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Biomedical subjects

P Sharon

Publications and source records attributed to P Sharon.

At least 19 recordsLinked to original sources
PubMed1995

Up-regulation of E-selectin and intercellular adhesion molecule-1 differs between Crohn's disease and ulcerative colitis.

In present study, we investigated if inflammatory mediators secreted by the inflamed colonic mucosa from patients with Crohn's disease and ulcerative colitis had the ability to up-regulate the expression of two adhesion molecules, E-selectin and intercellular adhesion molecule-1. Organ culture techniques and enzyme-linked immunoassays were used to quantify these up-regulations in human umbilical vein endothelial cells. Our results show that, in Crohn's disease patients, the expression of E-selectin was up-regulated 5.5-fold over control values and intercellular adhesion molecule-1 expression was increased 2.4-fold. In ulcerative colitis patients, E-selectin expression was up-regulated twofold over controls with only a 1.5-fold increase in intercellular adhesion molecule-1 expression. Histologically, there was no difference in the degree of inflammation between the two disease groups. Sulfasalazine, in a dose-dependent manner, inhibited E-selectin expression up to 58% and intercellular adhesion molecule-1 up to 62% when stimulated by lipopolysaccharide. The up-regulation of E-selectin and intercellular adhesion molecule-1 may play an important role in mediating the inflammatory process in inflammatory bowel disease. The observed difference between Crohn's disease and ulcerative colitis may reflect differences in inflammatory cell infiltrates or the histopathological differences between the two diseases.

Adult↗
PubMed1994

Endothelial proliferation in experimental granulomatous colitis. Autoradiography and immunohistochemistry studies.

The time sequence and magnitude of endothelial cell proliferation was investigated in an experimental model of granulomatous colitis in rats, induced by intramural inoculations of mycobacterium Bacillus Calmette-Guerin. Colonic tissues were assessed by gross examination, histopathology, autoradiography, and immunohistochemistry. Gross examination of the colonic tissue showed thickening of the colonic wall, erythema, hemorrhage, and scattered ulcers. Histopathological findings were characterized by an acute transmural inflammation, progressing to chronic inflammation accompanied by regenerative changes in the glandular epithelium, goblet cell depletion, mucosal atrophy and fibrosis. Well-developed noncaseating granulomas were first observed at day 5 and were found to be a dominant feature up to day 17. Autoradiographic studies showed increased endothelial cell labeling up to 17% at 48 hr, compared to less than 1% labeling in control animals. Immunostaining for factor VIII-related antibody, an endothelial cell marker, showed increased numbers of microvessels and individual positive cells located in areas of inflammation as early as 24 hr. At day 5 these individual cells along with dilated neocapillaries were found surrounding the granulomas. This model of granulomatous colitis mimics many features of the human disease state. The early increase in endothelial cell proliferation that precedes granuloma formation during the course of the inflammatory response may suggest that the events leading to the expression of granulomatous colitis are dependent on endothelial proliferation.

Animals↗
PubMed1992

The effect of sulfasalazine on bovine endothelial cell proliferation and cell cycle phase distribution. Comparison with olsalazine, 5-aminosalicylic acid, and sulfapyridine.

