Colitis In Rabbits Research Articles

Choosing the optimal concentration of dextran sulfate sodium for reproducing chemically induced colitis in rabbits

Background. Due to the fact that inflammatory bowel diseases (IBD) are widespread among the population, the development of new drugs for the treatment of IBD is a public health priority. Preclinical drug testing is inextricably linked with the modeling of IBD in laboratory animals. This study purpose was to develop a model of chemically induced colitis in rabbits. Methods. The study was performed on male rabbits of the “Soviet Chinchilla” breed. Colitis was simulated by oral administration of dextran sulfate sodium (DSS) in a concentration of 0.1% to 2% solution for five consecutive days. Euthanasia of laboratory animals was carried out on the seventh day, after the end of taking the DSS solution. A histological examination of the intestine was performed. Results. It was found that using 0.1% DSS solution allows to obtain a model of mild erosive colitis. The use of 0.5% DSS solution gave the intermediate severity of erosive ulcerative colitis. DSS concentration of more than 1% led to the development of severe ulcerative colitis in rabbits and the death rate of 71.4% among them. Conclusion. The obtained results indicate that the use of 0.5% DSS solution makes it possible to create a model of erosive ulcerative colitis in rabbits suitable for studying human IBD.

Colon Targeting of Naringin for Enhanced Cytoprotection Against Indomethacin-Induced Colitis in Rabbits.

BackgroundNaringin is a promising anti-inflammatory drug against various disorders including ulcerative colitis. However, its oral bioavailability is low (8%) possibly due to cleavage at the upper gut. Consequently, colon targeting would be necessary for drug protection at the upper gut, enhanced oral bioavailability and potentiated cytoprotection against colitis.MethodologyThis study involved the formulation of compression-coated tablets of naringin employing mixtures of pH-sensitive Eudragit L100-55 (EUD-L100-55) and different time-dependent polymers including ethyl cellulose (EC), sodium alginate (ALG) and sodium carboxymethyl cellulose (SCMC). Drug–polymer interaction during release was assessed using Fourier transform-infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). Tablets were evaluated in vitro. Surface morphology of the optimized tablets either before or after exposure to the different release media was examined employing scanning electron microscopy (SEM). Cytoprotection potential of the optimized tablets against indomethacin-induced colitis in rabbits was screened and compared to core tablets through a histopathological examination of colon, measurement of serum perinuclear antineutrophil cytoplasmic antibodies (pANCA) and immunohistochemical localization of tumor necrosis factor-alpha (TNF-α).ResultsFT-IR and DSC results may indicate drug–polymers interaction during release. Release retardation could be related to polymer swelling that was in the order of SCMC > ALG > EC. SEM examination indicated more porous coats at the buffers relative to the acidic medium. Colon targeting was expected in case of coats of 5% ALG, 5% SCMC and 10% EC (w/w) in combination with EUD-L100-55; thus, they were selected for in vivo evaluation. Effective cytoprotection of selected tablets against indomethacin-induced colitis was indicated by a significant (P<0.05) reduction in mucosal damage, serum levels of pANCA and TNF-α expression compared to untreated colitis and core-pretreated groups. Compared to EC, higher cytoprotection potential of ALG- and SCMC-based tablets was reflected by lower concentration (5% w/w) to provide cytoprotection against indomethacin-induced colitis.

Oral administration of dextran sodium sulphate induces a caecum-localized colitis in rabbits.

