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PubMed2000

Role of inducible nitric oxide synthase in postoperative intestinal smooth muscle dysfunction in rodents.

BACKGROUND & AIMS: We have shown that intestinal manipulation leads to a significant inhibition of circular muscle contraction. We hypothesized that the inflammatory mediator inducible nitric oxide (NO) plays a role in surgically induced ileus. METHODS: Rats and inducible NO synthase (iNOS) knockout and wild-type mice underwent a simple intestinal manipulation. Reverse-transcription polymerase chain reaction and immunohistochemistry were used to detect and localize iNOS expression. Nitrite and NO production were measured in muscularis cultures. Spontaneous and bethanechol-stimulated jejunal circular muscle contractions were measured in an organ bath. RESULTS: Intestinal manipulation resulted in significant iNOS messenger RNA induction in mucosa and muscularis. Immunohistochemistry localized iNOS in phagocytes within the muscularis. Nitrite and NO production increased 59.8-fold 24 hours after manipulation. L-n(6)-(1-iminoethyl) lysine (L-NIL) inhibited this response. In control rats, selective iNOS inhibition did not increase spontaneous muscle activity, but after manipulation L-NIL significantly improved spontaneous activity. iNOS knockout mice showed a significant 81% decrease in neutrophil infiltration into the muscularis after intestinal manipulation compared with wild-types. Contractile activity was normal in knockout mice after intestinal manipulation. CONCLUSIONS: These results show that leukocyte-derived inducible NO inhibits gastrointestinal motility after manipulation and plays an essential role in the initiation of intestinal inflammation.

Animals↗
PubMed2005

Progress in inflammatory bowel disease.

During the past 20 years, advances have been made in Crohn's disease and chronic ulcerative colitis. Despite impressive progress, it is still necessary to call these diseases 'idiopathic', as the details of their etiology remain obscure. Four areas will be reviewed in this article: genetics; intestinal inflammation; the relationship between the gut flora and the mucosa; and medical therapy.

Antibodies, Monoclonal↗
PubMed2002

Adoptive transfer of BALb/c mouse splenocytes reduces lesion severity and induces intestinal pathophysiologic changes in the Mycobacterium avium Subspecies paratuberculosis beige/scid mouse model.

Successful immune reconstitution would enhance resistance of beige/scid mice to chronic infection with Mycobacterium avium subspecies paratuberculosis, but may cause damage to intestinal tissue. Therefore, we investigated the effect of adoptive transfer of BALB/c mouse splenocytes on lesion severity and intestinal physiology in beige/scid mice infected with M. paratuberculosis. Mice were inoculated intraperitoneally (i.p.) with M. paratuberculosis, and two weeks later were inoculated i.p. with viable spleen cells from immune-competent BALB/c mice. Mice were necropsied 12 weeks after infection when engraftment of lymphocytes, clinical disease, pathologic lesions, and intestinal electrophysiologic parameters were evaluated. Lymphocytes were rare in control beige/scid mice not inoculated with spleen cells. In contrast, high numbers of CD4+, CD8+, and B220+ lymphocytes were detected in the spleen of all beige/scid mice (n = 24) inoculated with spleen cells, indicating that adoptive transfer resulted in successful engraftment of donor lymphocytes (immune reconstitution). Immune reconstitution of M. paratuberculosis-infected beige/ scid mice significantly reduced the severity of clinical disease and pathologic lesions, and numbers of bacteria in the liver. However, intestinal electrophysiologic parameters studied in vitro indicated that intestinal tissues from reconstituted beige/scid mice had reduced short-circuit current responses (due to reduced ion secretion) following electrical, glucose, and forskolin stimulation. These abnormal responses suggested that neural or epithelial cells in the intestine were damaged. We conclude that successful immune reconstitution of beige/scid mice enhance their resistance to M. paratuberculosis infection, but may cause pathophysiologic changes associated with intestinal inflammation.

Adoptive Transfer↗
PubMed1995

Egg deposition of the intestinal nematode Heterakis spumosa: stimulation by soluble colon factors of mice.

The nematode Heterakis spumosa lives and develops in the upper colon of mice. The colon mucosa contains soluble factors that significantly increase release of eggs by female H. spumosa in vitro. Egg release is stimulated more when colon factors are prepared from mice harboring adult H. spumosa. Also, soluble factors stimulating egg release can be prepared from homogenates of H. spumosa but are not contained in H. spumosa-conditioned medium. Moreover, soluble factors from the small intestine of mice infected with Heligmosomoides polygyrus also stimulate egg release by H. spumosa females in vitro to about the same extent as soluble factors from the colon of H. spumosa-infected mice. Our data suggest that colon factors are involved in the regulation of egg deposition of H. spumosa, the efficiency of these factors is increased by intestinal inflammation, and that these factors are accumulated by H. spumosa worms.

