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Biomedical subjects

Y R Mahida

Publications and source records attributed to Y R Mahida.

At least 55 records · Page 3Linked to original sources
PubMed1997

Role of T helper 2 cells in intestinal goblet cell hyperplasia in mice infected with Trichinella spiralis.

BACKGROUND & AIMS: The four principal types of intestinal epithelial cells are derived from multipotent stem cells. Currently, there is no information on factors that regulate commitment of stem cells to differentiate along one lineage vs. another. The aim of our study was to investigate the role of T cells in the regulation of small intestinal goblet cell hyperplasia in mice infected with the parasite Trichinella spiralis. METHODS: NIH mice were infected with T. spiralis, and intestinal goblet cells and cytokine response were studied. Interferon gamma and interleukin 5 were used as candidate T helper (Th)1 and Th2 cytokines, respectively. Adoptive transfer experiments were also performed. RESULTS: Small intestinal goblet cell hyperplasia occurred 8 days after infection with T. spiralis. Th1-type cells were predominant in the mesenteric lymph nodes early in the course of infection, with a switch to Th2-predominant cells around the time of goblet cell hyperplasia. Transfer of Th2-enriched mesenteric lymph node cells further enhanced goblet cell hyperplasia in recipient mice. Neutralization of interleukin 5 activity did not affect T. spiralis-induced goblet cell hyperplasia. CONCLUSIONS: Small intestinal goblet cell hyperplasia in T. spiralis-infected mice is probably regulated by Th2 cells. We postulate that Th2-derived factors (other than interleukin 5) induce stem cells to differentiate preferentially along the goblet cell lineage.

Animals↗
PubMed1997

Cytokines and the gut.

Cytokines are peptide regulatory factors which are involved in initiating, amplifying, perpetuating and resolving the immune and inflammatory responses. Each may have several actions, but can be broadly categorized into pro- and anti-inflammatory cytokines. The cytokine profile depends on the nature of the antigen, how it is presented to the host, and which cell types are involved in the response. Elucidation of the cytokine cascade will improve understanding of the mechanisms of inflammation, and may allow the identification of therapeutic targets in chronic inflammatory diseases of unknown aetiology.

Animals↗
PubMed1997

Adult human colonic subepithelial myofibroblasts express extracellular matrix proteins and cyclooxygenase-1 and -2.

Interactions between epithelial cells and subepithelial myofibroblasts are increasingly recognized as important in the regulation of epithelial cell function. We have established primary cultures of subepithelial myofibroblasts from adult human colonic mucosal samples denuded of epithelial cells and maintained in culture. During culture of mucosal tissue, subepithelial myofibroblasts migrated out via basement membrane pores before establishment in culture. Despite prolonged culture and passage, the myofibroblasts maintained their phenotype, as demonstrated by expression of alpha-smooth muscle actin and vimentin. The cells expressed transcripts and protein for cyclooxygenase (COX)-1 and -2 enzymes, and their release of prostaglandin E2 (PGE2) was inhibited by selective COX-1 and -2 inhibitors. The myofibroblasts also expressed the extracellular matrix (ECM) proteins collagen type IV, laminin-beta 1 and -gamma 1, and fibronectin. Adult human colonic subepithelial myofibroblasts may influence epithelial cell function via products of COX-1 and -2 enzymes, such as PGE2 and secreted ECM proteins.

Actins↗
PubMed1996

Effect of Clostridium difficile toxin A on human intestinal epithelial cells: induction of interleukin 8 production and apoptosis after cell detachment.

Clostridium difficile is the aetiological agent of pseudomembranous colitis, and animal studies suggest the essential role of secreted toxin A in inducing disease. This study examined the biological responses to toxin A by human intestinal epithelial cells. Confluent monolayers of Caco2, HT29, and T84 cells and primary epithelial cells in organ cultures of human colonic biopsy specimens and after detachment with EDTA were studied. Interleukin 8 was assayed using enzyme linked immunosorbent assay (ELISA). Purified C difficile toxin A induced cell rounding and detachment of monolayers of the epithelial cell lines. Cells in detached monolayers initially remained viable while adherent to each other. Subsequently, an increasing number of apoptotic cells appeared in suspension. Exposure to toxin A for 24 hours induced interleukin 8 production in T84 and HT29 cells. Toxin A also induced epithelial cell rounding, detachment, and apoptosis in organ cultures of human colonic biopsy specimens. During culture (in medium only), EDTA detached colonic epithelial cells produced interleukin 8 and cell death occurred by apoptosis. Colonic disease by C difficile may be initiated by toxin A mediated induction of epithelial cell interleukin 8 production and apoptosis after cell detachment from the basement membrane. Studies on isolated (toxin untreated) colonic epithelial cells suggest that interleukin 8 production and apoptosis occur as a consequence of cell injury and detachment.