Trichuris suis ova (TSO) have shown promising results in the treatment of inflammatory bowel disease (IBD) but the mechanisms which underlies this therapeutic effect cannot be studied in mice and rats as T.suis fails to colonize the rodent intestine, whilst hatching in humans and rabbits. As a suitable rabbit IBD model is currently not available, we developed a rabbit colitis model by administration of dextran sodium sulphate (DSS). White Himalayan rabbits (n=12) received 0.1% DSS in the daily water supply for five days. Clinical symptoms were monitored daily, and rabbits were sacrificed at different time points. A genomewide expression analysis was performed with RNA isolated from caecal lamina propria mononuclear cells (LPMC) and intestinal epithelial cells (IEC). The disease activity index of DSS rabbits increased up to 2.1±0.4 (n=6) at day 10 (controls <0.5). DSS induced a caecum-localized pathology with crypt architectural distortion, stunted villous surface and inflammatory infiltrate in the lamina propria. The histopathology score reached a peak of 14.2±4.9 (n=4) at day 10 (controls 7.7±0.9, n=5). Expression profiling revealed an enrichment of IBD-related genes in both LPMC and IEC. Innate inflammatory response, Th17 signalling and chemotaxis were among the pathways affected significantly. We describe a reproducible and reliable rabbit model of DSS colitis. Localization of the inflammation in the caecum and its similarities to IBD make this model particularly suitable to study TSO therapy in vivo.

A comparative study of the effect of Asacol and the ethanolic extracts of Matricaria chamomilla and Terminalia chebula on induced ulcerative colitis in rabbits

Twenty four local rabbits were used in this study separated into four groups. Ulcerative colitis (UC) was induced in all rabbits by rectal administration of 5% glacial acetic acid-30% ethanol (GAA 5%). Animals in the control group were orally (p.o) administered with distilled water, group 2 was administered with Asacol at a dose of 800 mg/kg BW/day p.o., where as group 3 was given ethanolic extract of Chamomile at a dose of 500 mg/kg BW/day p.o, and finally; the rabbits of group four were received 1000 mg/kg BW/day p.o of ethanolic extract of Haritaki. Each of the above agents was administered two days prior to induction of UC (as a single daily dose), the day of induction, and a dose 22 hours post-induction (i.e., 2 hours prior to sacrificing of the animal). The effects were observed as changes in the serum electrolytes (sodium and potassium), changes in haematological aspects including; Total white blood cell count (total WBC), lymphocytes count, Red blood cell count (RBC), Blood haemoglobin (HGB), and Packed cell volume (PCV%). Besides the examination of gross and histopathological changes of the colon segments for all the tested rabbits. In conclusion, GAA 5%-induced colitis in rabbits is preferred for testing the anti-inflammatory and anti-ulcer effectiveness of new therapeutic modalities. Asacol showed high potent anti-inflammatory and protective effect against ulceration and inflammation of colon. As well as, ethanolic extracts of both Chamomile and Haritaki have an accepted prophylactic activity against GAA 5%-induced colitis in rabbits through correction of the changed electrolytes, haematological parameters and histopathological signs.

Correlation of neutrophil and monocyte derived interleukin-1 receptor antagonist and interleukin-8 with colitis severity in the rabbit

Activated neutrophils and monocytes produce interleukin (IL)-8, a pro-inflammatory chemokine, but also IL-1 receptor antagonist (IL-1ra), which is an anti-inflammatory cytokine. We were interested to see the profiles of IL-8 and IL-1ra in the colonic tissue and in the peripheral blood leukocytes (PBL) during the development of immune complex induced colitis in rabbits. IL-1ra and IL-8 in PBL were measured in 26 rabbits at time 0h, 24h, and 48h after induction of colitis. The colons were removed at 48h for measuring myeloperoxidase (MPO), ulcer area, IL-1ra and IL-8. Epithelial damage, crypt abscess formation and leukocyte infiltration of the colonic tissue were major features of this colitis model. During the development of colitis, there was an increase in circulating neutrophils and monocytes (P<0.0001), but not lymphocytes. Likewise, elevated amounts of IL-1ra (P=0.0001) and IL-8 (P=0.0219) production by PBL were observed following induction of colitis. Flow cytometry revealed major source of IL-1ra was monocytes, while the main sources of IL-8 were neutrophils and monocytes. There was correlation between MPO and ulcer area (Rs=0.6327, P<0.0001). At 24h, PBL from MPOHigh group (n=11) showed increased IL-1ra (P=0.027) and IL-8 (P=0.0128) levels vs MPOLow group (n=15). IL-8 production by PBL showed correlation with tissue MPO (Rs=0.4273, P=0.0295). The colitis in this model was associated with an increase in circulating monocytes and neutrophils, which released increased amounts of IL-8 and IL-1ra. Further, IL-8 and IL-1ra showed correlation with the severity of colitis. These observations should significantly further understandings on the role of neutrophils and monocytes in the immunopathogenesis of ulcerative colitis.

