Application of natural products in experimental models of intestinal inflammation in rats.
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Acetic Acid↗
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[Diagnostic accuracy and clinical significance of combined small bowel enema and scintigraphy with pure fractions of neutrophil granulocytes labeled with HMPAO-Tc99m in chronic intestinal inflammation].
Enema is the primary imaging method in the diagnosis of Crohn's disease in the small bowel, with clinical follow-up examinations performed by gastroenterologists as the gold standard. The information provided by small bowel enema, in addition to endoscopic findings, is usually sufficient for the gastroenterologist to make the definitive diagnosis and to plan the whole treatment. Scintigraphy with leukocytes labelled with HMPAO-Tc99m has several unique characteristics favoring its use as a diagnostic imaging method in Crohn's disease and ulcerative colitis. It is a noninvasive method requiring no bowel preparation and it is safe in severely ill patients in whom such conventional imaging methods as barium enema or colonscopy might be hazardous. In this study, the authors report the results of their experience with diagnostic small bowel enema and leukocyte scintigraphy with HMPAO-Tc99m in 28 patients with inflammatory bowel disease (Crohn's disease in 18 patients, ulcerative colitis in 7 and radiation-induced inflammatory stenosis of the sigma-rectum, bowel inflammation after appendicectomy and bladder surgery, respectively, in 1 patient each). Scintigraphy with autologous granulocytes with HMPAO-Tc99m was positive in 26 patients and negative in 2. Twenty-five patients were true positives and 1 was a false positive. Fifteen patients were also submitted to small bowel enema: 12 of them were positive (true positive) and 3 negative (1 false negative and 2 true negative). The results of granulocytes scintigraphy were compared with those of small bowel enema: the radionuclide study appeared superior in the assessment of bowel inflammation associated with Crohn's disease and ulcerative colitis. Indeed, scintigraphy depicted granulocyte uptake in the colon where enema had shown no major findings in 4 patients with Crohn's disease. In the author's opinion, the overall sensitivity, specificity and positive predictive value of combined leukocyte scintigraphy and small bowel enema play a major role in the early diagnosis of Crohn's disease and ulcerative colitis and in the assessment of disease extent and activity.
Adolescent↗
[Effects of gavage with lactococcus lactis recombinant heme oxygenase-1 gene on inflammation of intestine and bacterial translocation in rats with hemorrhagic shock].
OBJECTIVE: To evaluate the effects of gavage with lactococcus lactis (L. Lactis) recombinant heme oxygenase-1 (HO-1) gene on alleviation of intestinal inflammation and protection of the intestinal mucosa in rats with hemorrhagic shock. METHODS: A model of rats with hemorrhagic shock was reproduced in 30 healthy SD male rats. The rats were randomly divided into the L. Lactis recombinant HO-1 gene group (HO group, n=10), L. Lactis group (LL group, n=10) and phosphate buffer group (PBS group, n=10). These agents were respectively gavaged 24 hours before the experiment. Rats were re-anesthetized 1 hour after fluid resuscitation. The mortality, myeloperoxidase (MPO) activity, bacterial translocation, the pathologic changes, the contents of HO-1, tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) in the intestine were determined and compared. RESULTS: Compared with LL group and PBS group, the mortality, Chiu's grade and the bacterial translocation rate of HO group were significantly decreased (all P<0.05) but the content of HO-1 and the level of IL-10 in HO group were markedly increased (both P<0.05). Compared with HO group and LL group, the MPO activity of PBS group was obviously increased (P<0.05). CONCLUSION: The recombinant L. Lactis has the effect to deliver HO-1, which has protective effect on the intestinal mucosa in lessening the inflammation of the intestine and the incidence of bacterial translocation.
Animals↗
Superior mesenteric artery blood flow and indomethacin-induced intestinal injury and inflammation.