Sulfasalazine is used in the treatment of chronic inflammatory states, for example, in inflammatory bowel disease and to a lesser degree in rheumatoid arthritis. In chronic inflammation, the formation of new blood vessels may play a key role in maintaining the inflammatory state. This process is dependent on the activation and proliferation of the endothelial cells. To investigate the possible role of sulfasalazine and its metabolites, sulfapyridine and 5-aminosalicylic acid, we examined the effect of these drugs on vascular endothelial cell proliferation in vitro. Cultures of bovine aortic endothelial cells were incubated with sulfasalazine and its metabolites. At 24 hours of incubation, sulfasalazine inhibited tritiated thymidine incorporation and cell proliferation and had already slowed S-phase progression at a concentration greater than 0.125 mmol/L. After 3 hours of incubation, sulfasalazine inhibition of tritiated thymidine incorporation into the DNA of endothelial cells was observed. This inhibition was completely reversible 24 hours after the drug was removed. One of the possible mechanisms for the inhibition of endothelial cell proliferation is interference with the de novo synthesis of thymidine that depends on folate-dependent enzymes. The effect of deoxyuridine and tetrahydrofolate on tritiated thymidine incorporation into cellular DNA, as well as release of tritium to water by [5-3H]-labeled deoxyuridine on methylation to thymidine, were used as probes for the de novo synthesis of thymidine. Deoxyuridine and tetrahydrofolate, when added to cells either individually or together for 3 hours, suppressed incorporation of tritiated thymidine into DNA through an increase in de novo thymidine synthesis. Sulfasalazine, but not its metabolites, reduced this suppression.2+ culture is inhibited by sulfasalazine and olsalazine but not by their metabolites. This inhibition appears to depend partly on the reduction of de novo synthesis of thymidine that is folate dependent.

Aminosalicylic Acids↗
PubMed1990

The effect of essential fatty acid deficiency on eicosanoid production in the inflamed rat colonic mucosa.

Eicosanoids are potent mediators of inflammation and are synthesized in increased quantity in active ulcerative colitis. To elucidate the role of prostaglandin E2, thromboxane A2, prostaglandin I2, and leukotriene B2 in acute chemical colitis induced by 4% acetic acid, we utilized an animal model which has a deficiency of arachidonic acid, the precursor of eicosanoids due to an essential fatty acid deficient diet. Forty-eight hours after colitis was induced, mucosal synthesis of the cyclooxygenase products, prostaglandin E2, thromboxane A2, and prostaglandin I2, was significantly decreased in essential fatty acid deficient rats compared to normal controls. However, the 5-lipoxygenase product, leukotriene B4, was not different between groups. The decrease in cyclooxygenase products did not correlate with any change in the severity of colonic inflammation as assessed by gross morphology, histology, or myleoperoxidase activity. Thus inhibition of formation of the cyclooxygenase products of arachidonate metabolism does not appear to improve the degree of inflammation under the experimental conditions employed in this study.

Acetates↗
PubMed1990

Cytokine secretion effected by synergism of the immunomodulator AS101 and the protein kinase C inducer bryostatin.

AS101, a synthetic organotellurium compound, was found to have immunomodulating properties by initiation of cytokine production in vitro and in vivo. Phase I/II clinical trials currently in progress on AIDS and cancer patients treated with AS101 show significant increases in various immunological parameters, with minimal toxicity. Recently, AS101 and the protein kinase C (PKC) inducer, phorbol myristate acetate (PMA), were shown to synergize in the secretion of interleukin-2 (IL-2) and colony-stimulating factor (CSF) in vitro, by human and mouse lymphoid cells. The bryostatins, a group of natural macrocyclic lactones isolated from marine invertebrates (Bugula neritina) have been reported to be potent PKC activators with no tumour promoting activity. In this study, we investigated the synergistic effect of AS101 and a partially purified preparation of bryostatin on the production of several cytokines. Our data confirm the presence of synergism, which greatly enhances cell proliferation, IL-2, tumour necrosis factor (TNF) and interferon-gamma (IFN-gamma) secretion by human mononuclear cells (MNC) and the production of IL-2 and TNF by mouse cells. The absence of tumour-promoting activity of the bryostatins makes them particularly good candidates, in combination with AS101, for immunomodulation in vivo in clinically immunosuppressed conditions.

Adjuvants, Immunologic↗
PubMed1987

Chemotactic activity in inflammatory bowel disease. Role of leukotriene B4.