Ulcerative colitis in rabbits fed degraded carrageenan

Journal Article Ulcerative colitis in rabbits fed degraded carrageenan Get access J Watt, J Watt Department of Pathology, University of Liverpool, Liverpool, UK Search for other works by this author on: Oxford Academic Google Scholar R Marcus R Marcus Clatterbridge Hospital, Bebington, Cheshire, UK Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 22, Issue 2, February 1970, Pages 130–131, https://doi.org/10.1111/j.2042-7158.1970.tb08406.x Published: 12 April 2011 Article history Received: 17 October 1969 Published: 12 April 2011

Sensory neuropeptides and epithelial cell restitution: the relevance of SP- and CGRP-stimulated mast cells

Calcitonin-gene-related peptide (CGRP) and substance P (SP) are neurotransmitters of extrinsic primary afferent neurons located within the dorsal root ganglia. In experimental models of colitis in rats and rabbits, a protective role of SP and CGRP on intestinal mucosa was presumed. The mucosal protection partly depends on a CGRP-mediated modulation of mucosal blood flow. Limited data are available regarding CGRP- or SP-mediated effects on epithelial cell restitution. Having shown earlier that SP-stimulated fibroblasts but not CGRP-stimulated fibroblasts induce epithelial cell migration in vitro, the aim of this study was to explore whether mast cells mediate effects of SP and CGRP on epithelial cell restitution in vitro. Mast cells (C57) were exposed to SP [10(-12)-10(-6 M)] and CGRP [10(-12)-10(-7 M)]. After a 24-h incubation period, the cell supernatants (conditioned media, CDM) were taken from mast cell cultures and directly applied to rat intestinal epithelial cell lines-18 or Caco-2 monolayers, which had been wounded with a razor blade 24 h prior to the experiments. Epithelial cell migration was assessed by counting cells across the wound edge and epithelial cell proliferation was measured using 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide test. CGRP significantly induced epithelial cell migration and proliferation via mast cells when supernatants were directly applied to epithelial cells in vitro. The effects on epithelial cell migration were abolished after neutralizing anti-transforming growth factor-beta (TGF-beta) had been added to the cell cultures. SP had no effects on epithelial cells following stimulation of mast cells. CGRP modulates epithelial cell restitution in vitro mediated by mast cells. The CGRP- and mast-cell-induced epithelial cell migration is TGF-beta dependent. This observation underlines an important role for extrinsic primary afferent neurons in mucosal defence and repair and in keeping the mucosal homeostasis. This knowledge leads to a better understanding of the interaction of the enteric nervous system and wound healing and may, in the future, lead to new therapeutic approaches to inflammatory diseases of the intestine.

Substance P induces intestinal wound healing via fibroblasts—evidence for a TGF-β-dependent effect

