Oral Administration Of Dextran Sodium Sulfate Research Articles

A westernized diet changed the colonic bacterial composition and metabolite concentration in a dextran sulfate sodium pig model for ulcerative colitis.

Ulcerative colitis (UC) is characterized by chronic inflammation in the colonic epithelium and has a blurred etiology. A western diet and microbial dysbiosis in the colon were reported to play a role in UC development. In this study, we investigated the effect of a westernized diet, i.e., increasing fat and protein content by including ground beef, on the colonic bacterial composition in a dextran sulfate sodium (DexSS) challenged pig study. The experiment was carried out in three complete blocks following a 2×2 factorial design including 24 six-week old pigs, fed either a standard diet (CT) or the standard diet substituted with 15% ground beef to simulate a typical westernized diet (WD). Colitis was induced in half of the pigs on each dietary treatment by oral administration of DexSS (DSS and WD+DSS, respectively). Samples from proximal and distal colon and feces were collected. Bacterial alpha diversity was unaffected by experimental block, and sample type. In proximal colon, WD group had similar alpha diversity to CT group and the WD+DSS group showed the lowest alpha diversity compared to the other treatment groups. There was a significant interaction between western diet and DexSS for beta diversity, based on Bray-Curtis dissimilarly. The westernized diet and DexSS resulted in three and seven differentially abundant phyla, 21 and 65 species, respectively, mainly associated with the Firmicutes and Bacteroidota phyla followed by Spirochaetota, Desulfobacterota, and Proteobacteria. The concentration of short-chain fatty acids (SCFA) was lowest in the distal colon. Treatment had a slight effect on the estimates for microbial metabolites that might have valuable biological relevance for future studies. The concentration of putrescine in the colon and feces and that of total biogenic amines was highest in the WD+DSS group. We conclude that a westernized diet could be a potential risk factor and an exacerbating agent for UC by reducing the abundance of SCFA-producing bacteria, increasing the abundance of pathogens such as Helicobacter trogontum, and by increasing the concentration of microbial proteolytic-derived metabolites in the colon.

The synbiotic mixture of Bacillus licheniformis and Saccharomyces cerevisiae extract aggravates dextran sulfate sodium induced colitis in rats

BackgroundUncertain effects of probiotics and/or prebiotics have been reported in experimental and clinical colitis. This study aims to examine the effects of a synbiotic combination comprising Bacillus licheniformis DSM 17236 and Saccharomyces cerevisiae cell wall extract on dextran sulfate sodium (DSS)-induced colitis in Sprague Dawley rats.MethodsAcute colitis was induced in rats by oral administration of DSS 3.5% for 7 days. Fifty rats were divided equally into five groups; one control group and the other groups were induced with colitis and treated with or without the tested synbiotic, mixed with diet, for 28 days and sulfasalazine (100 mg/kg) via intragastric tube once daily for 14 days.ResultsSymptomatically, the synbiotic administration raised the disease activity index (DAI) to comparable scores of the DSS group, specially from the 2nd to 7th days post DSS intoxication. It also induced a significant (p < 0.05) amplification of WBCs, myeloperoxidase (MPO), malondialdehyde (MDA), nuclear factor kappa B (NF-kB) expression and proinflammatory cytokines tumor necrosis factor alpha (TNFα), interferon gamma (INFγ), and interleukin-1 beta (IL-1β) while depressed the antioxidant enzymes glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) when compared with the DSS and control groups. The DSS intoxicated and Synbiotic+DSS groups showed desquamations of the covering epithelium, noticeable diffuse leukocytic infiltrations, sever catarrhal enteritis, ischemic colitis with diffuse coagulative necrosis of the entire colonic mucosa. Contrarily, sulfasalazine proved to be effective in the reduction of the tested inflammatory markers and the pathological degenerative changes of the DSS ulcerative colitis.ConclusionThe examined synbiotic did not ameliorate but aggravated the DSS-induced colitis, so it should be subjected to intensive experimental and clinical testing before their use in animals and human.