An important histologic feature of inflammatory bowel disease (IBD) is infiltration of the colonic mucosa with neutrophils. To investigate the nature of the chemotactic agents responsible for this infiltration, colonic mucosa from three normals and nine patients with inflammatory bowel disease (seven ulcerative colitis, two Crohn's colitis) was assayed for chemotactic activity for human neutrophils in vitro in a Boyden chamber. There was more (greater than 10-fold more) chemotactic activity in homogenates of inflammatory bowel disease mucosa than in homogenates of normal colonic mucosa. Analysis of the chemotactic activity in the inflammatory bowel disease mucosa revealed that most was lipid extractable. Moreover, when the lipid extract was fractionated by reverse-phase high-pressure liquid chromatography, the only fraction with significant chemotactic activity was the fraction that coeluted with leukotriene B4. The chemotactic response to IBD mucosa was blocked by anti-LTB4 antisera. The amount of chemotactic activity in lipid extracts of different inflammatory bowel disease specimens correlated well with the concentration of leukotriene B4 measured by UV absorbance (250 ng/g of mucosa). These data suggest that leukotriene B4 is an important stimulus to neutrophil chemotaxis in inflammatory bowel disease and, thus, may play a major role in the amplification of the inflammatory response in this condition.

Adult↗
PubMed1987

Rise of prostanoids in rat small intestinal mucosa following intestinal protein hypersensitivity.

The purpose of the present study was to establish whether there is an elevated prostaglandin concentration in the intestinal mucosa in rats suffering from an immediate type hypersensitivity reaction. Rats of the Hooded-Lister strain were sensitized and challenged with ovalbumin. Control rats were given adjuvant only. Prostanoid content of scraped mucosa was determined by radioimmunoassay. It was found that the prostaglandin E2 content in the sensitized intestine was significantly elevated as compared to the controls. There was no significant rise of 6-keto prostaglandin F alpha or thromboxane E2 in the sensitized rats. These results show that prostaglandin B2 participates in intestinal immediate type responses and may explain some of the clinical manifestations of food protein allergy.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Metabolism of arachidonic acid in acetic acid colitis in rats. Similarity to human inflammatory bowel disease.

We recently reported that human inflammatory bowel disease mucosa contains large amounts of leukotriene B4, a potent chemotactic agent formed from arachidonic acid through the lipoxygenase pathway. To more fully evaluate the role of arachidonic acid metabolites in the mediation of intestinal inflammation, we studied arachidonate metabolism in an animal model: acetic acid colitis in the rat. Incubation of acetic acid colitis mucosa with arachidonic acid resulted in the production of leukotriene B4 and a series of monohydroxy fatty acids, all products of the lipoxygenase pathway, plus much smaller amounts of cyclooxygenase products including prostaglandin E2. All of these metabolities were made in significantly greater quantities by mucosa from acetic acid-treated rats than by controls. The pattern of arachidonate metabolism in acetic acid colitis was strikingly similar to that in human inflammatory bowel disease. Moreover, the concentration of leukotriene B4 in acetic acid-treated mucosa was almost identical to that in human inflammatory bowel disease mucosa and was 50 times greater than that in normal rat colonic mucosa. These data indicate that lipoxygenase products, including leukotriene B4, may be important mediators of intestinal inflammation in a wide variety of inflammatory conditions. Moreover, the similarities in the metabolism of arachidonate by human inflammatory bowel disease and by acetic acid colitis may allow the use of this model, and perhaps other animal models of intestinal inflammation, in the screening of potential therapeutic agents for inflammatory bowel disease.

Acetates↗
PubMed1984

Effect of prostanoids on human intestinal Na-K-ATPase activity.

To elucidate whether prostanoids affect the activity of human intestinal Na-K-ATPase (an enzyme that has an important role in intestinal sodium and water absorption), basal human jejunal and colonic Na-K-ATPase activities were measured. In normal subjects, the mean (+/- SE) activities were 2.30 +/- 0.20 (n = 18) and 2.06 +/- 0.27 (n = 12) mumol/h . mg protein, respectively. Prostaglandin (PG) E2 (1.3 microM) induced significant inhibition of both the jejunal and the colonic enzyme activities: 82 +/- 5 and 50 +/- 8% inhibition, respectively. The inhibition of the colonic enzyme activity was apparent after 5 min of incubation and was linear in the first 20 min; it correlated with the amount of enzyme protein. PGD2, 6-keto-PGF1 alpha and thromboxane B2 did not affect either the jejunal or colonic Na-K-ATPase activities. These results indicate that PGE2 inhibits intestinal Na-K-ATPase activity. This inhibition may increase intestinal net fluid accumulation and thus may contribute to the diarrhea induced by several prostanoids.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Decreased colonic Na-K-ATPase activity in active ulcerative colitis.

