PubMed Health⌕ Search

Biomedical subjects

K Hillier

Publications and source records attributed to K Hillier.

At least 19 recordsLinked to original sources
PubMed1992

Catabolism of platelet-activating factor by human colonic mucosa. Calcium dependence of the catabolizing enzymes.

The catabolism of platelet-activating factor (PAF) and lyso PAF by a supernatant fraction of human colon mucosa homogenates has been studied in vitro. PAF is initially catabolized to lyso PAF by mucosal enzymes via removal of its acetyl group. Incubates in Ca(2+)-free Tris with EDTA showed that the acetyl hydrolase was Ca2+ independent. Addition of the hydrolase inhibitor, phenyl methyl sulphonyl fluoride, significantly reduced the catabolism of PAF. Lyso PAF was further catabolized in at least two ways. An acyl group was incorporated into the sn-2 position of lyso PAF to give 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine (alkyl acyl GPC); this step was Ca2+ independent as shown by omitting Ca2+ and adding EDTA to the incubate. Formation of alkyl acyl GPC was confirmed by HPLC. Alternatively, choline was removed from the head group of lyso PAF by a calcium-dependent lyso phospholipase D. Under the experimental conditions utilized a neutral lipid product was formed but significant amounts of the intermediate lysophosphatidic acid could not be detected. A substance with a chromatographic mobility of Rf = 0.8 on TLC plates having an intact phosphorylcholine head group was also formed but has not yet been identified. It is concluded that the human colon mucosa contains enzymes that actively catabolize pro-inflammatory PAF and lyso PAF.

Calcium↗
PubMed1992

The role of nitric oxide in mediating non-adrenergic non-cholinergic relaxation in longitudinal muscle of human taenia coli.

Electrical field stimulation (EFS) of isolated longitudinal muscle of human taenia coli at 4Hz produced relaxation which was abolished by tetrodotoxin but not adrenergic and cholinergic blockade (NANC-relaxation). NG-nitro L-arginine (L-NOARG; 1-100 microM), an NO synthesis inhibitor, produced a concentration-dependent partial inhibition of the NANC response; 10 microM L-NOARG inhibited EFS-induced relaxation by 48.6 +/- 5.20% and 100 microM L-NOARG by 54.2 +/- 10.1%. L-Arginine (1mM), but not D-arginine (1mM) partially reversed the inhibitory effect and this was inversely proportional to the concentration of L-NOARG used. Cumulative administration of NO (acidified sodium nitrite solution; 1-100 microM) produced a concentration-dependent relaxation of the strips. L-NOARG (1 mM) did not affect either NO or isoprenaline-induced relaxations. These results provide the first preliminary evidence that NO is partially responsible for the NANC inhibitory transmission in the longitudinal muscle of the taenia coli of human colon.

Adrenergic Fibers↗
PubMed1992

Inhibition profiles of sodium cromoglycate and nedocromil sodium on mediator release from mast cells of human skin, lung, tonsil, adenoid and intestine.

We have studied an aspect of the functional heterogeneity of human mast cells, namely responsiveness to the inhibitory effects of sodium cromoglycate and nedocromil sodium. The effects of these drugs were examined on the release of histamine and PGD2 from mast cells of human skin, lung, tonsils, adenoids and intestine. A high concentration, 1000 microM, of sodium cromoglycate was required to significantly inhibit histamine release from lung and tonsillar mast cells. Nedocromil sodium, 1000 microM, was more effective than sodium cromoglycate against histamine release from lung, tonsillar and adenoidal cells. Both compounds showed tachyphylaxis in lung and tonsillar mast cells but not in adenoidal and intestinal mast cells. In contrast, in intestinal mast cells, the effect of nedocromil sodium was weaker and more variable than sodium cromoglycate. Skin mast cells differed from mast cells of the other anatomical sites in being unresponsive to sodium cromoglycate and nedocromil sodium. Our results confirm that high concentrations of sodium cromoglycate and nedocromil sodium are required to achieve even modest inhibition of mediator release from human mast cells under in vitro conditions. Notwithstanding this, the results also indicate that differences exist among skin, lung, tonsillar, adenoidal and intestinal mast cells with respect to their sensitivity to sodium cromoglycate and nedocromil sodium, thus extending our knowledge of functional heterogeneity within the human mast cell populations.

Adenoids↗
PubMed1991

Incorporation of fatty acids from fish oil and olive oil into colonic mucosal lipids and effects upon eicosanoid synthesis in inflammatory bowel disease.