Substance P (SP) and calcitonin gene-related peptide (CGRP) are neurotransmitters of the afferent sensory nervous system. In experimental models of colitis in rats and rabbits, a protective role of SP and CGRP on the intestinal mucosa was presumed. In part, mucosal protection depends on a SP-mediated and CGRP-mediated modulation of mucosal blood flow after injury. We thought to explore whether there is a fibroblast-mediated effect of SP and CGRP on epithelial cell restitution in vitro. Rat kidney fibroblast (NRK-49F) cell lines were exposed to CGRP or SP in various concentrations. After incubation, the cell culture supernatants were taken from the fibroblast cultures and were directly applied to IEC-18 or Caco-2 monolayers, which had been wounded with a razor blade 24 h before the experiments. Epithelial cell migration was assessed by counting cells across the wound edge. Epithelial cell proliferation was assessed using the 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide (MTT) test. SP significantly induced epithelial cell migration and inhibited epithelial cell proliferation via stimulation of fibroblasts when supernatants were directly applied to epithelial cells in vitro. The effects on epithelial cell migration were abolished after neutralising anti-transforming growth factor-beta (TGF-beta) was added to the cell cultures. CGRP had no effect on epithelial cells via stimulation of fibroblasts. Neither CGRP nor SP had any effect on epithelial cell migration or proliferation when directly applied to epithelial cells. SP modulates epithelial cell restitution in vitro mediated by fibroblasts. The epithelial cell migration depends on a TGF-beta release from SP-stimulated fibroblasts. This observation underlines an important role for the sensory nervous system in mucosal defence and repair and in keeping mucosal homeostasis. Modulation of SP may be potentially useful for the treatment of various intestinal disorders characterised by injury and ineffective repair of the intestinal mucosa.

Orazipone, a locally acting immunomodulator, ameliorates intestinal radiation injury: A preclinical study in a novel rat model

Intestinal radiation injury (radiation enteropathy) is relevant to cancer treatment, as well as to radiation accidents and radiation terrorism scenarios. This study assessed the protective efficacy of orazipone, a locally-acting small molecule immunomodulator. Male rats were orchiectomized, a 4-cm segment of small bowel was sutured to the inside of the scrotum, a proximal anteperistaltic ileostomy was created for intraluminal drug administration, and intestinal continuity was re-established by end-to-side anastomosis. After three weeks postoperative recovery, the intestine in the "scrotal hernia" was exposed locally to single-dose or fractionated X-radiation. Orazipone (30 mg/kg/day) or vehicle was administered daily through the ileostomy, either during and after irradiation, or only after irradiation. Structural, cellular, and molecular aspects of intestinal radiation toxicity were assessed two weeks after irradiation. Orazipone significantly ameliorated histologic injury and transforming growth factor-beta immunoreactivity levels, both after single-dose and fractionated irradiation. Intestinal wall thickness was significantly reduced after single-dose and nonsignificantly after fractionated irradiation. Mucosal surface area and numbers of mast cells were partially restored by orazipone after single-dose irradiation. This work (1) demonstrates the utility of the ileostomy rat model for intraluminal administration of response modifiers in single-dose and fractionated radiation studies; (2) shows that mucosal immunomodulation during and/or after irradiation ameliorates intestinal toxicity; and (3) highlights important differences between single-dose and fractionated radiation regimens.

Protection against Hemorrhagic Colitis in an Animal Model by Oral Immunization with Isogeneic Rabbit Enteropathogenic Escherichia coli Attenuated by Truncating Intimin

Strains of Shiga toxin (Stx)-producing Escherichia coli, also called enterohemorrhagic E. coli (EHEC), are important food-borne pathogens for humans. Most EHEC strains intimately adhere to the intestinal mucosa in a characteristic attaching and effacing (A/E) pattern, which is mediated by the bacterial adhesin intimin. Subsequent release of Stx1 and/or Stx2 leads to the frequent development of hemorrhagic colitis and, less commonly, to hemolytic-uremic syndrome. The aim of the present study was to develop an attenuated A/E E. coli strain for use as a vaccine against EHEC infection encoding a truncated intimin lacking adhesive capacity, but which would still express somatic antigens, other products of the locus of enterocyte effacement pathogenicity island, and an immunogenic remnant of the intimin molecule. A single-nucleotide deletion was generated in the eae gene in the prototype rabbit A/E E. coli strain RDEC-1 (O15:H-), which resulted in truncation of intimin by 81 C-terminal residues (860 to 939 amino acids) containing a disulfide loop. Inoculation of rabbits with large doses of the truncated intimin mutant (RDEC-1Deltaeae(860-939)) was well tolerated, as observed by the absence of clinical signs of disease or evidence of intestinal A/E lesions. The efficacy of RDEC-1Deltaeae(860-939) as a vaccine was evaluated by orogastric inoculation of rabbits with RDEC-1Deltaeae(860-939) followed by challenge with the virulent strain RDEC-H19A, an Stx1-producing derivative of wild-type RDEC-1 capable of inducing hemorrhagic colitis in rabbits. Following RDEC-H19A challenge, nonimmunized control rabbits exhibited characteristic weight loss with watery to bloody diarrhea and demonstrated intimate bacterial attachment, effacement of microvilli, submucosal edema, mucosal heterophile infiltrates, and Shiga toxin-induced vascular lesions. In contrast, the RDEC-1Deltaeae(860-939)-immunized rabbits showed no clinical signs of disease, maintained normal weight gain, had reduced fecal shedding of challenge organisms, and showed an absence of gross or microscopic lesions in the intestinal mucosa. Serum antibodies specific to intimin were detected among rabbits immunized with RDEC-1Deltaeae(860-939), indicating that truncation of the intimin functional domain not only attenuated bacterial virulence, but also retained at least some of the immunogenicity of native intimin. Although it is not possible to gauge the exact contribution of residual intimin immunity to protection, this attenuation strategy for A/E E. coli strains shows promise for the development of effective vaccines to prevent EHEC infection in humans and animals.

