euthymic radiation chimeras reconstituted with bone marrow derived from IL-2(-/-), IL-2Ralpha(-/-), and IL-2Rbeta(-/-) donors. RESULTS: Intraintestinal T lymphopoiesis was ablated in the 3 mutant strains and was associated with cryptopatch abnormalities. The intestinal mucosa of mice reconstituted with lymphocytes from IL-2Rbeta(-/-) mice exhibited lesions of both the small and large bowel similar to those observed in the early stages of human gluten enteropathy and acute ulcerative colitis, respectively. Analysis of euthymic and athymic bone marrow radiation chimeras indicated that T cells located in the intestinal mucosa of unmanipulated IL-2(-/-), IL-2Ralpha(-/-), and IL-2Rbeta(-/-) mice are of thymic origin. CONCLUSIONS: Null mutations at IL-2/IL-2Ralpha and beta loci differentially affect intraintestinal and intrathymic T lymphopoiesis. These conditions are associated with lesions of intestinal inflammation that are mediated by thymus-derived T cells.

Animals↗