Animals↗
PubMed2000

Spontaneously developing chronic colitis in IL-10/iNOS double-deficient mice.

Mice deficient in both inducible nitric oxide synthase (iNOS) and interleukin (IL)-10 (iNOS(-/-)/IL-10(-/-)) were created to examine the role of iNOS in spontaneously developing intestinal inflammation. IL-10(-/-)/iNOS(-/-) mice were compared with IL-10(-/-) (iNOS(+/+)) littermates over 6 mo. RT-PCR, Western blot analysis, and immunohistochemistry were performed to measure iNOS message and protein levels. Plasma nitrate/nitrite (NO(x)) levels were assessed by HPLC. Damage scores (macroscopic and microscopic) and granulocyte infiltration were assessed. At 3-4 wk, IL-10(-/-) and IL-10(-/-)/iNOS(-/-) mice had no signs of colonic inflammation or granulocyte infiltration. Plasma NO(x) levels were not different from controls. By 3-4 mo, IL-10(-/-) mice had increased damage scores and granulocyte infiltration concurrent with increased mRNA and protein synthesis (restricted to the epithelium) for iNOS in intestinal tissues but not other tissues. Plasma NO(x) levels increased fivefold. Interestingly, in the absence of iNOS induction or increased plasma NO(x), iNOS(-/-)/IL-10(-/-) mice had damage and granulocyte infiltration equivalent to those observed in IL-10(-/-) littermates. These data suggest that iNOS does not impact on the development or severity of spontaneous chronic inflammation in IL-10-deficient mice.

Age Factors↗
PubMed1997

T cells and cytokines in Crohn's disease.

Recent findings indicate that activated T lymphocytes, showing restricted T-cell receptor repertoire and a Th1-like profile of cytokine production, are responsible for macrophage activation and release of inflammatory cytokines, toxic oxygen metabolites and nitric oxide, which initiate and maintain the transmural intestinal inflammation in Crohn's disease. A critical event in the promotion of Th1-type response at gut level may involve up-regulation of IL-12 production and the breakdown of tolerance against the intestinal flora.

Crohn Disease↗
PubMed2003

The prebiotic characteristics of fructooligosaccharides are necessary for reduction of TNBS-induced colitis in rats.

Fructooligosaccharides (FOS) increase the growth of lactic acid bacteria (LAB) and promote butyrate and lactate production. Because of these properties, FOS may benefit intestinal inflammation. The purpose of this study was to investigate the effect of FOS on colitis in rats and determine which factors are involved. Groups of rats with intracolonic trinitrobenzene sulfonic acid (TNBS)-induced colitis received intragastric infusions of 9 g/L NaCl, 1 g/d FOS or 10(11) colony-forming units (cfu)/d LAB (Experiment 1), or intracolonic infusions of 9 g/L NaCl, butyrate, lactate or butyrate + lactate with or without 10(9.5) cfu/d LAB (Experiment 2). Each infusion was administered twice daily for 14 d. Intragastric FOS reduced the gross score for inflammation (P < 0.001), myeloperoxidase (MPO) activity (P < 0.001) and pH (P < 0.001), and increased lactate (P = 0.02) and butyrate concentrations (P < 0.001) as well as LAB counts in the cecum (P < 0.01). Intragastric LAB (10(11) cfu/d) had the same beneficial effects as FOS and modified the cecal composition similarly. High doses of intracolonic butyrate and lactate reduced the indices of inflammation (P < 0.001), whereas administration of the lower concentrations found in the colon tended to decrease (P < 0.1) the gross score for inflammation and MPO activity. Addition of LAB (10(9.5) cfu/d) to the organic acids was necessary to reproduce the significant FOS-induced effects on these variables. Thus, under the experimental conditions used, FOS reduced intestinal inflammatory activity mainly by increasing LAB counts in the intestine.

Analysis of Variance↗
PubMed2006

Vitamin D receptor is required to control gastrointestinal immunity in IL-10 knockout mice.