Intestinal injury caused by nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with increased mucosal permeability, microvascular injury, focal intravascular thrombus formation, fibrin deposition, and neutrophil infiltration. Ulcerations and adhesions are also prominent feature of this injury. Although NSAID-induced inhibition of prostaglandin formation has been suggested to produce ischemic injury and inflammation, no studies have directly assessed intestinal blood flow in experimental NSAID-induced enteropathy. This study tested the hypothesis that indomethacin-induced small bowel injury and inflammation result from intestinal ischemia. With the use of pulsed Doppler flowmetry, superior mesenteric artery blood flow was continuously monitored in conscious rats after doses of indomethacin known to promote acute and then chronic small bowel inflammation (7.5 mg/kg, 2 sc doses spaced 24 h apart). After 72 h, rats were anesthetized and a section of small bowel was removed for histology and intestinal myeloperoxidase activity measurements. Mean arterial blood pressure was not affected until 32 h after indomethacin, when it decreased 20% (P < 0.05) to P < 0.01). Sustained blood flow changes first occurred at 20 h, when an increase of 15% (P < 0.01) was observed, whereas flow resistance decreased. Flow resistance continued to decrease for the remainder of the 72-h period, and there was an accompanying blood flow increase to +40% (P < 0.05 to P < 0.01). Intestinal ulcers developed in 86% of indomethacin-treated rats. Adhesions, dilation, and thickening of the distal jejunum and proximal ileum were observed in most indomethacin-treated rats. Histological grading of intestinal injury yielded scores of 7.1 +/- 1.2 and zero for indomethacin-treated and vehicle-injected rats, respectively (P < 0.01). Myeloperoxidase activity was greater in indomethacin-treated rats (6.7 +/- 1.9 vs. 1.8 +/- 0.3 U/cm, P < 0.05). These results suggest that indomethacin-induced enteropathy is associated with an increase, not a decrease, in superior mesenteric artery blood flow. Therefore, ischemia dose not appear to be a mechanism by which subcutaneous indomethacin administration produces small intestinal injury and inflammation.
Animals↗
Correlation of desensitisation of platelet activating factor (PAF) receptors with intensity of inflammation and intestinal PAF content during experimental ileitis in guinea pig.
AIM: To determine the kinetics of platelet activating factor (PAF) and prostaglandin E2 (PGE2) receptor desensitisation during intestinal inflammation induced by trinitrobenzenesulphonic acid (TNB) instillation and to study the relation between receptor regulation, inflammatory lesions, and PAF content of the gut wall. METHODS: Receptor desensitisation was assessed on isolated smooth muscle cells from the circular layer. PAF content of the intestinal wall was determined by thin layer chromatography and radioimmunoassay. RESULTS: After an acute inflammatory phase on day 1, subacute changes appeared in TNB instilled ileum, with a maximal intensity on day 6. In control animals, PAF 10 nM and PGE2 10 nM provoked a maximal contraction in the range of 24% of cell shortening. On days 1 and 3 after intestinal instillation of TNB, PAF induced contraction was not altered whereas the effect of PGE2 was progressively desensitised (2 logM rightward shift of its concentration-response curve: Cmax = 1 microM; p < 0.01). Between days 4 and 6, the concentration-response curve of PGE2 shifted by only 1 logM (p < 0.05) whereas the curve of PAF induced contraction shifted by 2 logM (Cmax = 1 microM; p < 0.01). The PAF content of the ileal wall was maximal between days 3 and 5 (300 ng/mg tissue). On days 10 and 15, PAF and PGE2 induced contractions were similar to those observed on day 1, and PAF content returned to basal. CONCLUSION: Inflammation induced by TNB instillation triggers PAF and PGE2 receptor desensitisation; this is dependent on the duration of inflammation and correlates with PAF content in the ileum. This receptor desensitisation may play a protective role by preventing overstimulation of intestinal smooth muscle cells.
Acetylcholine↗
Chemokines in the inflammatory bowel diseases.