Dandelion root extracts abolish MAPK pathways to ameliorate experimental mouse ulcerative colitis.

Dextran sodium sulfate (DSS)-triggered ulcerative colitis (UC) model in animals provides a valuable platform to preclinically evaluate the outcome of drug candidates for UC. Dandelion root extracts (DRE) have a therapeutic effect on UC. However, the protective mechanism of DRE against UC remains unknown. To discover the targeting pathway involved in DRE-induced protection against UC. The UC model was developed in C57BL/6 mice by oral administration of DSS. Following DSS exposure, sulfasalazine (SASP), low dose of DRE (DRE-L), moderate dose of DRE (DRE-M), high dose of DRE (DRE-H), and DRE-H plus mitogen-activated protein kinases (MAPK) agonist (DRE-H+MA) were administered to the mice. Colon Mucosal Damage Index (CMDI) and histopathological analysis were used to evaluate the colonic mucosal damage. The cytokine levels were detected using commercial enzyme-linked immunosorbent assay (ELISA) kits. The MAPK pathway activation was determined with western blotting. We found that DRE-H attenuated DSS-triggered colonic mucosal damage. The DSS-induced inflammatory responses and oxidative stress in the bloodstream and colon tissues were dramatically inhibited by DRE-H administration. Also, this plant impaired DSS-provoked phosphorylation levels of extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK), p38 mitogen-activated protein kinases (p38), p65, and IκB. More importantly, MAPK agonist, BIM-23A760, removed the protective effect of DRE-H on the bloodstream and colon tissues. The DRE-H is capable of relieving DSS-induced UC, and its mechanism links to the MAPK pathways.

Abstract 1779: Dietary supplementation of haskap berry anthocyanin and probiotics attenuate the severity of DSS-induced acute colitis in Balb/c mice

Abstract Introduction: Colitis-associated colorectal cancer is a specific type of colorectal cancer that develops from long-standing chronic inflammatory conditions in colorectal epithelium. Genotoxic compounds produced by inflammatory cells can damage DNA and thereby can initiate malignant transformation. Haskap (Lonicera caerulea L.) berry, is a rich source of dietary anthocyanins, specifically cyanidin-3-O-glucoside (C3G). C3G has been shown to possess anti-inflammatory and anti-cancer properties. This study aimed at investigating the oral supplementation of free- or microencapsulated-haskap anthocyanin (310 mg/kg of body weight/mouse) alone or with probiotics (1×109 CFU/day) on the severity reduction of dextran sulphate sodium (DSS)- induced acute colitis in Balb/c mice. Methodology: The study was carried out in two main phases: 1) optimization of microencapsulation of haskap anthocyanin using novel coating materials; and 2) Investigating the combined effect of anthocyanin and probiotics on DSS-induced acute colitis in vivo. Maltodextrin and inulin (3:1 w/w) were used as coating materials and four different core to shell ratios (1:1, 1:1.5, 1:2 and 1:3) were tested. The best ratio (1:1.5) was selected based on the physical characteristics, encapsulation yield, efficiency, recovery, and anthocyanin retention in the particles and was then used in DSS induced acute colitis model. Thirty-five Balb/C male mice of seven weeks old were divided into seven dietary supplementation groups (n=5) to receive either free anthocyanin, microencapsulated anthocyanin, or probiotics alone or as combinations of anthocyanin and probiotics. The colonic inflammation of mice was induced by oral administration of DSS at 3% for 7 days. Attenuation of acute colitis was investigated through clinical data, western blot, histopathology, and ELISA. Results: None of the dietary supplements showed hepatotoxicity in experimental mice hence the tested amounts were in safe limits. Compared with the DSS alone group, anthocyanin + probiotics supplemented group significantly inhibited the severity of colitis as measured by colon shortening, and disease activity index score. All the supplementary diets reduced the expression of occludin but had no effect on claudin-3 and claudin-4 expressions. Histological assessments, measures of inflammatory mediators and characterization of the gut microbiome will be presented. Conclusions: Dietary supplementation of haskap berry anthocyanin + probiotics protects against DSS-induced colitis possibly through attenuating the epithelial inflammation. Citation Format: K.V. Surangi Dharmawansa, Andrew Stadnyk, H.P. Vasantha Rupasinghe. Dietary supplementation of haskap berry anthocyanin and probiotics attenuate the severity of DSS-induced acute colitis in Balb/c mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1779.