The vitamin D receptor (VDR) is a nuclear receptor expressed in a number of different cells of the immune system. This study was performed to determine the effect of VDR deficiency on immune function and inflammation of the gastrointestinal tract in a model of inflammatory bowel disease, namely interleukin-10 (IL-10) knockout mice. IL-10 knockout mice were generated which either could or could not respond to vitamin D (double IL-10/VDR knockout; DKO). The distribution and function of lymphocytes in both the primary and secondary lymphoid organs were compared and determined as a function of the severity of intestinal inflammation. DKO mice had normal thymic development and peripheral T-cell numbers at 3 weeks of age, but a week after intestinal disease was detected the thymus was dysplastic with a reduction in cellularity. The atrophy was coupled with increased apoptosis. The spleen weight of DKO mice increased as a result of the accumulation of red blood cells; however, there was a 50% reduction in the numbers of T and B cells. Conversely, the mesenteric lymph nodes were enlarged and contained increased numbers of lymphocytes. The T cells from DKO mice were of a memory phenotype and were hyporesponsive to T-cell receptor stimulation. Colitis in the DKO mice was associated with local and high expression of IL-2, interferon-gamma, IL-1beta, tumour necrosis factor-alpha and IL-12. The primary and secondary lymphoid organs in DKO mice are profoundly altered as a consequence of the fulminating inflammation in the gastrointestinal tract. VDR expression is required for the T cells and other immune cells to control inflammation in the IL-10 KO mice.

Animals↗
PubMed2000

Neuromuscular dysfunction in the jejunum and colon of human leukocyte antigen B27 transgenic rats.

HLA-B27 transgenic rats are a model of spontaneous gastrointestinal inflammation associated with expression of human leukocyte antigen (HLA) B27 and beta(2)-microglobulin. Our goal was to investigate in vitro enteric nerve regulation and contractile activity in isolated longitudinal muscles from the jejunum and colon of HLA-B27 rats. Nontransgenic age-matched Fisher 344 rats were used as controls. Intestinal inflammation and tissue injury, quantified histologically and through tissue myeloperoxidase activity, were evident in both the jejunum and colon of HLA-B27 rats. Although resting tension and spontaneous activity of the jejunal and colonic muscles from HLA-B27 rats did not differ significantly from controls, responses to both enteric nerve stimulation or direct muscle activation were significantly inhibited. In muscles from HLA-B27 rats, electrical field stimulation (0.5 ms, 0.5-20 Hz) induced low-amplitude contractions (maximal reduction 60-65%) compared with respective controls. In the presence of atropine and guanethidine, nonadrenergic and noncholinergic contractile responses to higher frequencies of stimulation (8-20 Hz) were also of lower amplitude. These changes were accompanied by a shift in neurally mediated contractions from predominantly cholinergic in the jejunum and colon of Fisher 344 rats to predominantly nonadrenergic and noncholinergic in HLA-B27 rats. Furthermore, maximal contractions to carbachol or KCl depolarization were reduced (up to 2.7-fold) compared with respective controls. In the jejunum of HLA-B27 rats the EC(50) level for carbachol was decreased. The data indicate that gastrointestinal inflammation induced by expression of HLA-B27 is associated with hypocontractility and inhibition of enteric cholinergic control of the longitudinal muscle in both the small and large intestine.

Adrenergic Agents↗
PubMed2002

Physical and psychological stress in rats enhances colonic epithelial permeability via peripheral CRH.

Stress may be a contributing factor in intestinal inflammatory disease; however, the underlying mechanisms have not been elucidated. We previously reported that acute stress altered jejunal epithelial physiology. In this study, we examined both physical and psychological stress-induced functional changes in colonic mucosa. Colonic mucosal tissue from rats subjected to either 2 hr of cold-restraint stress or 1 hr of water-avoidance stress demonstrated altered ionic transport as well as significantly elevated baseline conductance (ionic permeability) and flux of horseradish peroxidase (macromolecular permeability). Intraperitoneal pretreatment with the corticotropin-releasing hormone (CRH) antagonist, a helical CRH(9-41), inhibited the stress-induced abnormalities, while exogenous intraperitoneal administration of CRH, to control rats, mimicked the stress responses and in vitro CRH increased the macromolecular permeability. These results suggest that peripheral CRH mediates stress-induced colonic pathophysiology. We speculate that a stress-induced barrier defect may allow uptake of immunogenic substances into the colonic mucosa, initiating or exacerbating intestinal inflammation.

