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At least 1,603 records · Page 89Linked to original sources
PubMed2001

Cytokines influence mRNA expression of cytochrome P450 3A4 and MDRI in intestinal cells.

Inflammation and infection may have the potential to increase the bioavailability of drugs. This effect could be because of a reduced metabolism of xenobiotics in the liver and/or the intestines, or because of alterations in small intestinal permeability, mucosal flow, and expression of drug efflux transporters such as P-glycoprotein (Pgp). To assess the impact on intestinal epithelium of some proinflammatory cytokines and macrophages on permeability and mRNA expression of CYP3A4 and MDRI (multidrug resistance, coding for Pgp), we used the Caco-2 cell line as a model. Exposure to proinflammatory cytokines and macrophages decreased the mRNA expression of CYP3A4 and increased the expression of MDR1 mRNA in the Caco-2 cells. In parallel, the cell layer permeability, as measured by sodium fluorescein flux, increased for all cytokine and macrophage treatments, whereas the effect on transepithelial electrical resistance (TEER) varied. Our findings suggest that inflammation and infection trigger several different cellular responses that may affect drug bioavailability; that is hampered CYP3A4 expression, increased permeability of the epithelial cell layer, and enhanced Pgp-mediated counteractive transport.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Effect of vitamin E nutritional supplementation on the pathological changes induced in the ileum of rabbits by experimental infection with enteropathogenic Escherichia coli.

A well-established rabbit model of enteropathogenic E. coli (EPEC) disease was used to examine whether vitamin E (VE) nutritional supplementation had an effect on the pathological changes induced in the bowel by EPEC. Quantitative methods were used to evaluate the influence of VE on bacterial colonization, intestinal mucosal architecture and inflammation, and intestinal epithelial proliferation and apoptosis. VE did not affect EPEC colonization and did not give significant protection against EPEC-induced changes and diarrhoea. Although VE had no effect on the EPEC-related increase of enterocyte apoptosis, it clearly contributed to an acceleration of epithelial cell proliferation in the ileal crypts. This finding may explain why ileal morphometry undertaken in this study showed that VE ameliorated somewhat the effects of EPEC on intestinal mucosal architecture. Quantitative studies on inflammatory cells in the intestinal mucosa revealed that VE nutritional supplementation resulted in an increased neutrophilic and mononuclear inflammatory cell response to EPEC infection, which did not contribute, however, to the clearance of infection.

Animals↗
PubMed2002

Colonic postoperative inflammatory ileus in the rat.

OBJECTIVE: To investigate local inflammatory events within the colonic muscularis as a causative factor of postoperative ileus. SUMMARY BACKGROUND DATA: Surgically induced intestinal muscularis inflammation has been hypothesized as a mechanism for postoperative ileus. The colon is a crucial component for recovery of gastrointestinal motor function after surgery but remains unaddressed. The authors hypothesize that colonic manipulation initiates inflammatory events that directly mediate postoperative smooth muscle dysfunction. METHODS: Rats underwent colonic manipulation. In vivo transit and colonic motility was estimated using geometric center analysis and intraluminal pressure monitoring. Leukocyte extravasation was investigated in muscularis whole mounts. Mediator mRNA expression was determined by real-time reverse transcriptase-polymerase chain reaction. In vitro circular muscle contractility was assessed in a standard organ bath. The relevance of iNOS and COX-2 inhibition was determined using DFU or L-NIL perfusion. RESULTS: Colonic manipulation resulted in a massive leukocyte recruitment and an increase in inflammatory mRNA expression. This inflammatory response was associated with an impairment of in vivo motor function and an inhibition of in vitro smooth muscle contractility (56%). L-NIL but not DFU significantly ameliorated smooth muscle dysfunction. CONCLUSIONS: The results provide evidence for a surgically initiated local inflammatory cascade within the colonic muscularis that mediates smooth muscle dysfunction, which contributes to postoperative ileus.

Animals↗
PubMed1998

[Ulcerative colitis and intestinal bleeding].

Ulcerative colitis is a nonspecific inflammatory disease of large intestine. Its inflammation is limited to intestinal mucosa. The most essential symptom is hematochezia, bloody stool and intestinal bleeding. Differential diagnosis among diseases having intestinal bleeding is clinically important. These diseases include Crohn disease, ischemic colitis, intestinal Behçet disease, Enterohemorrhagic E. coli including O157, antibiotics associated hemorrhagic colitis and so on. Drugs for the treatment of ulcerative colitis are sulphapyridine, 5-aminosalicylic acid, prednisolone, betamethasone and immunosuppressive drugs. Recently, leukocytapheresis and massive immunoglobulin 7S treatment are available for the treatment of ulcerative colitis.