Na-K-ATPase has an important role in intestinal sodium and fluid absorption. We tested the colonic activity of this enzyme in patients with active ulcerative colitis to elucidate its role in the pathogenesis of the diarrhea associated with this disease. Colonic Na-K-ATPase activity in 13 patients with active ulcerative colitis prior to therapy was one-fourth of its activity in 14 normal subjects: 0.68 +/- 0.13 (SE) and 2.60 +/- 0.45 mumol/h . mg protein, respectively. In six patients with active ulcerative colitis on steroid therapy, the enzyme activity was similar to that observed in normal subjects. These results indicate an inhibition of colonic Na-K-ATPase activity in active ulcerative colitis, which may contribute to intestinal fluid accumulation and thus to the diarrhea in this disease.

Adult↗
PubMed1984

Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Assessment of inflammation in rat and hamster models.

An assay was devised to quantitate acute intestinal inflammation based on the assessment of myeloperoxidase activity. Myeloperoxidase is an enzyme found in neutrophils and, in much smaller quantities, in monocytes and macrophages. Myeloperoxidase was solubilized with hexadecyltrimethylammonium bromide and myeloperoxidase activity was measured with a dianisidine-H2O2 assay. In neutrophil suspensions, myeloperoxidase activity was directly related to cell number down to as few as 500 cells. Myeloperoxidase activity was assayed in two animal models of inflammation: acetic acid-induced colitis in rats and Clostridium difficile enterotoxin-induced enteritis in hamsters. In both models, the activity of myeloperoxidase solubilized from the inflamed tissue was directly proportional to the number of neutrophils seen in histologic sections. Histologic evaluation of neutrophil accumulation was performed by counting the number of neutrophils in a histologic section 0.18 mm long and 5 micron thick. In both animal models, myeloperoxidase activity was linearly related to neutrophil number from 400 and 4000 cells/mm. Myeloperoxidase activity from chronically inflamed colon, in which both neutrophils and histiocytes were present, was directly related to neutrophil content. Histiocytes did not contribute significantly to myeloperoxidase activity. The determination of myeloperoxidase activity in the intestine is a simple biochemical assay that can be used to quantitate inflammation.

Acetates↗
PubMed1984

Enhanced synthesis of leukotriene B4 by colonic mucosa in inflammatory bowel disease.

Leukotriene B4, an arachidonic acid metabolite, is a potent chemotactic agent, and is thought to be an important mediator of inflammation. To investigate the role of this compound as a mediator of inflammation in inflammatory bowel disease, arachidonic acid was incubated with ionophore and colonic mucosa from patients with inflammatory bowel disease and from normal subjects. Mucosa from patients with inflammatory bowel disease converted 2.17% of exogenous arachidonate to leukotriene B4; mucosa from normal subjects converted 0.37%. The production of leukotriene was blocked by sulfasalazine. To determine if inflammatory bowel mucosa contained endogenous leukotriene B4, lipid extracts were analyzed by high pressure liquid chromatography. Mucosa from patients with inflammatory bowel disease contained 254 ng of leukotriene B4 per gram and mucosa from normal subjects contained less than 5 ng of leukotriene B4 per gram. The presence of significant amounts of leukotriene B4 in colonic mucosa in patients with inflammatory bowel disease, combined with the known biologic effects of leukotriene B4, suggests that it may be an important mediator of inflammation in inflammatory bowel disease.

Adolescent↗
PubMed1984

Effect of cimetidine on human gastric and duodenal prostanoid synthesis.