Animals↗
PubMed2003

Role of cannabinoid CB1 receptors and tumor necrosis factor-alpha in the gut and systemic anti-inflammatory activity of SR 141716 (rimonabant) in rodents.

(1) We investigated the effect of the cannabinoid CB1 receptor antagonist, SR 141716, on indomethacin-induced small intestine inflammation and Escherichia coli lipopolysaccharide (LPS)-induced plasma TNF-alpha (TNF) release in comparison to the cannabinoid CB2 receptor antagonist, SR 144528, in rodents. (2) In rats, indomethacin induced significant ulcer formation in the small intestine; this was accompanied by an increase in tissue TNF levels and myeloperoxidase (MPO) activity. SR 141716 prevented the ulcers and the rise in TNF levels (ID50 3.3, 0.4 mg kg-1, respectively) and MPO activity. SR 144528 prevented intestinal ulcers only. (3) The effect of SR 141716 against indomethacin-induced ulcers and increase of plasma TNF levels after LPS was also studied in wild-type and CB1 receptor knockout mice. Indomethacin induced intestinal ulcers in mice, but not tissue TNF production and MPO activity. SR 141716 reduced the ulcers to a similar extent in wild-type and CB1 receptor knockout mice. In rats and wild-type mice, but not in CB1 receptor knockout mice, SR 141716 inhibited the LPS-induced increase in plasma TNF levels. (4) These findings provide evidence that the indomethacin model of intestinal lesions differs in rat and mouse and support the existence of several mechanisms for the antiulcer activity of SR141716, the most important involving the inhibition of TNF production. The potent anti-inflammatory activity of SR141716 in rodents indicated its potential therapeutic interest in chronic immune-inflammatory diseases.

Animals↗
PubMed1999

Neutral endopeptidase (EC 3.4.24.11) terminates colitis by degrading substance P.

Neurogenic inflammation is regulated by sensory nerves and characterized by extravasation of plasma proteins and infiltration of neutrophils from post-capillary venules and arteriolar vasodilatation. Although it is well established that substance P (SP) interacts with the neurokinin 1 receptor (NK1R) to initiate neurogenic inflammation, the mechanisms that terminate inflammation are unknown. We examined whether neutral endopeptidase (NEP), a cell-surface enzyme that degrades SP in the extracellular fluid, terminates neurogenic inflammation in the colon. In NEP knockout mice, the SP concentration in the colon was approximately 2.5-fold higher than in wild-type mice, suggesting increased bioavailability of SP. The extravasation of Evans blue-labeled plasma proteins in the colon of knockout mice under basal conditions was approximately 4-fold higher than in wild-type mice. This elevated plasma leak was attenuated by recombinant NEP or the NK1R antagonist SR140333, and is thus caused by diminished degradation of SP. To determine whether deletion of NEP predisposes mice to uncontrolled inflammation, we compared dinitrobenzene sulfonic acid-induced colitis in wild-type and knockout mice. The severity of colitis, determined by macroscopic and histologic scoring and by myeloperoxidase activity, was markedly worse in knockout than wild-type mice after 3 and 7 days. The exacerbated inflammation in knockout mice was prevented by recombinant NEP and SR140333. Thus, NEP maintains low levels of SP in the extracellular fluid under basal conditions and terminates its proinflammatory effects. Because we have previously shown that intestinal inflammation results in down-regulation of NEP and diminished degradation of SP, our present results suggest that defects in NEP expression contribute to uncontrolled inflammation.

Animals↗
PubMed2006

Glutamine pretreatment reduces IL-8 production in human intestinal epithelial cells by limiting IkappaBalpha ubiquitination.

Glutamine, the most abundant amino acid in the human body, plays several important roles in the intestine. Recent studies showed that glutamine regulates protein metabolism and intestinal inflammation among other mechanisms by reducing proinflammatory cytokine release. Because regulation of the inflammatory response was shown to be linked to proteolysis regulation, we hypothesized that glutamine pretreatment could act on IL-8 production in human intestinal epithelial cells through the regulation of inhibitor kappaB (IkappaB) ubiquitination. The HCT-8 cells were pretreated for 24 h with 0.6, 2, or 10 mmol/L glutamine. IL-8 concentration and IkappaB (free and ubiquitinated) expressions were assessed by ELISA and immunoblotting, respectively. A pretreatment with 10 mmol/L glutamine decreased IL-8 production under both basal and proinflammatory conditions (both P < 0.05). In the presence of a proteasome inhibitor (MG132), the ubiquitin-IkappaBalpha complex expression was not significantly modified by glutamine under basal conditions but decreased significantly under proinflammatory conditions (P < 0.05). After the addition of 10 mmol/L of glutamine, the free IkappaBalpha expression increased under basal and stimulated conditions (both P < 0.05). A glutamine pretreatment of 10 mmol/L did not affect ubiquitin expression or proteasome activity. This study indicates that glutamine pretreatment may reduce the intestinal inflammatory response by limiting the proteolysis of IkappaBalpha.