Garcinia mangostana Linn. pericarp and alpha-mangostin ameliorate dextran sulfate sodium-induced hepatic injury in mice.

Anti-inflammatory and antioxidant effects of Garcinia mangostana (GM) and α-mangostin (MGS) on dextran sulfate sodium (DSS)-induced hepatotoxicity were examined. Male Institute of Cancer Research (ICR) mice were orally administered GM (40, 200, and 1000 mg/kg/day), MGS (30 mg/kg/day), or sulfasalazine (100 mg/kg/day) for 7 days. Hepatic injury was induced by oral administration of DSS (40 kDa, 6 g/kg/day) on days 4 - 7. Colitis disease activity index (DAI) and serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) were determined on day 7. The livers were removed for histological analysis by hematoxylin and eosin staining, and for determination of myeloperoxidase (MPO) activity, malondialdehyde (MDA) and nitric oxide (NO) levels, and superoxide dismutase (SOD) and catalase (CAT) activities. Expression of inflammatory associated genes, including pro-inflammatory cytokines tumor necrosis factor α (Tnfα) and interleukin 1 beta (Il1β), vascular and intercellular adhesion molecules (Vcam1 and Icam1), chemokine (C-C motif) ligand 2 (Ccl2), nuclear factor of kappa light polypeptide gene enhancer in B cells 1 (Nfkb1), nuclear factor erythroid derived 2 like 2 (Nfe2l2), and toll-like receptor 2 and 4 (Tlr2 and Tlr4) were examined by RT-qPCR. DSS-induced hepatic histopathological changes (cell membrane disruption, pyknotic nuclei, and necrotic areas) corresponded with increases in DAI, serum AST and ALT, MPO activity, and MDA and NO levels, and decreases in SOD and CAT activities. GM and MGS prevented DSS-induced hepatic histopathological changes, reduced MPO activity and MDA and NO levels, and enhanced SOD and CAT activities. GM and MGS prevented DSS-induced upregulation of Tnfα, Il1β, Vcam1, Icam1, Ccl2, Nfkb1, and Tlr4. Sulfasalazine did not indicate any improvement. GM and MGS ameliorated DSS-induced hepatotoxicity via suppression of inflammatory and oxidative responses.

Ethanolic Garcinia mangostana extract and α-mangostin improve dextran sulfate sodium-induced ulcerative colitis via the suppression of inflammatory and oxidative responses in ICR mice

Ethnopharmacological relevanceUlcerative colitis (UC) is an inflammatory disorder of the colon. Garcinia mangostana Linn. (GM) has been traditionally used for its anti-inflammatory and antioxidant activities. Aim of the study:The effects of GM and its bioactive constituent α-mangostin on dextran sulfate sodium (DSS)-induced UC in mice were investigated. Materials and methodsAdult ICR mice (n = 63) were pretreated with ethanolic GM extract at 40, 200, and 1000 mg/kg/day (GM40, GM200, and GM1000), α-mangostin at 30 mg/kg/day, or sulfasalazine at 100 mg/kg/day (SA) for 7 consecutive days. On days 4–7, UC was induced in the mice by the oral administration of DSS (40 kDa, 6 g/kg/day), while control mice received distilled water. The UC disease activity index (DAI) and histological changes were recorded. The activities of myeloperoxidase, catalase, and superoxide dismutase, and the levels of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA) were determined. The mRNA expression of inflammatory related genes including proinflammatory cytokine Tnf-α, Toll-like receptor (Tlr-2), adhesion molecules (Icam-1 and Vcam-1), and monocyte chemoattractant protein (Mcp-1) were evaluated. ResultsTreatment with GM or α-mangostin decreased the UC DAI and protected against colon shortening and spleen and kidney enlargement. GM and α-mangostin prevented histological damage, reduced mast cell infiltration in the colon, and decreased myeloperoxidase activity. GM and α-mangostin increased catalase and superoxide dismutase activity and decreased ROS, NO, and MDA production. GM downregulated mRNA expression of Tnf-α, Tlr-2, Icam-1, Vcam-1, and Mcp-1. ConclusionsGM and α-mangostin attenuated the severity of DSS-induced UC via anti-inflammatory and antioxidant effects. Therefore, GM is a promising candidate for development into a novel therapeutic agent for UC.