Anti-Infective Agents↗
PubMed2006

ST2, an IL-1R family member, attenuates inflammation and lethality after intestinal ischemia and reperfusion.

Ischemia reperfusion injury is characterized by local and systemic inflammation leading to considerable mortality. Previously, we have reported that soluble T1/ST2 (sST2), a member of the IL-1 receptor gene family, inhibits LPS-induced macrophage proinflammatory cytokine production. Here, we report the therapeutic effect of sST2-Fc in a murine model of intestinal ischemia reperfusion-induced injury. Administration of sST2-Fc fusion protein i.v., 10 min before reperfusion, reduced the production of TNF-alpha dose-dependently in the intestine and in the lungs. The sST2-Fc treatment with the highest dose (100 mug) resulted in inhibited vascular permeability, neutrophilia, and hemorrhage in the intestine and the lungs compared with controls treated with normal IgG. This was associated with down-regulated tissue levels of proinflammatory cytokines, markedly reduced serum TNF-alpha levels, and increased survival of mice from the sST2-Fc-treated group after ischemia and reperfusion injury. The beneficial effect of sST2-Fc treatment was associated with elevated IL-10 production in intestine and lung. sST2-Fc was not able to prevent the inflammatory response associated with intestinal ischemia and reperfusion in IL-10-deficient mice, suggesting that sST2 exerts its anti-inflammatory effect in a IL-10-dependent manner. These results also demonstrate that sST2-Fc may provide a novel, complementary approach in treating ischemic reperfusion injury.

Animals↗
PubMed2006

Motility disorder in experimentally obstructed intestine: relationship between muscularis inflammation and disruption of the ICC network.

We designed a model of small intestinal obstruction in rats to investigate changes in intestinal contractility associated with the immunologically activated components in the tunica muscularis. Although histochemical study did not reveal any typical inflammatory signs such as leucocyte infiltration in the distended intestinal regions of model rats 2-3 weeks after surgical induction of intestinal obstruction, the number of ED2-positive macrophages appeared to be increased in the tunica muscularis. Expression of tumour necrosis factor (TNF)-alpha mRNA was also significantly increased, and the level of CD14 was also increased significantly in the tunica muscularis. Functional studies of distended intestinal muscle segments showed a marked decrease in absolute force stimulated by a cholinergic agent. In addition, the number of spontaneous rhythmic contractions was also reduced in the distended intestinal regions of the obstructed intestine, and this decrease was associated with a reduction in the number of interstitial cells of Cajal (ICC), as revealed by Kit-like immunoreactivity. These results suggest that, under the pro-inflammatory conditions of the tunica muscularis associated with intestinal obstruction, the release of bioactive substances, possibly from activated resident macrophages, may affect smooth muscle contractility. Furthermore, under these conditions, both the number and the function of neighbouring ICC may also be affected.

Animals↗
PubMed2000

Role of M cells in intestinal barrier function.

M cells are known as specialized epithelial cells of the follicle-associated epithelium of the gastrointestinal tract. As M cells have a high capacity for transcytosis of a wide range of microorganisms and macromolecules, they are believed to act as an antigen sampling system. The primary physiological role of M cells seems to be the rapid uptake and presentation of particular antigens and microorganisms to the immune cells of the lymphoid follicle to induce an effective immune response. In contrast to absorptive enterocytes, M cells do not exert direct defense mechanisms to antigens and pathogens in the gut lumen. Therefore, they provide functional openings of the epithelial barrier. Although M cells represent a weak point of the epithelial barrier, even under noninflamed conditions, there seems to be a balance between antigen uptake and immunological response. The low number of M cells in the gastrointestinal tract and the direct contact to immune cells in the lamina propria usually prevent the occurrence of mucosal inflammation. During chronic intestinal inflammation we observe an increase of M cell number and apoptosis selectively in M cells. M cell damage seems to be responsible for the increase of the uptake of microorganisms that is observed during intestinal inflammation. Under inflammatory conditions in the intestine, the maintenance of the epithelial barrier is broken and M cells seem to play a major role during this process.

Animals↗
PubMed2002

Interleukin 18 is a primary mediator of the inflammation associated with dextran sulphate sodium induced colitis: blocking interleukin 18 attenuates intestinal damage.