Cells, Cultured↗
PubMed2006

Comparative proteomic analysis of two Entamoeba histolytica strains with different virulence phenotypes identifies peroxiredoxin as an important component of amoebic virulence.

Entamoeba histolytica is a protozoan intestinal parasite that causes amoebic colitis and amoebic liver abscess. To identify virulence factors of E. histolytica, we first defined the phenotypes of two E. histolytica strains, HM-1:IMSS, the prototype virulent strain, and E. histolytica Rahman, a strain that was reportedly less virulent than HM-1:IMSS. We found that compared with HM-1:IMSS, Rahman has a defect in erythrophagocytosis and the ability to cause amoebic colitis in human colonic xenografts. We used differential in-gel 2D electrophoresis to compare the proteome of Rahman and HM-1:IMSS, and identified six proteins that were differentially expressed above a fivefold level between the two organisms. These included two proteins with antioxidative properties (peroxiredoxin and superoxide dismutase), and three proteins of unknown function, grainin 1, grainin 2 and a protein containing a LIM-domain. Overexpression of peroxiredoxin in Rahman rendered the transgenic trophozoites more resistant to killing by H2O2 in vitro, and infection with Rahman trophozoites expressing higher levels of peroxiredoxin was associated with higher levels of intestinal inflammation in human colonic xenografts, and more severe disease based on histology. In contrast, higher levels of grainin appear to be associated with a reduced virulence phenotype, and E. histolytica HM-1:IMSS trophozoites infecting human intestinal xenografts show marked decreases in grainin expression. Our data indicate that there are definable molecular differences between Rahman and HM-1:IMSS that may explain the phenotypic differences, and identify peroxiredoxin as an important component of virulence in amoebic colitis.

Animals↗
PubMed2005

Bacterial interactions with cells of the intestinal mucosa: Toll-like receptors and NOD2.

Toll-like receptors (TLR) and NOD2 are emerging as key mediators of innate host defence in the intestinal mucosa, crucially involved in maintaining mucosal as well as commensal homeostasis. Recent observations suggest new (patho-) physiological mechanisms of how functional versus dysfunctional TLRx/NOD2 pathways may oppose or favour inflammatory bowel disease (IBD). In health, TLRx signalling protects the intestinal epithelial barrier and confers commensal tolerance whereas NOD2 signalling exerts antimicrobial activity and prevents pathogenic invasion. In disease, aberrant TLRx and/or NOD2 signalling may stimulate diverse inflammatory responses leading to acute and chronic intestinal inflammation with many different clinical phenotypes.

Bacteria↗
PubMed2026

Metabolic Engineering of Probiotic Saccharomyces boulardii Enables Intestinal 3-Hydroxybutyrate Delivery and Alters Short-Chain Fatty Acid Profiles in Mice.

3-Hydroxybutyric acid (3-HB) is a bioactive ketone body involved in the regulation of intestinal inflammation and metabolic homeostasis. Although engineered bacterial probiotics have been developed for localized 3-HB delivery, their susceptibility to antibacterial antibiotics may limit their use during concurrent antibiotic treatment. The probiotic yeast Saccharomyces boulardii offers an alternative host for intestinal 3-HB delivery because of its compatibility with antibacterial antibiotics and the availability of well-established genetic engineering tools. Here, we engineered S. boulardii for 3-HB production using Cas9-mediated genome editing. A heterologous 3-HB biosynthetic pathway was introduced into S. boulardii MYA-797, and endogenous acetyl-CoA and ethanol metabolism was subsequently rewired by overexpressing ACS1, deleting ADH1, and overexpressing ADH7. The optimized strain, SbDY02, produced 1.7 g/L 3-HB under microaerobic conditions. Oral administration of SbDY02 to C57BL/6J mice increased fecal 3-HB and short-chain fatty acid (SCFA) concentrations by 1.89-fold and 1.68-fold, respectively, compared with mice receiving the parental strain. Repeated administration also increased fecal acetate and circulating total SCFAs, butyrate, and propionate. In human colonic epithelial cells, purified 3-HB attenuated lipopolysaccharide-induced p38 MAPK phosphorylation, supporting its direct activity toward inflammation-associated epithelial signaling. To our knowledge, this study provides the first demonstration of a 3-HB-producing probiotic yeast and links central metabolic engineering of S. boulardii with increased 3-HB availability, altered SCFA profiles, and a host-relevant epithelial response.