Intestinal inflammation induced by dextran sodium sulphate causes liver inflammation and lipid metabolism disfunction in laying hens

Gut inflammation caused by various factors including microbial infection leads to disorder of absorption of dietary nutrients and decrease in egg production in laying hens. We hypothesized that intestinal inflammation may affect egg production in laying hens through its impact on liver function. Dextran sodium sulphate (DSS) is known to induce intestinal inflammation in mammals, but whether it also induces inflammation in laying hens is not known. The goal of this study was to assess whether oral administration of DSS is a useful model of intestinal inflammation in laying hens and to characterize the effects of intestinal inflammation on egg production using this model. White Leghorn hens (350-day old) were administrated with or without 0.9 g of DSS/kg BW in drinking water for 5 D (n = 8, each). All laid eggs were collected, and their whole and eggshell weights were recorded. Blood was collected every day and used for biochemical analysis. Liver and intestinal tissues (duodenum, jejunum, ileum, cecum, cecal-tonsil, and colon) were collected 1 D after the final treatment. These tissue samples were used for histological analysis and PCR analysis. Oral administration of DSS in laying hens caused 1) histological disintegration of the cecal mucosal epithelium and increased monocyte/macrophage infiltration and IL-1β, IL-6, CXCLi2, IL-10, and TGFβ-4 gene expression; 2) decreased egg production; 3) increased leukocyte infiltration and IL-1β, CXCLi2, and IL-10 expression in association with a high frequency of lipopolysaccharide-positive cells in the liver; and 4) decreased expression of genes related to lipid synthesis, lipoprotein uptake, and yolk precursor production. These results suggested that oral administration of DSS is a useful method for inducing intestinal inflammation in laying hens, and intestinal inflammation may reduce egg production by disrupting egg yolk precursor production in association with liver inflammation.

Alterations in biomechanical properties and microstructure of colon wall in early-stage experimental colitis.

The aim of the current study was to investigate the effects of early-stage dextran sodium sulfate (DSS)-induced mouse colitis on the biomechanical properties and microstructure of colon walls. In the present study, colitis was induced in 8-week-old mice by the oral administration of DSS, and then 10 control and 10 experimental colitis samples were harvested. Uniaxial tensile tests were performed to measure the ultimate tensile strength and ultimate stretches of colon tissues. In addition, histological investigations were performed to characterize changes in the microstructure of the colon wall following treatment. The results revealed that the ultimate tensile stresses were 232±33 and 183±25 kPa for the control and DSS groups, respectively (P=0.001). Ultimate stretches at rupture for the control and DSS groups were 1.43±0.04 and 1.51±0.06, respectively (P=0.006). However, there was no statistically significant difference in tissue stiffness between the two groups. Histological analysis demonstrated high numbers of inflammatory cells infiltrated into the stroma in the DSS group, leading to significant submucosa edema. Hyperplasia was also identified in the DSS-treated submucosa, causing a disorganized microstructure within the colon wall. Furthermore, a large number of collagen fibers in the DSS-treated muscular layer were disrupted, and fiber bundles were thinner when compared with the control group. In conclusion, early-stage experimental colitis alters the mechanical properties and microstructural characteristics of the colon walls, further contributing to tissue remodeling in the pathological process.