Ulcerative colitis and Crohn's disease are characterized by chronic intestinal inflammation. Intestinal bacteria initiate the activation of intestinal inflammatory processes, which are mediated by proinflammatory cytokines and chemokines. In inflammatory bowel disease, intestinal inflammation is not downregulated, in part due to defective or absent inhibitory processes. Studies to date have demonstrated that IL-8, MCP-1, and ENA-78 are highly expressed in the intestinal mucosa in areas of active Crohn's disease and ulcerative colitis. Neutrophils and macrophages in the inflamed intestine synthesize and secrete large amounts of chemokines in patients with inflammatory bowel disease. Increased chemokine expression has also been observed in epithelial cells, endothelial cells, and smooth muscle cells. Future trials of specific agents capable of inhibiting chemokine synthesis and secretion or blocking chemokine-chemokine receptor interaction will be important to study in patients with ulcerative colitis and Crohn's disease.
Animals↗
Antigen-specific T-cell factors induce isotype-like suppression of mast cell and eosinophil-rich T-cell-dependent inflammation in the intestine of mice infected with Trichinella spiralis.
The recent identification of a T-cell-derived antigen-binding molecule (TABM), Trichinella spiralis factor (Tric-F), isolated from culture supernatants of lymphoid cells from mice infected with the intestinal helminth T. spiralis, has led to investigation of the ability of Tric-F to induce a T-cell-dependent feedback circuit that ultimately suppresses the production of other TABMs with similar (isotype-like) features. This form of regulation that has been identified in contact hypersensitivity and in delayed-type hypersensitivity (DTH) responses to tumor cells, was shown not to be antigen-specific but to be DTH-specific. Injection of mice with the TABM called picryl chloride factor (PCl-F) induced suppression of the production of DTH-initiating TABMs of other antigenic specificities. In this study, we report that intravenous injection of mice with Tric-F or PCl-F, 8 days before an oral infection with T. spiralis, induced suppressor cells that inhibited the T-cell-dependent influx into the gut of inflammatory cells, comprising mast cells and eosinophils. Similar results were obtained when the mice were skin sensitized with PCl 8 days prior to a T. spiralis infection, i.e. in a system where TABMs are known to be produced. The phenotype of these suppressor cells was Lyt-1-2+. This suppression preferentially affected the parasite-induced DTH-like response in the gut. In contrast, increased levels of IgA plasma cells in the gut, and worm expulsion were not affected by these treatments. In reciprocal experiments, intravenous injection of Tric-F, or PCl-F, or an oral infection with T. spiralis (that results in the production of TABMs) given 8 days before contact sensitizing mice with PCl, resulted in a suppression of elicitation of cutaneous DTH, as measured by ear swelling. In contrast, pretreatment with anti-dinitrophenyl IgE antibody did not interfere with intestinal inflammation to T. spiralis nor with DTH to PCl. Our results suggest that similar to cutaneous DTH, T. spiralis-specific T-cell factors are involved in the initiation and regulation of the DTH-like mast cell and eosinophil-rich intestinal inflammation that accompanies T. spiralis infections in the gut. Since both Tric-F and PCl-F induce suppression of cellular immune responses in vivo, independent of antigen specificity, it is concluded that Tric-F belongs to the same isotype of TABMs as PCl-F that therefore can be regulated by a non-antigen-specific, isotype-like, T-cell-dependent feedback mechanism.
Animals↗
Modulatory effect of nitric oxide on mast cells during induction of dextran sulfate sodium colitis.
Nitric oxide (NO) is implicated in the pathophysiology of intestinal inflammation. Intestinal mast cells may amplify inflammatory response and mucosal injury in inflammatory bowel disease. Our aim was to examine the role of NO and intestinal mast cells by investigating the effects of NO synthase (NOS) inhibitors and a mast cell stabilizer during induction of dextran sulfate sodium (DSS) colitis. Colitis was induced by 4% DSS in drinking water, in rats pretreated with L-NAME or aminoguanidine. In another set of experiments, we investigated the effect of ketotifen in this setting. Inhibition of NO by L-NAME worsened DSS-induced inflammation, however, aminoguanidine had no effect. On the other hand, ketotifen abolished the deleterious effects of L-NAME on colonic inflammation, suggesting that hyperactivation of mast cells by NOS inhibition amplifies mucosal injury induced by DSS. Our results suggest that constitutive isoforms of NOS prevent mast cell activation.
Animals↗
Relationship between intestinal permeability and calprotectin concentration in gut lavage fluid.
