Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils.
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We have generated mice with a cell type-specific disruption of the Stat3 gene in macrophages and neutrophils. The mutant mice are highly susceptible to endotoxin shock with increased production of inflammatory cytokines such as TNF alpha, IL-1, IFN gamma, and IL-6. Endotoxin-induced production of inflammatory cytokines is augmented because the suppressive effects of IL-10 on inflammatory cytokine production from macrophages and neutrophils are completely abolished. The mice show a polarized immune response toward the Th1 type and develop chronic enterocolitis with age. Taken together, Stat3 plays a critical role in deactivation of macrophages and neutrophils mainly exerted by IL-10. (+info)
Early detection by ultrasound scan of severe post-chemotherapy gut complications in patients with acute leukemia.
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BACKGROUND AND OBJECTIVE: Acute leukemia patients may develop life-threatening gut complications after intensive chemotherapy. We evaluated the role of abdominal and pelvic ultrasound (US) examination in early detection of these complications. DESIGN AND METHODS: A cohort of twenty adult acute leukemia patients undergoing intensive chemotherapy for remission induction entered the study. All chemotherapy regimens included cytarabine by continuous i.v. infusion for several days. RESULTS: Three patients had severe gut complications: 2 cases of enterocolitis and 1 case of gall bladder overdistension in the absence of calculi. In all cases the abnormality was documented by US examination: US scan showed thickening of the intestinal wall (two cases), and gall bladder overdistension with biliary sludge (one case). Immediate medical care included bowel rest, a broad-spectrum antibiotic, antimycotic treatment, and granulocyte colony-stimulating factor. All patients recovered from the complication. INTERPRETATION AND CONCLUSIONS: We believe that the favorable outcome obtained in our small series can be attributed to early diagnosis followed by appropriate treatment. Early recognition by US and immediate medical management can lead to complete recovery of severe intestinal complications in patients with acute leukemia undergoing intensive chemotherapy. (+info)
A previously fit 23 year old adult male who presented with a sudden onset of profound autonomic neuropathy, for which no cause could be found, is described. The patient subsequently developed ischaemic enterocolitis that ultimately necessitated colectomy and subtotal enterectomy. Potential neural and humoral mechanisms are discussed. (+info)
Integration of neuro-endocrine immune responses in defense of mucosal surfaces.
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Neuro-endocrine immunology, a field arising from curiosity about the mind-body connection, is evolving rapidly. From intriguing, but seemingly unexplainable observations with human infections and disease, experimental systems have been developed that provide a solid scientific basis for new understanding. There have been major efforts to understand influences of the nervous system on immune and inflammatory responses, e.g., innervation of the immune system, molecular communication pathways, and complex phenomena such as conditioning of immune responses and mechanisms of host defenses. In turn, the immune system communicates with the neuro-endocrine systems. Imbalances in the neuro-endocrine-immunologic circuitry are relevant in host defenses and in injury and repair. Examples of these themes in neuro-endocrine-immunology arise in several host-parasite models of neurogenic inflammation, immediate hypersensitivity responses, and granuloma formation. The hypothalamic-pituitary-adrenal axis and the cervical sympathetic trunk-submandibular gland axis provide important models to enhance understanding of this poorly known component of the host-parasite relationship. (+info)
Eosinophilic gastroenterocolitis in iron lactate-overloaded rats.
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Eosinophilic gastroenterocolitis with peripheral eosinophilia was induced in rats fed a diet containing 2.5% or 5.0% iron lactate for 3 mo. Additional findings consistent with iron overload were also observed. Microscopically, the lesions consisted of eosinophilic infiltrations in the mucosa and submucosa along the whole length of the gastrointestinal tracts, increased surface area of the gastric mucosal propria covered with mucous cells, and increased apoptotic bodies in the gastric glandular neck of rats in the 2.5% and 5.0% groups. An increased number of intraepithelial globule leukocytes in the gastric and intestinal lamina propria was also observed in the 5.0% group. Globule leukocytes in the gastric mucosa contained obviously enlarged granules in their cytoplasm in these rats. The granules of the globule leukocytes were positive for rat mast cell protease II, suggesting the mastocyte origin of these cells. Although severe infiltration of eosinophils and globule leukocytes suggested a type-1 hypersensitivity reaction, other features such as an increasing vascular permeability were not detected. Serum IgE levels in the 5.0% and control groups were < 3 ng/ml. Final body weights of male and female rats of the 5.0% group were suppressed to 70% and 90%, respectively, of those of the control rats, whereas food consumption was comparable to that of the control group. The morphologic characteristics of the gastrointestinal lesions and peripheral eosinophilia induced in rats fed iron lactate were very similar to those in some cases of eosinophilic gastroenterocolitis in humans and other animals. (+info)
Molecular basis of the interaction of Salmonella with the intestinal mucosa.