BACKGROUND AND AIMS: Persistent inflammation observed in inflammatory bowel disease may be the consequence of an increased or aberrant immune response to normal gut constituents or an overall immune dysregulation and imbalance. Cytokines play an important role in immune regulation and interleukin 18 (IL-18) is one such cytokine that has emerged as being instrumental in driving CD4+ T cell responses towards a Th1-type. IL-18 can also directly mediate inflammation, moderate interleukin 1 activity, and can act on cell types other than T cells. It has been reported recently that IL-18 mRNA and protein are upregulated in gut tissue from IBD patients. The aim of this study was to understand more about the role of IL-18 in contributing to the pathology of IBD and to assess whether blocking IL-18 activity may be of therapeutic benefit as a treatment regimen for IBD. METHODS: Mice with dextran sulphate sodium (DSS) induced colitis were treated with recombinant IL-18 binding protein (IL-18bp.Fc), a soluble protein that blocks IL-18 bioactivity. Histopathological analysis was performed and RNA from the large intestine was analysed using the RNase protection assay and gene arrays. RESULTS: IL-18 RNA levels increased very early in the colon during DSS colitis. Treatment of mice with IL-18bp.Fc inhibited IBD associated weight loss and significantly inhibited the intestinal inflammation induced by DSS. IL-18bp.Fc treatment also attenuated mRNA upregulation of multiple proinflammatory cytokine genes, chemokine genes, and matrix metalloprotease genes in the large intestine that are commonly elevated during IBD. CONCLUSIONS: IL-18bp treatment attenuated inflammation during DSS induced colitis in mice. Neutralising IL-18 activity may therefore be of benefit for ameliorating the inflammation associated with human intestinal diseases.

Animals↗
PubMed2004

Bacterial overgrowth in the cystic fibrosis transmembrane conductance regulator null mouse small intestine.

We recently reported the inflammation of the cystic fibrosis (CF) mouse small intestine, and we hypothesized bacterial overgrowth as a possible cause. Quantitative PCR of bacterial 16S genomic DNA in the CF mouse small intestine revealed an increase of greater than 40-fold compared to controls. Sequencing of 16S PCR products and Gram staining showed that the majority of bacteria in the CF mouse intestine were gram negative. Bacteria were observed to colonize the mucus that accumulates in the intestinal lumen of mice with CF. Impaired Paneth cell defenses were suggested by observation of partially dispersed Paneth granules in the mucus plugs of CF mouse intestinal crypts, and this mucus was strongly immunoreactive for Paneth cell bactericidal products. The role of bacterial overgrowth in intestinal inflammation in CF was tested by treating mice with oral antibiotics (ciprofloxacin and metronidazole) for 3 weeks, which reduced bacterial load in the CF mouse small intestine over 400-fold. Antibiotic treatment decreased the expression of the inflammation-related genes mast cell protease 2, leucine-rich alpha2 glycoprotein/leucine-rich high endothelial venule glycoprotein, suppressor of cytokine signaling 3, hematopoietic cell transcript 1, and resistin-like molecule beta/found in inflammatory zone 2, all of which were no longer expressed at levels significantly different from control levels. The reduction of intestinal bacteria also significantly improved the growth of CF mice but had no effect on the growth of wild-type mice. These data suggest that bacterial overgrowth in the CF mouse small intestine has a role in inflammation and contributes to the failure to thrive in this mouse model of CF.

Animals↗
PubMed2004

Fecal lactoferrin: a new parameter to monitor infliximab therapy.

The glycoprotein lactoferrin is found in many body fluids but also in the granules of neutrophilic granulocytes. Fecal lactoferrin levels increase quickly with the influx of leukocytes into the intestinal lumen during inflammation. This biomarker has recently been shown to be a sensitive and specific marker of disease activity in chronic inflammatory bowel disease. Our aim was the determination of fecal lactoferrin as a marker of intestinal inflammation and therapeutic response following infliximab therapy in pediatric patients with Crohn's disease (CD). A total of five patients (ages 10-15 years) with severe Crohn's disease as defined by the Pediatric Crohn's Disease Activity Index (PCDAI) was enrolled in the study. The fecal lactoferrin levels were determined before and after therapy with infliximab by a quantitative lactoferrin ELISA (IBD-SCAN; TechLab, Inc.). Of the five patients on infliximab therapy, three received a single infusion and the remaining two underwent a regime with three maintenance infusions. All five patients responded to infliximab clinically after the first infusion, and in all patients, fecal lactoferrin levels significantly and rapidly decreased from elevated to near baseline in parallel to clinical assessment and the PCDAI. The reduction in fecal lactoferrin at days 7-10 was 93.43 +/- 4.49%, in comparison with the level before infliximab therapy, and correlated with a mean decrease in the PCDAI from 48.50 to 14.0. For the patients followed during multiple infusions, one remained with mild disease and the other reached remission (subjective and PCDAI). Fecal lactoferrin is a sensitive and specific biomarker representing intestinal inflammation and response to therapy in pediatric patients with Crohn's disease. It may be a helpful noninvasive diagnostic tool for monitoring therapeutic efficiency in pediatric IBD patients. Future studies are needed to further establish the relationship between endoscopic changes and the level of fecal lactoferrin as well as the possible role of lactoferrin as being an early and preclinical indicator of relapse.