BACKGROUND: Calprotectin is released from neutrophils and monocytes, and increased calprotectin levels in stool may serve as a marker of intestinal inflammation. Intestinal permeability is increased in inflammatory bowel diseases, especially in Crohn disease. We studied the relationship between intestinal permeability and calprotectin concentration in intestinal lavage fluid in patients with known or suspected inflammatory bowel disease (IBD). METHODS: Thirty-eight patients were examined; 17 had Crohn disease; 3, ulcerative colitis; and 18, irritable bowel syndrome. Intestinal lavage was performed by means of a nasojejunal tube positioned by gastroduodenoscopy. By means of a peristaltic pump 2 l isotonic polyethylene glycol solution (MW, 3350) containing 50 microCi 51Cr-labelled ethylenediaminetetraacetic acid (EDTA) were administered through the tube over a period of 40 min. The first clear fluid passed per rectum was collected and analysed for calprotectin levels with an enzyme-linked immunosorbent assay method. Urine was collected for 5 h and analysed for gamma radioactivity. 51Cr-EDTA excretion in urine was expressed as percentage of dose administered (that is, intestinal permeability). RESULTS: Both intestinal permeability and calprotectin concentration were significantly higher in patients with IBD than in patients with functional conditions. In Crohn disease the values depended on disease activity but not on whether the disease was located in the small or in the large bowel. There was a highly significant correlation between calprotectin concentration in gut lavage fluid and intestinal permeability (r=0.79, P<0.0001). CONCLUSION: The significant correlation between calprotectin concentration in gut lavage fluid and intestinal permeability supports the view that increased intestinal permeability in IBD might, at least in part, be a consequence of increased transepithelial migration of neutrophils.
Adult↗
Probiotics and gut inflammation.
The intestine's mucosal surface provides a defense barrier against antigens encountered by the enteric route. In this system a balance is generated and maintained between host and microfloral bacteria. In intestinal inflammation, the integrity of the barrier is disrupted, a greater amount of antigens traverses the mucosal barrier, and the routes of transport are altered, possibly evoking aberrant immune responses and release of proinflammatory cytokines with further impairment of the barrier function. Nutritional therapy remains an attractive tool in the management of intestinal inflammation. The advances this past year are related to the ecologic system provided by specific strains of gut microflora, the concept of healthy microflora, and ways in which gut barrier function could be strengthened by consumption of mono-and mixed cultures of beneficial live microorganisms as probiotics.
Journal Article↗
Inflammation causes hyperplasia and hypertrophy in smooth muscle of rat small intestine.
Inflammation of the rat jejunum with Trichinella spiralis causes altered smooth muscle contractility by day 6 postinfection (PI). We investigated the association of structural change in the smooth muscle layers with inflammation. By day 6 PI, smooth muscle area in cross sections of jejunum increased (P less than 0.05) in longitudinal (LM) and circular (CM) muscle layers. Nuclei counting in cross sections showed that cell number increased two- to threefold in CM and LM, and this increase was not reversed on day 23 PI. Estimation of cell size showed significant hypertrophy by day 6 PI in both muscle layers. [3H]thymidine autoradiography showed that the labeling index (LI) of jejunal LM and CM increased sharply on day 4 PI and peaked on day 6 PI (10- to 15-fold increase). The noninflamed ileum showed a smaller trophic response, with no significant change in area or nuclei number, the LI was increased only on day 6 PI in the ileal CM and was unchanged in LM. Thus extensive hyperplasia and hypertrophy of smooth muscle cells are associated with intestinal inflammation.
Animals↗
[Measuring blood flow velocity in healthy and indomethacin-induced inflammation in rat small intestine serosa with FITC-marked erythrocytes].
Intravital microscopy was performed in normal and indomethacin-induced intestinal inflammation at serosal postcapillary venules of the small bowel in rats. Standard parameters of microcirculation as red blood cell velocity, diameter of venules, blood flow and adherent leucocytes were successfully investigated using FITC-labelled red blood cells. Since postcapillary venules are responsible for the venous drainage of the inflammed small bowel segments this method is reliable and effective for further investigation of intestinal microcirculation under special conditions such as intestinal inflammation.