In 13 patients with endoscopically proven duodenal ulcer, biopsies were obtained from the stomach body and antrum and from the duodenal bulb before and, in 10, after 4 weeks of cimetidine treatment (1 g/day). The specimens were organ-cultured for 90 min, and prostanoid accumulation in the medium was determined by radio-immunoassay. After 4 weeks of cimetidine treatment, prostaglandin E2 and 6-keto-prostaglandin F1 alpha synthesis by cultured specimens obtained from the body of the stomach (1304 +/- 197 and 497 +/- 124, no. +/- 10) was significantly higher than their respective synthesis before therapy (734 +/- 90 and 222 +/- 26; no. = 13) (X +/- SE, pg/mg wet wt/90 min). Prostanoid synthesis by cultured specimens from the antrum and duodenum was not significantly different before and after cimetidine treatment. It is therefore suggested that cimetidine, in addition to its antisecretory effects, accelerates ulcer healing also by induction of endogenous gastric prostanoid synthesis.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Prostanoid synthesis by cultured gastric and duodenal mucosa: Possible role in the pathogenesis of duodenal ulcer.

Cultured duodenal mucosa obtained from normal subjects synthesized and secreted significantly less prostaglandin E2 (PGE2), 6-keto-PGF1 alpha, and thromboxane B2 (TXB2) than cultured gastric mucosa obtained from the same subjects. Accumulation of PGE2, 6-keto-PGF1 alpha, and TXB2--the stable metabolites of prostacyclin I2 and thromboxane A2, respectively--by cultured gastric mucosa obtained from 21 untreated patients with active duodenal ulcer was significantly lower than their respective accumulation by cultured gastric mucosa obtained from 14 normal subjects. Accumulation of all three prostanoids by cultured duodenal mucosa obtained from patients with active duodenal ulcer and from normal subjects was not significantly different. PGE2, 6-keto-PGF1 alpha, and TXB2 accumulation was five to six times higher than their respective content in fresh tissue before culture and was inhibited by flufenamic acid. These results suggest that a decrease in endogenous gastric prostanoid synthesis may have a role in the pathogenesis of peptic ulcer disease.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

Gastrointestinal effects of long-term colchicine therapy in patients with recurrent polyserositis (familial mediterranean fever).

Twelve patients with recurrent polyserositis (RP, familial Mediterranean fever) on colchicine prophylaxis (1.0-2.0 mg daily) for three years or more were evaluated for the presence of gastrointestinal effects possibly attributable to the drug. Two patients had bulky stools, two others had transient diarrhea, and one had heartburn. Serum vitamin B12, calcium, and carotene levels were normal in all cases, and D-xylose absorption was normal in 11 of the 12. Three patients had mild steatorrhea (7.5, 7.9, and 9.9 g daily). Jejunal biopsies from these and a fourth patient with bulky stools but normal fecal fat excretion showed no abnormal histological changes. However, (Na + K)-ATPase activity was significantly decreased in all four cases. Colchicine had to be discontinued in only one of the 12 cases. It is concluded that mild steatorrhea and enzyme inhibition may occur in patients on long-term colchicine prophylaxis and that careful periodic observations for this and other adverse effects is imperative in such patients.

Adolescent↗
PubMed1982

Endoscopic diagnosis of duodenal neoplasms causing upper gastrointestinal bleeding.

Duodenal neoplasms are a rare and not often considered cause of massive upper gastrointestinal bleeding. During a 4-year period, 859 endoscopies in patients with upper gastrointestinal bleeding revealed a duodenal tumor to be the cause of bleeding in eight patients. Three patients had a primary duodenal neoplasm, two had metastatic involvement, and in three others pancreatic tumors had invaded the duodenum. In view of our findings, we recommend careful endoscopic scrutiny of all parts of the duodenum in patients with upper gastrointestinal bleeding especially when the cause of bleeding is not found in the esophagus, stomach, or duodenal bulb.

Adenocarcinoma↗