3-hydroxybutyrate↗
PubMed2004

Review article: the aetiopathogenesis of inflammatory bowel disease--immunology and repair mechanisms.

Although the aetiopathogenesis of Crohn's disease and ulcerative colitis, remains unsolved, current evidence indicates that defective T-cell apoptosis and impairment of intestinal epithelial barrier function play important roles in the pathogenesis of both conditions. Without appropriate control of T-cell proliferation and death during an immune response, an inappropriate accumulation of T cells and subsequent intestinal inflammation may occur. Differences in T-cell responses between Crohn's disease and ulcerative colitis have been identified, with mucosal T-cell apoptosis being defective in Crohn's disease, but not in ulcerative colitis. Furthermore, cell cycling is considerably faster, with a vigorous clonal expansion, in Crohn's disease, whereas, in ulcerative colitis, T cells cycle normally, but have a remarkably reduced capacity to divide and expand. The elimination of excessive T cells therefore seems to be a reasonable approach to restore the gut to a physiological state or, at least, a controlled state of inflammation. The tumour necrosis factor-alpha blocker, infliximab, exerts its beneficial effects, at least in part, by the induction of apoptosis in lamina propria T cells and monocytes. In addition, repeated damage and injury of the intestinal surface is a hallmark of inflammatory bowel disease and may facilitate the entry of luminal antigens into the mammalian organism and the initiation and perpetuation of both nonspecific and specific immune responses. A better understanding of and enhancement of intestinal repair mechanisms may thus provide future approaches for the treatment of inflammatory bowel disease.

Gastrointestinal Tract↗
PubMed1998

Quantitative analysis of small intestinal microcirculation in the mouse.

Impairment of intestinal nutritive perfusion and accumulation of inflammatory cells in the intestinal microvasculature are well-known sequelae of mesenteric ischemia/reperfusion, sepsis, and shock. However, the molecular mechanisms underlying these alterations are still not fully understood. The mouse is particularly suitable for the study of these mechanisms since in this species the involvement of, for example, adhesion receptors or pro-/anti-adhesive mediators can be selectively investigated by the use of monoclonal antibodies or gene-targeted strains. The aim of our present study was, therefore, to establish a model to investigate the microcirculation in the mouse small intestine. Under anesthesia by inhalation of isoflurane-N2O, Balb/c mice (n = 16) were laparotomized, and a segment of the jejunum was exteriorized for intrvital fluorescence microscopy. Using FITC-dextran (MW 150,000) as a plasma marker, functional capillary density (FCD) of both the intestinal mucosa and muscle layer was analyzed. Nutritive perfusion was homogeneous in both compartments with values for FCD of 512 +/- 15 cm-1 in mucosa and 226 +/- 21 cm-1 in the muscle layer. No significant changes were observed throughout the observation period of 2 h (FCD values at the end of the observation period: 524 +/- 31 cm-1 and 207 +/- 7 cm-1 in mucosa and muscle, respectively). Besides capillary perfusion, leukocyte-endothelial cell interaction was analyzed in postcapillary venules of the intestinal submucosa using rhodamine-6G as an in vivo leukocyte stain. Under physiological conditions only a few white blood cells were found rolling along or firmly adherent to the microvascular endothelium (number of rolling leukocytes 1 +/- 0.2 cells/mm per second; number of adherent leukocytes: 18 +/- 7 cells/mm2). In a separate group rhodamine-6G-labeled syngeneic platelets were infused to analyze platelet-endothelial cell interactions quantitatively in vivo. Platelets rolled along or attached to the endothelium in a manner similar to leukocytes. However, in contrast to leukocytes the interactions were not restricted to venules, but were also observed in small arterioles. The newly established model allows for the visualization and quantitative assessment of both nutritive perfusion and platelet/leukocytendothelial cell interactions within the distinct layers of the mouse small intestine. Using this model in combination with gene-targeted mice or monoclonal antibodies it is possible to investigate the molecular mechanisms of intestinal inflammation reactions.

Analysis of Variance↗