99mTc] liposomes for localizing experimental colitis in arabbit model

[ 99mTc] liposomes (TL) and [ 111In]WBCs (WBCs) were compared for imaging colitis in rabbits. At 24 h, liver was the major organ of accumulation (7.8% TL vs 39.7% WBCs), besides blood (44.1% TL vs 24.4% WBCs) and spleen (0.3% TL vs 7% WBCs). The inflamed colon accumulated 37.1 times more of [ 99mTc] liposomes than the normal colon whereas the ratio was only 15.2 in case of [ 111In] WBCs. The study demonstrates the usefulness of [ 99mTc] liposomes for imaging inflammatory bowel diseases.

Effects of free radicals and leukocytes on increases in blood-brain barrier permeability during colitis.

This study examined the role of leukocytes and free radicals on increases in permeability of the blood-brain barrier (BBB) in rabbits with acute colitis. Trinitrobenzene sulfonic acid (TNBS) was used to induce colitis in male New Zealand White rabbits. The extraction ratio of fluorescein was used as an index of the permeability of the BBB. The extraction ratio for fluorescein was 1.0 x 10(-3) +/- 2 x 10(-4) ml/g and 1.1 x 10(-3) +/- 3 x 10(-4)ml/g (mean +/- SE) for saline (N = 7) and ascorbic acid-treated (N = 8) rabbits with sham colitis. Conversely, TNBS-induced acute colitis increased the extraction ratio over 70% in saline (N = 8) and ascorbic acid-treated (N = 8) animals. Vinblastine significantly reduced the number of circulating leukocytes, whereas the permeability of the BBB was augmented by 54% in rabbits with TNBS-induced acute colitis (N = 8). Vinblastine had no effect on the permeability of the BBB in rabbits with sham colitis (N = 8). These data suggest that free radicals are not responsible for BBB disruption, and leukocytes may protect the BBB during acute colitis.

Anti-Inflammatory Effect of Interleukin-10 in Rabbit Immune Complex-Induced Colitis

Background: Interleukin-10 (IL-10) is an anti-inflammatory cytokine that downregulates the secretion of pro-inflammatory cytokines and additionally induces the secretion of anti-inflammatory cytokines, thus possibly leading to reduction of chronic inflammation in inflammatory bowel disease. In this study we evaluated the anti-inflammatory effect of IL-10 in a model of acute colitis in rabbits. Methods