In-Vivo Effects of GM-CSF Treated Monocytes in Chronic DSS Colitis

Background. Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) has been shown to induce clinical response and remission in patients with active Crohn’s disease (CD). Moreover the beneficial role of GM-CSF was shown in a mouse model of acute colitis induced by Dextran Sodium Sulfate (DSS). Since it is known that GM-CSF has pleiotropic effects on monocytes and since those cells represent the exclusive source of macrophages in inflamed intestinal mucosa we characterized GM-CSF treated mouse monocytes in vitro and analyzed their function in vivo in a model of chronic DSS colitis. Methods. Mouse bone marrow-derived monocyte precursors were treated for 48 hours with GM-CSF in vitro and phenotypical changes were assessed by real-time polymerase chain reaction (qRT-PCR) and flow cytometry. Functional properties were evaluated in mixed lymphocyte reactions (MLR), by phagocytosis assays, adherence to plastic surface, cytokine production upon lipopolysaccharide (LPS) stimulation and measurement of reactive oxygen species (ROS) production. Therapeutic effects of GM-CSF-treated monocytes were evaluated in a model of chronic colitis induced by repeated oral administration of DSS (2%) on three days per week. GM-CSF treated monocytes were administered i.v. one day prior start of the third DSS treatment cycle and the severity of developed colitis was evaluated by body weight change, colon length, histology and expression of inflammatory markers. The distribution of injected GM-CSF-monocytes across intestine was evaluated by in vivo near infrared imaging. Results. We found that GM-CSF-treated monocytes express higher levels of anti-inflammatory molecules on mRNA and protein levels (e.g. IL1-Ra, IL4-R and ARG1). Functionally, GM-CSF promotes ROS production of the cells but reduces phagocytosis and adherence. In MLR we observed an induction of Foxp3 in naive T cells. Clinically, in chronic DSS-induced colitis, treatment of mice with GM-CSF-monocytes showed an overall better outcome compared to mice treated with control monocytes. This encompasses body weight, colon length, mRNA expression of inflammatory marker molecules (e.g. IL6 and TNF) and histological observations. Using in vivo imaging technology we found that a higher percentage of GM-CSF treated monocytes enter the inflamed intestine compared to control monocytes. In addition, GM-CSF-monocytes persisted longer at sides of inflammation. Conclusion. We showed that the beneficial effects of GM-CSF in CD are probably due to its modifying action especially on monocytes and concomitant anti-inflammatory alterations in phenotype and function of macrophages developed from these cells in an experimental model of colitis.

Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome

Aims: The proinflammatory cytokines IL-1β and IL-18 are central players in the pathogenesis of inflammatory bowel disease (IBD). In response to a variety of microbial components and crystalline substances, both cytokines are processed via the caspase-1 activating multi-protein complex, the NLRP3 inflammasome. Here, we examined the role of the NLRP3 inflammasome in experimental colitis induced by dextran sulfate sodium (DSS). Methods: IL-1β production in response to dextran sulfate sodium (DSS) was studied in macrophages of wild-type (WT), caspase-1–/–, NLRP3–/–, ASC–/–, cathepsin B–/– or cathepsin L–/– mice. Colitis was induced in C57BL/6 and NLRP3–/– mice by oral DSS administration. A clinical disease activity score was evaluated daily. Histological colitis severity and expression of cytokines were determined in colonic tissue. Results: Macrophages incubated with DSS in vitro secreted high levels of IL-1β in a caspase-1-dependent manner. IL-1β secretion was abrogated in macrophages lacking NLRP3, ASC or caspase-1, indicating that DSS activates caspase-1 via the NLRP3 inflammasome. Moreover, IL-1β secretion was dependent on phagocytosis, lysosomal maturation, cathepsin B and L, and reactive oxygen species (ROS). After oral administration of DSS, NLRP3–/– mice developed a less severe colitis than WT mice and produced lower levels of proinflammatory cytokines in colonic tissue. Pharmacological inhibition of caspase-1 with pralnacasan achieved a comparable level of mucosal protection as NLRP3 deficiency. Conclusions: We identified the NLRP3 inflammasome as a critical check-point of intestinal inflammation in the DSS colitis model. The NLRP3 inflammasome may serve as a novel target for the development of therapeutics for patients with IBD.

Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome

BackgroundThe proinflammatory cytokines interleukin 1β (IL-1β) and IL-18 are central players in the pathogenesis of inflammatory bowel disease (IBD). In response to a variety of microbial components and crystalline substances,...

Thymic Involution Correlates with Severe Ulcerative Colitis Induced by Oral Administration of Dextran Sulphate Sodium in C57BL/6 Mice but not in BALB/c Mice

There is accumulating evidence to support the interactions between psychological stress and inflammatory bowel disease (IBD). In order to elucidate the relationship between psycoimmunological stress and IBD, we examined the alteration of immune system during the disease course of experimental Ulcerative colitis(UC)-model induced by dextran sulfate sodium (DSS). When C57BL/6 mice were treated with 4.5% DSS, they developed progressive weight loss. In contrast, the same treatment applied to BALB/c mice led to a small weight loss from which they soon recovered. Surprisingly, we found significant involution of the thymus and a reduction in the number of double positive thymocytes in DSS-treated C57BL/6 mice but not in DSS-treated BALB/c mice. Double negative thymocytes, especially DN1 (CD25-CD44+) and DN2 (CD25+CD44+) thymocytes, were relatively upregulated. The weights of spleens were slightly increased in both C57BL/6 and BALB/c mice following oral administration of DSS. In C57BL/6 spleens, both CD4 and CD8 single positive T cells gradually decreased (day 3), then recovered (day 14) after treatment. Because oral administration causes starvation, we examined the effects of starvation on the thymus and spleen. Although involution of thymus was observed both in starvation and DSS-treatment, the weight of spleen was reduced only in starvation. Also, the population changes in thymocytes in starvation was different from DSS-treatment. The administration of the steroid inhibitor RU486 partially reversed the thymic involution in C57BL/6 mice, thus DSS-treated UC might induce psycoimmunological changes partly through hypothalamic-pituitary-adrenal axis.

A2B Adenosine Receptor Gene Deletion Attenuates Murine Colitis

The A(2B) adenosine receptor (A(2B)AR) is the predominant adenosine receptor expressed in the colonic epithelia. We have previously shown that A(2B)AR mRNA and protein levels are up-regulated during colitis. In this study, we addressed the role of the A(2B)AR in the development of murine colitis and the potential mechanism underlying its effects. Dextran sodium sulfate (DSS), 2,4,6-trinitrobenzene sulfonic acid (TNBS), and Salmonella typhimurium were used to induce colitis in A(2B)AR-null mice (A(2B)AR(-/-)). Colitis was determined using established clinical and histologic scoring. Keratinocyte-derived chemokine (KC) measurements were performed using an enzyme-linked immunosorbent assay. Colonic inflammation induced by DSS, TNBS, or S typhimurium was attenuated in A(2B)AR(-/-) compared with their wild-type counterparts. Clinical features, histologic score, and myeloperoxidase activity were significantly decreased in A(2B)AR(-/-) mice. However, A(2B)AR(-/-) showed increased susceptibility to systemic Salmonella infection. Tissue levels of the neutrophil chemokine, KC was decreased in colitic A(2B)AR(-/-) mice. In addition, flagellin-induced KC levels were attenuated in A(2B)AR(-/-) mice. Neutrophil chemotaxis in response to exogenous interleukin-8 was preserved in A(2B)AR(-/-) mice, suggesting intact neutrophil migration in response to appropriate stimuli. These data demonstrate, for the first time, that the A(2B)AR plays a proinflammatory role in colitis. A(2B) receptor antagonism may be an effective treatment for acute inflammatory intestinal diseases such as acute flare of inflammatory bowel disease.