Animals↗
Role of the Salmonella pathogenicity island 1 effector proteins SipA, SopB, SopE, and SopE2 in Salmonella enterica subspecies 1 serovar Typhimurium colitis in streptomycin-pretreated mice.
Salmonella enterica subspecies 1 serovar Typhimurium (serovar Typhimurium) induces enterocolitis in humans and cattle. The mechanisms of enteric salmonellosis have been studied most extensively in calf infection models. The previous studies established that effector protein translocation into host cells via the Salmonella pathogenicity island 1 (SPI-1) type III secretion system (TTSS) is of central importance in serovar Typhimurium enterocolitis. We recently found that orally streptomycin-pretreated mice provide an alternative model for serovar Typhimurium colitis. In this model the SPI-1 TTSS also plays a key role in the elicitation of intestinal inflammation. However, whether intestinal inflammation in calves and intestinal inflammation in streptomycin-pretreated mice are induced by the same SPI-1 effector proteins is still unclear. Therefore, we analyzed the role of the SPI-1 effector proteins SopB/SigD, SopE, SopE2, and SipA/SspA in elicitation of intestinal inflammation in the murine model. We found that sipA, sopE, and, to a lesser degree, sopE2 contribute to murine colitis, but we could not assign an inflammation phenotype to sopB. These findings are in line with previous studies performed with orally infected calves. Extending these observations, we demonstrated that in addition to SipA, SopE and SopE2 can induce intestinal inflammation independent of each other and in the absence of SopB. In conclusion, our data corroborate the finding that streptomycin-pretreated mice provide a useful model for studying the molecular mechanisms of serovar Typhimurium colitis and are an important starting point for analysis of the molecular events triggered by SopE, SopE2, and SipA in vivo.
Animals↗
Mucosal immunoregulation: transcription factors as possible therapeutic targets.
Much progress has been recently made with regard to our understanding of the mucosal immune system in health and disease. In particular, it has been shown that uncontrolled mucosal immune responses driven by lymphocytes or non-lymphoid cells may lead to immunological diseases such as allergy, hypersensitivity and inflammation. Thus, a more detailed understanding of mucosal immune regulation and decision making at mucosal surfaces is essential for a better understanding of mucosal immune responses in health and disease. Antigen presenting cells and T lymphocytes play a key role in controlling mucosal immune responses. To deal with this key task, T helper cells differentiate into functionally distinct subsets: TH1 (CD4+ T Helper cells), TH2, TH3, Tr1, and CD4+CD25+ T (Treg) cells. This review summarizes the role of antigen presenting cells, eosinophils, mast cells and T-cell subsets in the pathogenesis of allergic inflammation and intestinal inflammation. Furthermore, we discuss novel immunological treatment modalities for allergic inflammation (e.g. allergic asthma) and chronic intestinal inflammation (e.g. inflammatory bowel diseases (IBD)) such as the control of the expression of transcription factors to redirect pathological immune responses.
Animals↗
How to express pharmacological contractions of the inflamed rat intestine.
Inflammation leads to intestinal dysmotility which can be due to both functional and trophic alterations of the neuromuscular apparatus. To discriminate between trophic and functional changes, several normalization procedures are used in contractility studies. It is important to know how normalization procedures may influence the obtained results. In a rat model of TNBS-induced ileitis, we compared seven known normalization procedures for pharmacological contractions of longitudinal muscle strips. During acute ileitis, contractility was significantly decreased, irrespective of the normalization procedure used. During the post-inflammation phase, hypertrophy and hyperplasia of smooth muscle cells led to increased contractility on raw strip chart recordings. However, when contractions were corrected for the increase in muscle mass, the contractility was either normal or decreased, depending on the normalization procedure used. Normalization of contractions to the cross-sectional area (CSA) of the longitudinal muscle is the gold standard. Comparison of three methods to determine the CSA, showed that the commonly used equation to calculate the CSA, based on the tissue weight, length and density, might overestimate the CSA. We conclude that this equation should be adapted by a muscle thickness ratio, or alternatively the CSA can be determined on histological sections.