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Salmonella is one of the most extensively characterized bacterial pathogens and is a leading cause of bacterial gastroenteritis. Despite this, we are only just beginning to understand at a molecular level how Salmonella interacts with its mammalian hosts to cause disease. Studies during the past decade on the genetic basis of virulence of Salmonella have significantly advanced our understanding of the molecular basis of the host-pathogen interaction, yet many questions remain. In this review, we focus on the interaction of enterocolitis-causing salmonellae with the intestinal mucosa, since this is the initiating step for most infections caused by Salmonella. Animal and in vitro cell culture models for the interaction of these bacteria with the intestinal epithelium are reviewed, along with the bacterial genes that are thought to affect this interaction. Lastly, recent studies on the response of epithelial cells to Salmonella infection and how this might promote diarrhea are discussed. (+info)
Reduced oxidative and nitrosative damage in murine experimental colitis in the absence of inducible nitric oxide synthase.
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BACKGROUND: Oxidative and nitrosative stress have been implicated in the pathogenesis of inflammatory bowel diseases. AIMS: To study the role of nitric oxide (NO) derived from inducible NO synthase (iNOS) in an experimental model of murine enterocolitis. METHODS: Trinitrobenzene sulphonic acid (TNBS) was instilled per rectum to induce a lethal colitis in iNOS deficient mice and in wild type controls. The distal colon was evaluated for histological evidence of inflammation, iNOS expression and activity, tyrosine nitration and malondialdehyde formation (as indexes of nitrosative and oxidative stress), myeloperoxidase activity (as index of neutrophil infiltration), and tissue localisation of intercellular adhesion molecule 1 (ICAM-1). RESULTS: TNBS administration induced a high mortality and weight loss associated with a severe colonic mucosal erosion and ulceration, increased myeloperoxidase activity, increased concentrations of malondialdehyde, and an intense staining for nitrotyrosine and ICAM-1 in wild type mice. Genetic ablation of iNOS gene conferred to mice a significant resistance to TNBS induced lethality and colonic damage, and notably reduced nitrotyrosine formation and concentrations of malondialdehyde; it did not, however, affect neutrophil infiltration and intestinal ICAM-1 expression in the injured tissue. CONCLUSION: Data show that activation of iNOS is required for nitrosative and oxidative damage in experimental colitis. (+info)
Bacterial cell wall polymers promote intestinal fibrosis by direct stimulation of myofibroblasts.
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Normal luminal bacteria and bacterial cell wall polymers are implicated in the pathogenesis of chronic intestinal inflammation. To determine the direct involvement of bacteria and their products on intestinal fibrogenesis, the effects of purified bacterial cell wall polymers on collagen and cytokine synthesis were evaluated in intestinal myofibroblast cultures established from normal fetal and chronically inflamed cecal tissues. In this study, the intestines of Lewis rats were intramurally injected with peptidoglycan-polysaccharide polymers. Collagen and transforming growth factor (TGF)-beta1 mRNA levels were measured and correlated with mesenchymal cell accumulation by immunohistochemistry. The direct effects of cell wall polymers on fibrogenic cytokine and collagen alpha1 (type I) expression were evaluated in intestinal myofibroblast cultures. We found that intramural injections of bacterial cell wall polymers induced chronic granulomatous enterocolitis with markedly increased collagen synthesis and concomitant increased TGF-beta1 and interleukin (IL)-6 expression. Intestinal myofibroblast cultures were established, which both phenotypically and functionally resemble the mesenchymal cells that are involved in fibrosis in vivo. Bacterial cell wall polymers directly stimulated collagen alpha1 (I), TGF-beta1, IL-1beta, and IL-6 mRNA expression in the intestinal myofibroblasts derived from both normal and inflamed cecum. Neutralization of endogenous TGF-beta1 inhibited in vitro collagen gene expression. From our results, we conclude that increased exposure to luminal bacterial products can directly activate intestinal mesenchymal cells, which accumulate in areas of chronic intestinal inflammation, thus stimulating intestinal fibrosis in genetically susceptible hosts. (+info)