The ICE Inhibitor Pralnacasan Prevents DSS-Induced Colitis in C57BL/6 Mice and Suppresses IP-10 mRNA but Not TNF-α mRNA Expression

Previously we demonstrated an ameliorating effect of the interleukin-1beta converting enzyme (ICE) inhibitor pralnacasan on dextran sulfate sodium (DSS)-induced colitis. This study investigates the effects of pralnacasan on cytokine expression in DSS-induced colitis. Colitis was induced by oral administration of DSS. Mice were treated intraperitoneally with the ICE inhibitor pralnacasan (50 mg/kg body weight twice daily). Body weight as well as the presence of occult blood or diarrhea was monitored daily. Subgroups were sacrificed at days 4, 8, and 11 after the beginning of DSS application. Cytokine profiles in colonic tissue were analyzed on the protein level by ELISA and on the mRNA level by real time RT-PCR. Administration of DSS led to an increase in IL-18, IL-12, TNF-alpha, and IFN-gamma protein as well as IP-10 and TNF-alpha mRNA. The increase in IL-18 and IFN-gamma was reduced by ICE inhibition. Pralnacasan prevented DSS-induced colitis in C57BL/6 mice. In C57BL/6 mice, the DSS-induced increase in IP-10 mRNA, but not TNF-alpha mRNA, was completely prevented by ICE inhibition. In conclusion, prevention of colitis in C57BL/6 mice was associated with a suppresion of IP-10 mRNA, but not TNF-alpha mRNA expression, indicating that IL-18-mediated cytokine production is a key element in the pathogenesis of DSS-induced colitis.

A paradoxical reduction in susceptibility to colonic injury upon targeted transgenic ablation of goblet cells.

Goblet cells are the major mucus-producing cells of the intestine and are presumed to play an important role in mucosal protection. However, their functional role has not been directly assessed in vivo. In initial studies, a 5' flanking sequence of the murine intestinal trefoil factor (ITF) gene was found to confer goblet cell-specific expression of a transgene. To assess the role of goblet cells in the intestine, we generated transgenic mice in which approximately 60% of goblet cells were ablated by the expression of an attenuated diphtheria toxin (DT) gene driven by the ITF promoter; other cell lineages were unaffected. We administered 2 exogenous agents, dextran sodium sulfate (DSS) and acetic acid, to assess the susceptibility of mITF/DT-A transgenic mice to colonic injury. After oral administration of DSS, 55% of control mice died, whereas DT transgenic mice retained their body weight and less than 5% died. Similarly, 30% of the wild-type mice died after mucosal administration of acetic acid, compared with 3.2% of the transgenic mice. Despite the reduction in goblet-cell number, the total amount of ITF was increased in the mITF/DT-A transgenic mice, indicating inducible compensatory mechanisms. These results suggest that goblet cells contribute to mucosal protection and repair predominantly through production of trefoil peptides.

Keratinocyte growth factor ameliorates dextran sodium sulfate colitis in mice.

Keratinocyte growth factor (KGF) is emerging as an important mediator of mucosal defense and repair in the colon. The aim of the present study was to evaluate and further characterize the effects of exogenous KGF administration utilizing the dextran sodium sulfate (DSS) model of colitis in mice. Colitis was induced via oral administration of DSS (5 g/100 ml) to Balb/c mice for eight days. Intraperitoneal administration of KGF (5 mg/kg, once daily) or vehicle (VEH) was initiated 1 hr prior to the induction of the colitis (N = 10, each group). Mucosal injury of the entire colon was histologically assessed and graded. An approximately fourfold reduction in the crypt damage score was noted in the KGF group when compared to controls (VEH) (2.8 +/- 1.03 and 11.4 +/- 0.78, respectively). The significant reduction of mucosal injury in KGF treated mice confirms that KGF is a key mediator maintaining the integrity of the colonic mucosa.