The incorporation of the fatty acids in fish and olive oil into the colonic mucosa of patients with inflammatory bowel disease was examined during 12 weeks' dietary supplementation with the oils, and the influence on colonic mucosal prostaglandin and thromboxane generation was measured. With a dietary supplement of 18 g fish oil daily, concentrations of the major polyunsaturated fatty acids in fish oil, eicosapentaenoic acid and docosahexaenoic acid, were significantly raised in mucosal lipids. The first time these were measured, after three weeks' supplementation, the mean increases in eicosapentaenoic and docosahexaenoic acid were seven fold and 1.5 fold respectively, and these increases were maintained during the 12 week study. Arachidonic acid values fell throughout the study and this reduction was significant at 12 weeks. Mucosal prostaglandin E2 (PGE2), thromboxane B2, and 6-keto prostaglandin F1 alpha synthesis were suppressed, and this reached significance (p less than 0.05) at three and 12 weeks for PGE2 and at 12 weeks for thromboxane B2. The predominant fatty acid in olive oil is oleic acid. Supplementation with 18 g/day resulted in a significant increase in oleic acid in colonic mucosa at 12 weeks (p less than 0.05) and a fall in stearic acid and docosahexaenoic acid; there was no significant change in eicosanoid synthesis. It is concluded that colonic lipids and prostaglandin and thromboxane synthesis can be readily altered by dietary supplementation with fish oil. The extent of incorporation of the fatty acids present in oils is dependent upon the individual fatty acid.

Adult↗
PubMed1990

Prostaglandin catabolism and ulcerative colitis: effect of sulphasalazine, 5-aminosalicylic acid and other drugs.

1. Evidence is presented for the occurrence of type 1 prostaglandin 15-hydroxydehydrogenase in human rectal mucosa. No evidence of the presence of type 2 enzyme was found. 2. A 15-keto-prostaglandin reductase, responsible for the breakdown of 13,14-dihydro-15-keto prostaglandins to 13,14-dihydro prostaglandins, was also present in human rectal mucosa. 3. Ulcerative colitis patients catabolized prostaglandins to the same extent as the control group. PGE1 was catabolized significantly better than PGF2 alpha. 4. 5-Aminosalicylic acid and sulphapyridine did not affect prostaglandin catabolism. Sulphasalazine, methylsulphasalazine, indomethacin, flurbiprofen, disodium cromoglycate, sodium salicylate and carbenoxolone sodium inhibited prostaglandin catabolism to the same extent in both groups. Salicylazosulphadimidine was a more potent inhibitor of PGE1 catabolism than of PGF2 alpha. 5. The increased prostaglandin synthesis reported for ulcerative colitis patients was not paralleled by increased catabolism, a fact possibly contributing to the accumulation of such compounds in the diseased state.

Adult↗
PubMed1989

Effect of sucralfate and cimetidine on rheumatoid patients with active gastroduodenal lesions who are taking nonsteroidal anti-inflammatory drugs. A pilot study.

In a pilot study, 26 rheumatoid arthritic patients taking continuous, stable dosage regimens of nonsteroidal anti-inflammatory drugs and with developed gastric and duodenal lesions were administered sucralfate 1 g four times per day (14 patients) or cimetidine 400 mg twice daily (12 patients) in a single-blind regimen for six weeks. Eleven of the patients given sucralfate and eight of the patients taking cimetidine had improved lesion scores. The lesion score of 10 of the 14 patients taking sucralfate and four of the 12 patients taking cimetidine improved by 50 percent or better (not significant). The antrum and body of the gastric mucosa and the mucosa of the duodenum synthesized prostanoids and thromboxane A2, and there was no significant difference in the synthesis of individual prostanoids at entry to the trial in the groups assigned to sucralfate or cimetidine. After six weeks of administration of sucralfate, prostaglandin E2 (PGE2) synthesis by the antrum and body, but not the duodenum, was significantly greater than observed in the biopsy specimens at entry despite continuation of non-steroidal anti-inflammatory drug therapy. After six weeks of cimetidine treatment, no change in PGE2 synthesis was noted in any biopsy specimens when compared with the synthesis at entry. No change in the synthesis of PGF2 alpha, 6-oxo-PGF1 alpha, or thromboxane B2 was noted in gastric or duodenal biopsy specimens in any treatment group. Sucralfate and cimetidine administration resulted in improved gastroduodenal lesion scores in rheumatoid arthritic patients continuing with nonsteroidal anti-inflammatory drug therapy.