Substance P gene expression in acute experimental colitis

We have previously shown (Gastroenterology, 101 (1991) 1211–1219), that substance P (SP) decreases early in the colon muscle layer after induction of colitis in rabbits. Since the SP content in the colonic muscle layer was unchanged by sensory denervation with capsaicin, we assume that SP is located predominantly in intrinsic neurons of the colon, and that the decrease of SP during inflammation reflects changes in intrinsic SP content. However, damage of SP neurons by inflammation would be another likely explanation for the decrease in SP content. The aim of this study was to determine SP gene expression in intrinsic (colonic muscle layer) and extrinsic (dorsal root ganglia, DRG) neurons to prove that SP transcription is preserved during colitis as an indicator of neuronal integrity. Colitis was induced in adult white New Zealand rabbits by formalin enemas (4 ml of 0.4% formalin) followed by 0.85 ml immune complex i.v. 2 h later. The animals were sacrificed 48 h after induction of colitis, and SP content and gene expression were determined by radioimmunoassay (RIA) and Northern blot analysis, respectively. Immunoreactive SP was reduced by 40% in the colon muscle layer and by 60% in the dorsal root ganglia (L 4 S 4) in the animals with colitis compared to controls without colitis. In contrast to the protein data, SP gene expression was not significantly altered in the colon muscle layer and the dorsal root ganglia 48 h after induction of inflammation compared to the control tissue. The preserved SP gene expression suggests that the intrinsic and extrinsic SP neurons are viable in this inflammatory model. The decreases of immunoreactive SP in the colonic extracts and the DRG after induction of colitis suggest that SP is released from extrinsic and intrinsic neurons during inflammation.

Mucosal eicosanoid synthesis and epithelial permeability in E. Coli O157:H7 colitis in rabbits: [formula omitted], E. Elliott & E. O'Loughlin. Royal North Shore Hospital, St Leonards, The Children's Hospital, Camperdown & The John Hunter Hospital, New Lambton, NSW, Australia

Mucosal eicosanoid synthesis and epithelial permeability in E. Coli O157:H7 colitis in rabbits: [formula omitted], E. Elliott & E. O'Loughlin. Royal North Shore Hospital, St Leonards, The Children's Hospital, Camperdown & The John Hunter Hospital, New Lambton, NSW, Australia

Colonic inflammation in the rabbit induced by phorbol-12-myristate-13-acetate

Neutrophil (PMNL) infiltration of inflamed colonic tissue is a prominent feature of human inflammatory bowel disease (IBD). Colitis was established in New Zealand white rabbits by the intrarectal instillation of 1.5 mg/kg (in 10 ml 20% ethanol) phorbol-12-myristate-13-acetate (PMA) and assessed by visual grading of colonic inflammation, levels of the neutrophil marker enzyme myeloperoxidase (MPO), and histological examination. After 24 h there was a significant (P less than 0.001) increase in MPO levels in the PMA-treated colons compared to ethanol control. There was also increased inflammation based on visual scoring. Histologically, PMA-treated colons were necrotic with focal ulceration, heavy PMNL infiltration and edema at 24 h; by 96 h colitis was sustained with mild edema, crypt abscesses, and a staining pattern suggesting altered mucus quality. These results suggest that PMA-induced colitis in rabbits may be a new model of IBD in which to evaluate drugs known to mitigate the inflammatory process.

Chemotactic peptide-induced acute colitis in rabbits

Bacterial chemotactic peptides from the intestinal lumen could potentially induce inflammation if they reached the mucosa. We tested several peptides chemotactic for different inflammatory cells, as well as a nonchemotactic peptide, bradykinin, for their ability to induce colitis in vivo in rabbits. These peptides were also assessed for their ability to stimulate release of the eicosanoids leukotrienes B 4 and C 4 and prostaglandin E 2 from normal rabbit colons perfused ex vivo. Intracolonic administration of n-formyl-methionyl-leucyl-phenylalanine (chemotactic for neutrophils); its methyl ester (chemotactic for monocytes), and alanyl-glycyl-seryl-glutamic acid (chemotactic for eosinophils) all produced colitis (assessed grossly and histologically) within 4 days. Bradykinin did not induce colitis although it did release prostaglandin E 2. n-Formyl-methionyl-leucyl-phenylalanine methyl ester induced the greatest degree of colitis in vivo and released prostaglandin E 2 and leukotrienes ex vivo. n-Formyl-methionylleucyl-phenylalanine and alanyl-glycyl-seryl-glutamic acid induced comparable degrees of inflammation, but alanyl-glycyl-seryl-glutamic acid produced no eicosanoid release while n-formyl-methionyl-leucyl-phenylalanine released both prostaglandin E 2 and leukotriene B 4 and leukotriene C 4 products from normal ex vivo perfused colons. Thus alanyl-glycyl-seryl-glutamic acid produces colitis independent of proinflammatory eicosanoids while eicosanoid release could contribute to colitis produced by n-formylmethionyl-leucyl-phenylalanine and n-formyl-methionyl-leucyl-phenylalanine methyl ester. This experimental model of colitis may reflect one possible etiology of inflammatory bowel disease in humans, when bacterial chemotactic peptides breach mucosal defenses in susceptible individuals.