Acetylcholine↗
Organochlorine concentrations in diseased vs. healthy gull chicks from the northern Baltic.
The population decline of the nominate lesser black-backed gull Larus fuscus fuscus in the Gulf of Finland (northern Baltic) is caused by an exceedingly high chick mortality due to diseases. The chick diseases include degeneration in various internal organs (primarily liver), inflammations (mainly intestinal), and sepsis, the final cause of death. The hypothesis of starvation causing intestinal inflammations (leading to sepsis) was tested by attempting to reproduce lesions in apparently healthy herring gull L. argentatus chicks in captivity. The herring gull chicks were provided a similar low food-intake frequency as observed for the diseased chicks in the wild. However, empty alimentary tract per se did not induce the intestinal inflammations and therefore, inflammations seem to be innate or caused by other environmental factors in the diseased lesser black-backed chicks. They had very high concentrations of PCB in their liver; but the concentrations were not significantly higher than those of the healthy herring gull chicks, indicating a common exposure area for both species (i.e. the Baltic Sea). When compared to NOEL and LOEL values for TEQs in bird eggs our TEQ levels clearly exceed most or all of the values associated with effects. Compared with published data on fish-eating waterbirds, the DDE concentrations in the diseased lesser black-backed chicks were well above the levels previously correlated with decreased reproduction, while the residues in apparently healthy herring gulls were below those levels. The DDE/PCB ratio in lesser black-backs was significantly elevated, indicating an increased exposure to DDTs as compared with most other Baltic and circumpolar seabirds. The possible exposure areas of DDT in relation to differential migration habits of the two gull species are discussed.
Animals↗
Intestinal infection and irritable bowel syndrome.
The observation that the symptoms of irritable bowel syndrome (IBS) in some patients might follow an episode of acute gastroenteritis came from epidemiological studies. Both retrospective and prospective studies suggest that between 4% and 26% of patients develop IBS for the first time after gastroenteritis. The diagnosis of post-infectious IBS is typically made from the history. In addition, as with the diagnosis of IBS more generally, it is important to exclude other clinical causes for persistent bowel dysfunction. There is little, if any, evidence to support the widely-held view that patients with post-infectious IBS carry a better prognosis than IBS patients more generally. The management of patients with post-infectious IBS is the standard approach that might be applied to all patients with IBS. Post-infectious IBS patients may differ from IBS patients in general in having a low-level of intestinal inflammation. Work in animal models, and detection of low-grade inflammation in intestinal biopsies combined with markers of intestinal inflammation such as faecal calprotectin all indicate a strong possibility that persisting inflammation after the acute infection may be important in the pathogenesis of post-infectious IBS.
Bacterial Infections↗
Different susceptibilities of spontaneous rhythmicity and myogenic contractility to intestinal muscularis inflammation in the hapten-induced colitis.
We examined the time-dependent changes in the immunoreactivity of the smooth muscle region and the accompanying motility disorder in a hapten-induced rat model of colitis. Histological analysis and myeloperoxidase (MPO) activity indicated that inflammatory cells infiltrated into the muscle layer at 2 days after 2,4,6-trinitrobenzenesulphonic acid (TNBS) treatment. The infiltrated immune cells then gradually decreased in number, but were still present at 14 days. The expression of proinflammatory cytokine mRNAs (TNF-alpha, IL-1beta and IL-6) and proteins in the muscle layer was increased at 2 days, then began to decrease, returning to control levels at 14 days. The frequency of spontaneous rhythmicity was suppressed at 2 and 7 days, and returned to control levels at 14 days. Consistent with these observations, the immunoreactivity of the interstitial cells of Cajal network was disrupted at 2 and 7 days, which then gradually reformed at 14 days. On the other hand, the myogenic contractions induced by high K(+) and carbachol were decreased at 2 days, and were still inhibited at 14 days. These results suggest that spontaneous rhythmicity dysfunction may improve more rapidly than myogenic contractility dysfunction in a hapten-induced rat model of colitis.
Animals↗