Adolescent↗
PubMed1990

Abnormal small bowel permeability and duodenitis in recurrent abdominal pain.

Thirty nine children with recurrent abdominal pain aged between 5.5 and 12 years, underwent endoscopic duodenal biopsy to find out if there were any duodenal inflammatory changes, and if there was a relationship between duodenal inflammation and intestinal permeability to 51Cr-EDTA. Duodenal inflammation was graded by the duodenitis scale of Whitehead et al (grade 0, 1, 2, and 3). In 13 out of 39 patients (33%) definite signs of inflammation were found (grade 2 and 3). Intestinal permeability to 51Cr-EDTA in patients with duodenitis (grade 1, 2, and 3) was significantly higher (4.42 (1.73)%) than in patients with normal (grade 0) duodenal biopsy appearances (3.3 (0.9)%). A significant association was found between duodenal inflammation and abnormal intestinal permeability. Our results give further evidence that there is an intestinal origin of these patients' complaints.

Abdominal Pain↗
PubMed2002

Protease inhibition in the intestinal lumen: attenuation of systemic inflammation and early indicators of multiple organ failure in shock.

Our recent evidence suggests that pancreatic digestive enzymes in the lumen of the intestine may play a major role in the production of cardiovascular stimulatory factors during splachnic artery occlusion and reperfusion. These stimulators are detected in plasma, but their origin and mechanism of production has remained uncertain. We examine here in the rat the role of pancreatic enzymes with and without administration of a serine protease inhibitor (FOY) into the lumen of the small intestine during splanchnic artery occlusion (90 min) and reperfusion (120 min). In the presence of pancreatic enzyme inhibition in the lumen of the intestine, there is significantly enhanced survival rate, lower levels of inflammatory mediator production, the femoral artery blood pressure is maintained close to control levels, and there are significantly lower levels of cell activators in plasma. These results support the hypothesis that pancreatic enzymes may escape across the brush border barrier during intestinal ischemia and thereby initiate the production of a powerful set of cytotoxic mediators. Blockade of pancreatic enzymes in the lumen of the intestine may be a tool to interfere with inflammation and early indicators of multiorgan failure.

Animals↗
PubMed2004

Hypertonic saline prevents inflammation, injury, and impaired intestinal transit after gut ischemia/reperfusion by inducing heme oxygenase 1 enzyme.

BACKGROUND: Hypertonic saline (HTS) has been shown to modulate the inflammatory response after shock. We have previously demonstrated that heme oygenase-1 (HO-1) induction is protective against gut dysfunction in models of shock-induced gut ischemia/reperfusion (I/R). We therefore hypothesized that HTS prevents gut inflammation, injury, and impaired transit by inducing HO-1 in a model of gut I/R. METHODS: Rats underwent 60 minutes of superior mesenteric artery occlusion (SMAO) and then were resuscitated with 4 mL/kg of HTS, an equal volume of lactated Ringer's (LR) solution (4 mL/kg, low volume), or equal salt LR solution (32 mL/kg, high volume) and compared with SMAO alone or shams. A separate group was pretreated with the HO-1 blocker Sn protoporphyrin IX (SNP IX) before SMAO plus HTS. At 6 hours of reperfusion, transit was determined and ileum harvested for HO-1 (anti-inflammatory) and inducible nitric oxide synthase (proinflammatory) immunoreactivity, myeloperoxidase (MPO) activity, and histologic injury. Data are expressed as mean +/- SEM (analysis of variance). RESULTS: Intestinal transit was severely impaired after SMAO (2.5 +/- 0.1), improved with low- and high-volume LR solution (3.2 +/- 0.2 and 3.1 +/- 0.1, not significant), but returned to sham (4.6 +/- 0.2) with HTS (4.8 +/- 0.2). Pretreatment with SNP abrogated this protective effect. Myeloperoxidase activity was significantly increased by SMAO (SMAO, 2.3 +/- 0.3; sham, 0.4 +/- 0.05), lessened by low- and high-volume LR solution (1.5 +/- 0.3 and 1.7 +/- 0.4), but returned to sham levels with HTS (1.0 +/- 0.01). Activity with SNP IX pretreatment was significantly increased (4.04 +/- 0.8). Mucosal injury followed a similar pattern. Inducible nitric oxide synthase was increased by SMAO and low- and high-volume LR solution (0.8 +/- 0.2, 0.8 +/- 0.03, and 0.8 +/- 0.02, respectively; sham, 0.5 +/- 0.02), but significantly reduced by HTS (0.7 +/- 0.02). HO-1 was induced by SMAO and low- and high-volume LR solution (0.33 +/- 0.02, 0.32 +/- 0.03, and 0.37 +/- 0.4, respectively; sham, 0.0 +/- 0.0), but was further increased with HTS (0.49 +/- 0.04). CONCLUSION: HTS resuscitation protects against inflammation, injury, and impaired intestinal transit after gut I/R in part by inducing HO-1. This is a novel mechanism of HO-1 protection.