Apoptosis↗
PubMed1993

Audit of outcome of long-term enteral nutrition by percutaneous endoscopic gastrostomy.

Percutaneous endoscopic gastrostomy (PEG) is the preferred method for administration of long-term enteral tube feeding. However, most published studies describe only short-term follow-up in any detail. We report the long-term outcome and complication rate after PEG insertion in 49 patients (mean [SE] age 64 [2] years) whose mean length of PEG feeding was 175 days (range 30-560). Data were collected prospectively. PEG insertion was technically successful in all cases, with a procedure-related mortality of 2%. Early (< 30 days) mortality and morbidity were 8% and 22%, respectively. Of 45 patients surviving for more than 30 days, 76% were able to return home and 6 patients were eventually able to revert to oral feeding. There were 27 late complications: 2 site infections, 17 mechanical problems, and 8 episodes of gastrointestinal dysfunction. 51% of patients had no problems at all and 22% had 2 or more complications. 47% of complications required a hospital visit for resolution. Long-term enteral feeding by PEG was safe, effective, and had a low complication rate. Our patients were managed by a specialist nutrition team, a policy that may reduce the complication rate and hospital visits for patients being fed at home, and allow early discharge of dysphagic patients, thereby reducing costs.

Aged↗
PubMed1993

Identification of human intestinal trefoil factor. Goblet cell-specific expression of a peptide targeted for apical secretion.

Trefoil peptides are a recently recognized group of small peptides abundantly produced at mucosal surfaces that offer the opportunity to define mechanisms of mucosal cell-specific differentiation and to illuminate new mechanisms for the preservation of mucosal integrity. We report the cDNA cloning of a 75-amino acid human trefoil factor expressed in small and large intestinal mucosas that is highly homologous to the intestinal trefoil factor, with 70% identity at the amino acid level of the predicted mature protein. This human intestinal trefoil factor is also homologous, although to a lesser extent, to trefoil peptides expressed at other sites in the gastrointestinal tract in man, exhibiting absolute conservation of the P domain motif (CX9CX9CX4CCX9WCF) that defines this family of peptides. These findings indicate a high degree of evolutionary conservation of organ/region-specific members of this peptide family. In situ hybridization of intestinal trefoil factor demonstrates a high degree of expression in mature small intestine villus and colonic epithelial goblet cells. Immunogold staining demonstrates high concentrations of intestinal trefoil factor in the rough endoplasmic reticulum and theca of goblet cells as well as throughout the mucosal surface, consistent with vectorial secretion of this factor by goblet cells onto the intestinal luminal surface. In addition, intestinal trefoil factor was also localized within columnar epithelial cells by immunogold labeling despite the absence of mRNA. These observations suggest that peptide secreted by goblet cells might be taken up from the luminal surface and transcytosed by enterocytes. Human intestinal trefoil factor expression was also detected in the HT-29N2 and HT-29H2 subclones in conjunction with the emergence of the goblet cell phenotype, but not in the CaCO2 cell line that exhibits enterocytic phenotype. In summary, these findings confirm the existence of a highly conserved family of peptides that are abundantly expressed in distinctive regions throughout the gastrointestinal tract in a highly cell-specific pattern reflecting a goblet cell differentiation pathway. They form one of the more abundant constituents of the interface between the mucosa and "outside" environment and may provide a new paradigm of regulation of the integrity of epithelial surfaces as well as a previously unrecognized dimension of goblet cell function.

Amino Acid Sequence↗
PubMed1993

Functional interleukin-2 receptors on intestinal epithelial cells.