Aged↗
PubMed1989

The effect of sulphasalazine on the in vitro activation of human peripheral blood mononuclear cells by phytohemagglutinin P.

The in vitro action of sulphasalazine, BW 755-C and indomethacin on phytohemagglutinin P-induced human peripheral blood mononuclear cell activation was studied. Sulphasalazine increased, while indomethacin and BW 755-C decreased, prostaglandin E2 (PGE2) accumulation in activated cultures. When used together with indomethacin or BW 755-C, sulphasalazine did not counteract the inhibition of PGE2 caused by the other two. Sulphasalazine inhibited phytohemagglutinin P-induced cell activation in a concentration-dependent manner even when used together with indomethacin or BW 755-C. BW 755-C inhibited cell activation at 350 microM, whereas at 11 microM it only increased sulphasalazine-induced inhibition. The implications of these findings on the etiopathology of inflammatory bowel disease are discussed.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1988

Effect of polyunsaturated fatty acids of the n-3 and n-6 series on lipid composition and eicosanoid synthesis of platelets and aorta and on immunological induction of atherosclerosis in rabbits.

The effect of dietary fish oil (rich in n-3 polyunsaturated fatty acids (PUFA], corn oil (rich in n-6 PUFA) and coconut oil (low in n-3 and n-6 PUFA) on the induction of atherosclerosis by serum sickness in rabbits was investigated over a 12-month period. Dietary fish oil led to a significant increase in the level of eicosapentaenoic acid (EPA) in all platelet phospholipid fractions and to a significant reduction in the level of platelet phosphatidylethanolamine arachidonic acid (AA). In aortic total phospholipids, rabbits given fish oil showed a significant reduction in AA and a significant increase in EPA. Rabbits given fish oil showed significantly lower collagen-induced platelet thromboxane A2 release and aortic production of 6-keto-PGF1 alpha. Serum total immune complex levels and anti-horse serum IgG levels were not influenced by diet. There was a significant reduction in total aortic atherosclerosis in fish oil-fed animals compared with coconut oil fed animals.

Animals↗
PubMed1988

Modification of upper gastrointestinal prostaglandin synthesis by dietary fatty acids.

The effects of dietary oils on gastric, duodenal mucosa and liver were investigated in a rat model. Unsaturated fatty acid profiles and in vitro prostaglandin (PG) synthesis (PGE2, PGF2 alpha, 6-oxo-PGF1 alpha and thromboxane B2), were measured after 14 days of dietary oil supplements. There were no significant differences in prostanoid synthesis between rats fed coconut oil (high saturated fat content) and standard diet. After fish oil supplement, tissue eicosapentaenoic acid and docosahexaenoic acid levels were higher, arachidonic acid levels were lower, and prostanoid synthesis was reduced in both stomach and duodenum. After corn oil and evening primrose oil, linoleic acid levels were variably increased, but there were no significant differences in arachidonic acid or prostanoid synthesis. Dihomogamma-linolenic acid levels were slightly increased after evening primrose oil. Dietary incorporation of fatty acids into gastroduodenal tissue is not uniform. When incorporated, fatty acids can modify prostaglandin synthesis.

Animals↗
PubMed1988

The secretory characteristics of mast cells isolated from the human large intestinal mucosa and muscle.

The use of a collagenase dispersion technique has allowed us to compare size, histamine content and the secretory characteristics of mast cells from the mucosal and muscle layers of the human large intestine. Mast cells from the mucosa, which constituted 1.8% of the total nucleated cells, contained approximately equal numbers of formalin-sensitive and -insensitive mast cells. Those dispersed from the muscle layer constituted 3.2% of the total nucleated cells and were almost all formalin insensitive. The cells from both layers were similar with respect to size and mean cell histamine content. Anti-IgE released up to 15.1% and 16.5% of total cell histamine in the mucosa and muscle, respectively, with similar concentration-response characteristics. The kinetics of anti-IgE-induced release, however, were different, mucosal mast cells releasing histamine 55 seconds (P less than 0.05) faster than cells dispersed from intestinal muscle. Cells from both layers also released histamine in response to A23187 in a similar concentration-related fashion. Neither mucosal or muscle mast cells released significant amounts of histamine in response to compound 48/80, substance P, morphine, poly-L-lysine or f-met-leu-phe. Our results show intestinal mast cells possess secretory characteristics similar to those of human lung, adenoids and tonsils, but are different from human skin mast cells. The absence of significant histamine release in response to basic secretagogues from either layer of the human intestine contrasts with studies in the rodent intestine. Furthermore it suggests that in human mast cells, histochemical properties, protease content and secretory characteristics may not be closely associated.