Animals↗
PubMed1989

[The effect of vasoactive intestinal polypeptide (VIP) on ocular inflammation in rabbit ocular tissue].

Intravitreous injection of vasoactive intestinal polypeptide (VIP) induced ocular inflammation in albino rabbits. Protein amounts and cell numbers in aqueous humor were measured. The effect of VIP on the release of cyclic AMP (cAMP) and prostaglandin E2 (PGE2) from the isolated albino rabbit irides was investigated. Mydriatic response was obtained by intravitreous injection of 0.5 microgram or less VIP. 5 microgram or more of VIP induced miosis and breakdown of the blood aqueous barrier. Intravitreous injection of VIP induced on increase of cAMP in the aqueous humor dose-dependently and a slight increase of PGE2. VIP induced a dose-dependent increase of cAMP release and slightly inhibit PGE2 release from isolated irides. In this study, a large quantity of VIP was injected intravitreously induced breakdown of the blood aqueous barrier. The effect of VIP on isolated irides was to activate the release of cAMP and to inhibit that of PGE2.

Animals↗
PubMed1994

Mechanisms of transit of lipid mediators of inflammation and bacterial peptides across intestinal epithelia.

The transit of two lipid mediators of inflammation, leukotriene B4 (LTB4) and prostaglandin E2 (PGE2), and a formylated peptide produced by intestinal bacteria, N-formylmethionylleucylphenylalanine (FMLP), across Caco-2 cell monolayers was characterized and compared with the transit of mannitol, a hexose known to cross epithelial monolayers by paracellular pathways. The permeability of less mature low-resistance ( < 200 ohm.cm2) monolayers to all four test compounds was similar, but as monolayers matured and the transmonolayer resistance increased, the transit of LTB4, PGE2, FMLP, and mannitol decreased to different degrees, resulting in a selectivity of permeability to the four test compounds in the order LTB4 > PGE2 > mannitol > FMLP. The transit of all four test compounds across Caco-2 cell monolayers was bidirectional, nonsaturable, and energy independent. A small portion of the added LTB4 was incorporated into the cells, whereas the other three compounds were not. Thus the transit of PGE2, mannitol, and FMLP across Caco-2 monolayers appears to be solely by the paracellular pathway, whereas the transit of LTB4 also involves the paracellular pathway but may also involve diffusion through the cell membrane and around tight junctions.

Bacterial Proteins↗
PubMed2005

Effect of chronic cold stress on intestinal epithelial cell proliferation and inflammation in rats.

The present study evaluated the effect of chronic cold stress on intestinal epithelial cell proliferation and inflammation. Male Wistar rats were subjected to cold exposure for three weeks. At the end of the cold exposure, intestinal cell proliferation, luminal nitrite and protein levels, intestinal myeloperoxidase activity and mast cell numbers were evaluated. Severely compromised proliferation rate of the crypt-base cells was observed under chronic stress conditions. Cells isolated from stressed rats showed a decreased DNA content in villus and lower villus cell fractions and an increased DNA content in the crypt cells, as compared to controls. Chronic cold stress resulted in increased luminal nitrite, luminal protein levels, and intestinal myeloperoxidase activity. The number of mast cells was significantly elevated under chronic stress conditions. Chronic cold stress resulted in a compromised intestinal epithelial cell proliferation rate and induced inflammation in the rat small intestine, through the combined action of nitric oxide, neutrophils and mast cells.

Animals↗