The presence of receptors for the cytokine IL-2 was assessed in the IEC-6 cell line established from normal rat crypt epithelium and primary intestinal epithelial cells. 125I-IL-2 was found to specifically bind to subconfluent IEC-6 cells. Maximal binding was observed within 30 min after addition of the ligand; binding could be inhibited by excess unlabeled IL-2 or addition of antibody to the IL-2 receptor. Both intermediate and low affinity receptors with approximate Kd of 10 and 100 pM, respectively were present. Kinetic analysis were consistent with the results of Western blot analysis using an antisera to the 75-kD IL-2 receptor beta chain. IL-2 receptors appeared to be functional; addition of IL-2 led to modulation of proliferation with initial stimulation at 24 h followed by inhibition at 48 h. This effect could be blocked by addition of antibody to the IL-2 receptor beta chain. IL-2 treatment could be shown to enhance expression (range = 4- to 50-fold stimulation) of TGF-beta, as well as the lectin protein mac-2, in IEC-6 cells. The relevance of observations in the IEC-6 cell line to intestinal mucosa in vivo was supported by the demonstration of a gradient of expression of the IL-2 receptor in primary rat intestinal epithelial cells by Western blot analysis. In addition, mRNA for the IL-2 receptor-beta chain was demonstrated by Northern blot analysis using mRNA from primary rat intestinal epithelial cells depleted of detectable contaminating intraepithelial lymphocytes by two cycles of fractionation on Percoll gradients. Collectively, these observations suggest that the range of cellular targets of the putative lymphokine IL-2 is broader than appreciated, and IL-2 may serve to integrate epithelial and lymphocyte responses in the intestinal mucosa.

Animals↗
PubMed1992

Therapeutic interventions in gastrointestinal disease based on an understanding of inflammatory mediators.

Whatever initiates inflammation, the final message mediating cellular invasion is chemical. This consideration allows rational development of anti-inflammatory treatments. Two main classes of chemotactic mediator are recognised. Water-soluble peptides, e.g. cytokines derived from macrophages and other cells, play an important integrating part in the early recruitment of neutrophils and mononuclear cells, and in the amplification of immune responses. Lipid-soluble mediators, of which leukotriene B4 is the most highly chemotactic for neutrophils, are important in secondary amplification. In inflammatory bowel disease, we have shown evidence of increased synthesis of cytokines interleukin 1, 6 and 8. These are associated with activation of circulating monocytes in active Crohn's disease, of lamina propria macrophages in relapse of both ulcerative colitis and Crohn's disease, and development of adhesion molecules on vascular endothelium. Our studies show that interleukin 6 is selectively increased in Crohn's disease, whilst preliminary findings suggest that enhanced synthesis of interleukin 8 is particularly characteristic of ulcerative colitis. Patterns of cytokine synthesis may, therefore, be of diagnostic value. They also offer the potential for therapeutic strategies since cytokine antagonists are becoming available. We have also demonstrated increased synthesis of leukotrienes in active inflammatory bowel disease. Since leukotriene B4 is quantitatively the main chemotactic signal in the mucosa in inflammatory bowel disease during relapse, we investigated the therapeutic effect of suppressing leukotriene B4 synthesis by treating patients with fish oil (as Hi-EPA), giving 4.5 g daily of eicosapentaenoic acid. This competes for the 5-lipoxygenase enzymes, inhibiting leukotriene B4 and promoting synthesis of the less chemotactic product, LTB5.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminosalicylic Acids↗
PubMed1992

Enhanced synthesis of neutrophil-activating peptide-1/interleukin-8 in active ulcerative colitis.

1. We studied neutrophil-activating peptide-1/interleukin-8 in inflammatory bowel disease. 2. Mucosal levels of neutrophil-activating peptide-1/interleukin-8 were significantly higher in patients with active ulcerative colitis [median 74.5 (range 17.7-450.8) pg/mg] than in patients with active Crohn's disease [10.4 (4-46.9) pg/mg; P less than 0.002] or in normal control subjects [10.4 (4-16.6) pg/mg; P less than 0.002]. 3. Circulating neutrophil-activating peptide-1/interleukin-8 was generally undetectable but there were higher levels of anti-neutrophil-activating peptide-1/interleukin-8 antibodies in patients with active ulcerative colitis [62.9 (3.4-239) ng/ml] than in patients with active Crohn's disease [5.9 (2.1-18.10) ng/ml; P less than 0.001] or in control subjects [6.1 (3.2-15.8) ng/ml; P less than 0.001]. 4. Neutrophil-activating peptide-1/interleukin-8 may be of specific functional importance in mediating inflammation in ulcerative colitis.

Antibodies↗
PubMed1992

Monoclonal antigranulocyte antibody imaging in inflammatory bowel disease: a preliminary report.

The 99Tcm-labelled antigranulocyte antibody BW250/183 has been used in the detection of intestinal inflammation in patients with active ulcerative colitis and Crohn's disease. Planar images were obtained up to 24 h after intravenous injection of the antibody. Eight out of nine patients with ulcerative colitis and six out of seven patients with Crohn's disease gave positive images. In 11 patients distribution of the inflammation was confirmed by barium studies, colonoscopy or surgery, whilst in two the antibody scan suggested more extensive disease than barium enema. None of the patients had any adverse reactions. Imaging with BW250/183 appears to give an accurate indication of the extent of inflammation in inflammatory bowel disease.