Cell Count↗
PubMed1987

Increased arachidonic acid levels in phospholipids of human colonic mucosa in inflammatory bowel disease.

1. Colonic mucosa from 19 patients with ulcerative colitis, eight with Crohn's disease and 14 controls were analysed for arachidonic acid (C20:4), linoleic acid (C18:2), oleic acid (C18:1), stearic acid (C18:0) and palmitic acid (C16:0). 2. Gas-liquid chromatography of lipid extracts showed that arachidonic acid was significantly higher in ulcerative colitis (19 +/- 4) and Crohn's disease (20 +/- 3) than in controls (13 +/- 5 micrograms/mg of protein) (means +/- SD). Neither the degree of inflammation nor treatment with sulphasalazine or prednisolone appeared to influence the fatty acid concentrations. 3. Seventy-five to ninety-five per cent of the arachidonic acid was found in the phospholipid fraction after separation by thin-layer chromatography. There were no significant changes in the concentrations of the other fatty acids measured, although oleic acid was lower in inflammatory bowel disease. The ratios of oleic acid to stearic acid and to palmitic acid were lower in inflammatory bowel disease. 4. The alteration in the fatty acid profile may partly explain the increased synthesis of eicosanoids in colonic mucosa in inflammatory bowel disease.

Adolescent↗
PubMed1987

Effect of human chorionic gonadotrophin and indomethacin on ovulation, steroidogenesis and prostaglandin synthesis in preovulatory follicles of PMSG-primed immature rats.

Immature rats were treated with PMSG followed 56 h later by 10 i.u. hCG. Follicles were removed at intervals after hCG injection. Transient increases in progesterone, testosterone and oestradiol synthesis were first evident 1 h after hCG, but values peaked at 3-5 h and returned to control levels by 10 h. Increased synthesis of PGE-2 and PGF-2 alpha was not evident until 3 h and peaked at more than 10 h after hCG. Ovulation began between 8 and 10 h after hCG and 83% of animals had ovulated within 12 h. Doses of 90 or 1800 micrograms indomethacin given together with hCG substantially inhibited ovulation and PG synthesis, but only the higher dose inhibited the hCG-induced elevation of progesterone and testosterone synthesis; hCG-induced oestradiol synthesis was not affected by either dose of indomethacin. We conclude that the peak of PG synthesis after hCG treatment related closely to the timing of ovulation; the steroidogenic response to hCG was not blocked by doses of indomethacin sufficient to inhibit synthesis of PGE-2 and PGF-2 alpha by more than 80%.

Animals↗
PubMed1987

Inflammatory bowel disease: the in vitro effect of sulphasalazine and other agents on prostaglandin synthesis by human rectal mucosa.

1. Prostaglandin (PG) E2 and F2 alpha synthesis in vitro by human rectal mucosa was significantly greater in patients with Inflammatory Bowel Disease (IBD) than in controls. 2. The addition of 250 microM sulphasalazine (SASP) significantly increased synthesis by rectal mucosa from patients with IBD, (ulcerative colitis and Crohn's disease) and controls after 1 h of incubation in Krebs' solution at 37 degrees C. 3. Flurbiprofen, indomethacin, sodium salicylate and 5-aminosalicylic acid decreased PGE2 and F2 alpha synthesis. 4. Sodium carbenoxolone decreased PGF2 alpha synthesis but had no effect on PGE2. Disodium cromoglycate, sulphapyridine, salicylazosulphadimidine and methylsulphasalazine had no effect on PG synthesis. 5. The data show marked variations in effect on PG synthesis in vitro of substances that have been investigated clinically for their actions on IBD.

Aged↗
PubMed1986

Kinetics of prostaglandin E2 and thromboxane A2 synthesis and suppression of PHA-stimulated peripheral blood mononuclear leucocytes.