Immunoglobulin-containing cells in the colonic mucosa of rabbits with carrageenan-induced colitis.

Immunohistochemical analysis of immunocompetent cells in the colonic mucosa was performed with carrageenan-induced experimental colitis in rabbits. Colitis was induced by seven months of oral administration of lambda-degraded carrageenan following immunization with the same substances containing Freund's complete adjuvant. In the colonic mucosa with colitis, IgG- and IgM-containing cells were significantly increased in number (IgG: 540 +/- 94/mm2 in experimental group, vs. 120 +/- 54/mm2 in control, P less than .05, IgM: 55.0 +/- 19.7/mm2 in experimental group, vs. 6.7 +/- 2.4/mm2 in control, P less than .05). There was no significant increase of IgA-containing cells either in number or in proportion to the total mononuclear cells. These changes, induced by carrageenan in rabbits, had resembled those in human ulcerative colitis well. These observations suggested an impairment of the IgA-regulated local immune system and an abnormality in the differentiation process of immunoglobulin-secreting cells.

Function of phagocytes in experimentally induced colitis in rabbits. I. The Arthus phenomenon in the colon.

Adhesion, random and chemotactic migration, phagocytosis and nitroblue tetrazolium (NBT) dye reduction of peritoneal exudate polymorphonuclear leukocytes (PMN) and macrophages were examined in 110 rabbits with immune complex-mediated colitis and in controls. We may conclude that Arthus-like colitis in rabbits is accompanied by an impairment of adhesion and phagocytosis, and an increase in chemotactic and random migration of both PMN and macrophages. The examined phagocytes were obtained from the peritoneal cavity, and the changes in their function are related much more directly to the presence of circulating immune complexes than to the colitis. The mentioned impairment in their function may be responsible for prolonged persistence of immune complexes in the serum of rabbits with colitis; however, it does not prolong the time of healing of the ulcers.

Lipopolysaccharide-induced colitis in rabbits.

An experimental animal model of human ulcerative colitis using lipopolysaccharide (LPS) was studied. Rabbits were skin-sensitized by LPS and challenged with intrarectal instillation of LPS after 1% formalin enema. The course of experimental colitis was followed by performing serial colonofiberscopic examinations and biopsy. Petechiae appeared from the 8th hour, and ulcers and bleeding on the 3rd day. Mild macroscopic changes continued for about 2 weeks. By repeating the LPS enema after the initial treatment, the colitis was maintained for over 1 month. Control groups without formalin enema revealed no macroscopic changes, and the groups with only formalin enema showed mild transient changes. The endotoxin level in the blood during the experiment increased (36 pg/ml) at 24 h after the treatment in the LPS-sensitized group, while non-sensitized control rabbits had higher levels of endotoxin. Though fibrinogen and PTT levels had increased at 24 and 72 h, these levels were marked in the control rabbits. The direct reaction of LPS was minimal, and local immune reaction by LPS seems to play an important role in the perpetuation of experimental colitis. Tissue fibrinolysis of the colon increased significantly as the mucosal damage appeared. This experimental colitis with LPS may be useful as a model of human ulcerative colitis.