Colitis, Ulcerative↗
PubMed1992

Ranitidine: differential effects on gastric bleeding and mucosal damage induced by aspirin.

This study investigated the influence of ranitidine on mucosal injury and gastric bleeding in 20 normal volunteers taking 600 mg aspirin q.d.s. This study was a double-blind placebo controlled crossover study comparing ranitidine, as 150 mg b.d., 300 mg q.d.s. and 600 mg b.d. with placebo. Gastric mucosal injury was assessed at unsedated endoscopy by counting haemorrhagic and non-haemorrhagic erosions; bleeding was measured in gastric washings. Aspirin alone increased mucosal injury from 0 to 11.4 erosions (mean, P < 0.01) and bleeding from 1.77 to 9.11 microliters blood/10 min (mean P < 0.001). Ranitidine prophylaxis reduced bleeding to 5.34, 3.18 and 3.47 microliters/10 min with 150 mg b.d., 300 mg q.d.s. and 600 mg b.d. respectively (overall effect of ranitidine P < 0.001) and also reduced haemorrhagic erosions though it had no effect on the total number of erosions. Ranitidine is effective at reducing aspirin-induced gastric bleeding and whilst not reducing aspirin-induced gastric erosions, it does reduce the number that appear haemorrhagic. Ranitidine may have a role in the prophylaxis of aspirin-induced gastric bleeding.

Adult↗
PubMed1991

Two-color immunofluorescence and flow cytometric analysis of lamina propria lymphocyte subsets in ulcerative colitis and Crohn's disease.

By using two-color immunofluorescence with fluorescein isothiocyanate (FITC) and phycoerythrin (PE)-labelled monoclonal antibodies and multiparameter flow cytometry, we investigated lamina propria lymphocyte subsets of patients with ulcerative colitis (UC) and Crohn's disease (CD). Leu-3/Leu-2 (CD4/CD8) ratio of lamina propria lymphocytes (LPL) of CD (mean +/- SD: 1.9 +/- 0.8, P less than 0.01) was significantly decreased compared with controls (3.3 +/- 1.1), because of an increased number of CD8+ lymphocytes. The majority of lamina propria CD4+ cells were CD4+, Leu-8- and CD4+, CD45R- both in controls and IBD tissue. Many lamina propria T lymphocytes were activated, expressing HLA-DR antigen not only in IBD but also in controls. NK cells defined by CD16 and CD 56 (3.0 +/- 1.4%, P less than 0.01) were significantly decreased in patients with UC compared with controls (6.5 +/- 3.0%). A low proportion of B cells in the intestinal mucosa expressed Leu-8 antigen and CD23 antigen. The proportion of activated B cells of LPL was high in IBD mucosa as well as normal mucosa. These findings suggest that local activation of B cells leads to the loss of the expression of Leu-8 antigen and CD23.

Adolescent↗
PubMed1991

Separation of the impairment of haemostasis by aspirin from mucosal injury in the human stomach.

1. An increasing body of data suggests that the antihaemostatic as well as the ulcerogenic actions of aspirin and other non-steroidal anti-inflammatory drugs may be operative when patients present with haematemesis and melaena. 2. We therefore developed methods to allow separate evaluation of the erosive and anti-haemostatic actions of aspirin in the human gastric mucosa. Volunteer subjects took 300 mg of aspirin daily in the morning or 600 mg of aspirin four times a day for 5 days under blinded randomized conditions. Changes in spontaneous gastric microbleeding, endoscopic signs of injury, spontaneous bleeding per gastric erosion, biopsy-induced bleeding and eicosanoids were studied. 3. Both doses of aspirin significantly inhibited gastric mucosal synthesis of prostaglandin E2 and reduced the serum thromboxane concentration. Erosions developed and regressed rapidly; compared with baseline 300 mg of aspirin daily in the morning caused substantial numbers of gastric erosions to develop (mean 5.3, 95% confidence limits 2.7-10.2) but this was significantly less than that caused by 600 mg of aspirin four times a day (10.9, 7.2-16.5, P less than 0.05). The presence of erosions was associated with enhanced spontaneous bleeding, but only during aspirin administration. 4. Aspirin significantly increased bleeding induced by mucosal biopsy and was associated with significant enhancements in the rate of bleeding per gastric erosion. Bleeding rate per erosion but not biopsy-induced bleeding showed a significant dose-related increase with 600 mg of aspirin four times a day. Enteric coating reduced endoscopic signs of injury, but did not affect the impaired haemostasis caused by aspirin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