The immunomodulatory effects of thromboxane A2 and prostaglandin E2 on peripheral blood mononuclear leucocytes stimulated with PHA in vitro, and the relationship of this to the time-course of their synthesis in culture, were investigated using prostaglandin E2, a thromboxane A2 synthesis inhibitor (UK37248), a thromboxane A2 mimic (U46619) and a thromboxane A2 receptor blocker (EP045). The inhibitory effect of prostaglandin E2 on PHA-induced human peripheral blood mononuclear leucocyte proliferation diminishes if the addition of PGE2 is delayed. If added 4 hr after a maximum concentration of PHA (5 micrograms/ml), the effect of PGE2 was reduced by 60%. If a submaximal concentration of PHA (1 microgram/ml) was used, the effect of PGE2 was not reduced if added 4 hr later but fell by about 60% after 16 hr. UK37248 moderately inhibited PHA-induced activation while substantially inhibiting thromboxane A2 synthesis and simultaneously enhancing PGE2 synthesis. The enhanced accumulation of PGE2 occurs while sensitivity to PGE2 is dropping. U46619, exogenously applied as a thromboxane A2 mimic, inhibited PHA-induced activation at concentrations that did not significantly alter PGE2 synthesis. EP045, which may modulate the effects of endogenous thromboxane A2 by blocking receptors, did not alter PHA-induced activation. We conclude that thromboxane A2 may have a role in inhibiting PHA-induced activation on the basis of the effect of U46619. However, this study highlights difficulties in utilizing prostaglandin and thromboxane receptor and synthesis inhibitors to examine their endogenous role in the modulation of mitogen-induced activation in vitro. If sensitivity to the purported endogenous substance is limited to the early stages of culture and if only low levels are synthesized at this early stage, then blocking drugs would have little effect.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1985

Stability of ascorbic acid and uptake of the vitamin by embryonic chick femurs during long-term culture.

Ascorbic acid was added to organ cultures of 15-day-old embryonic chick femurs. The ascorbate that was taken up into the cultured tissue reached maximal concentrations after 1.5 h. The half-life of tissue ascorbate was 12-24 h, whereas the half-life of medium ascorbate was 1-2 h. 24 h after supplementing with ascorbate, the tissue concentrations were still 30-60-fold higher than the medium concentrations at that time. If no ascorbate was added to the culture medium, the tissue concentration declined over a period of days: after 6 days 2-7% of the pre-culture tissue concentrations were still present. Embryonic chick femurs in vitro are therefore shielded from massive fluctuations in the concentration of ascorbic acid in the medium, resulting from intermittent supplementation. Hence, feeding a culture with the vitamin once every 24 h is sufficient to ensure adequate levels in the tissue.

Animals↗
PubMed1985

Ascorbic acid requirements for collagen synthesis (proline hydroxylation) during long-term culture of embryonic chick femurs.

Although ascorbate is essential for collagen synthesis, especially the hydroxylation of prolyl residues, femurs from 15-day-old chick embryos could be cultured for at least 5 days without ascorbate additions to the medium before the hydroxylation of proline was significantly impaired. Only when the ascorbate concentration in the tissue was less than 6 micrograms/g wet weight (compared with 50-70 micrograms/g wet weight in fresh tissue), was hydroxyproline formation reduced by 75-85%. When sufficient ascorbate was present in the culture medium, the femurs accumulated and stored the vitamin at concentrations which were 5-10-fold above the threshold required for collagen synthesis. This may represent an adaptive mechanism to the instability of the vitamin. Above the minimum required level, synthesis of collagen was not quantitatively related to ascorbate concentration. To obtain comprehensive data on changes in collagen content and collagen synthesis during culture, total hydroxyproline was measured as well as [3H]proline uptake and the formation of [3H]hydroxyproline. These three parameters were assessed with a new combined assay, which was modified from existing methods, yet was more sensitive and less tedious.

Animals↗
PubMed1985

Duodenal mucosa synthesis of prostaglandins in duodenal ulcer disease.

Synthesis of prostaglandins (PGE2, PGI2 and PGF2 alpha) and thromboxane A2 was investigated in short term incubates of duodenal mucosa biopsies. Mucosa close to the ulcer site synthesised significantly less PGF2 alpha (p less than 0.001) and PGI2 (p less than 0.002) measured as its stable metabolite 6-oxo-PGF1 alpha than healthy mucosa from non-ulcer patients. In paired biopsies taken from the ulcer site and opposite the ulcer in the same patient PGF2 alpha and PGI2 syntheses were both significantly and similarly depressed when compared with normal mucosa. Synthesis of PGE2 and TxA2 (as its stable metabolite TxB2) was not different in any tissue. There is a defect in the ability of the human duodenal mucosa in duodenal ulcer disease to synthesise PGF2 alpha and PGI2; the defect is not limited to the ulcer site.

Dinoprost↗