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M J Parnham

Publications and source records attributed to M J Parnham.

At least 55 records · Page 3Linked to original sources
PubMed1986

Pharmacological analysis of guinea-pig macrophage chemiluminescence responses to platelet activating factor and opsonized zymosan.

The luminol-dependent chemiluminescence (CL) response in vitro of guinea-pig C. parvum-activated peritoneal macrophages to platelet activating factor (PAF) has been compared with that to opsonized zymosan (OpZ). The response to PAF (5 X 10(-6) mol/l.) reached a peak within 1 min, that to OpZ (0.17 mg/ml) within 10-20 min. Peak responses to both stimuli were dose-dependently inhibited in a similar manner by p-hydroxymercuribenzoate (10(-5) - 10(-3) mol/l), sodium benzoate (10(-5) - 10(-3) mol/l.) and quinacrine (10(-6) - 10(-3) mol/l.). In contrast, the xanthine oxidase inhibitor allopurinol (IC50 vs OpZ, 220 mumol/l.; vs PAF greater than 1000 mumol/l.), the methylation-inhibiting combination homocysteine + 3-deazaadenosine (IC50 vs OpZ, 22 mumol/l.; vs PAF greater than 100 mumol/l.), the phospholipase A2 inhibitor and alkylating agent p-bromophenacylbromide (pBPB; IC50 vs OpZ, 2.6 mumol/l.; vs PAF 15 mumol/l.) and the beta-adrenoceptor agonist isoprenaline (IC50 vs OpZ, 0.1 mumol/l.; PAF greater than 10 mumol/l.) all exerted differential inhibitory effects on the CL responses to the two stimuli, though colour quenching by adrenochrome cannot be ruled out in the differential effect of isoprenaline. In screening studies, carried out with CL responses measured 2 or 5 min after PAF and OpZ, respectively, verapamil (less than or equal to 10(-4) mol/l.), trifluoperazine (less than or equal to 10(5) mol/l.) EDTA (less than or equal to 10(6) mol/l.), mannitol (less than or equal to 10(-2) mol/l.), metyrapone (less than or equal to 10(-5) mol/l.), SQ 22536 (less than or equal to 10 micrograms/ml.), iso-butyl methylxanthine (less than or equal to 10(-5) mol/l.).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Kadsurenone distinguishes between different platelet activating factor receptor subtypes on macrophages and polymorphonuclear leucocytes.

The effects of the antagonist kadsurenone on the platelet activating factor (Paf)-induced chemiluminescence of guinea-pig peritoneal macrophages and on pig peripheral blood leucocyte aggregation were compared. Linearity and slopes of unity of the Schild plots confirmed the competitive nature of the antagonism by kadsurenone. pA2 values indicated a 91 fold lower affinity of kadsurenone for leucocyte Paf receptors than for those in macrophages. It is concluded that these two types of Paf receptors are not identical and are provisionally designated Paf1 and Paf2 receptors, respectively.

Animals↗
PubMed1985

Improvement of the gastric tolerance of non-steroidal anti-inflammatory drugs by polyene phosphatidylcholine (Phospholipon 100).

The effect of co-administration with polyene phosphatidylcholine (Phospholipon 100) on the oral gastrotoxicity of various non-steroidal anti-inflammatory drugs (NSAIDs) was studied in the rat. The highly unsaturated phospholipid reduced gastric mucosal lesions measured 3.5 h after oral administration of aspirin, indomethacin, phenylbutazone, diclofenac, piroxicam and sudoxicam to rats which had received a 3 day bread diet followed by 24 h fasting. The extent of reduction of gastrotoxicity varied amongst the individual NSAIDs. Phospholipon 100 also reduced gastric lesions induced by 3 day oral piroxicam and diclofenac administration. A trend towards reduction of oral diclofenac gastrotoxicity was observed following intravenous Phospholipon 100 administration. Phospholipon 100 H (100% saturated phosphatidylcholine) was less effective than Phospholipon 100 in improving acute gastric tolerance to oral phenylbutazone, diclofenac and piroxicam. Administration of the NSAID-Phospholipon 100 combination produced little change in the anti-inflammatory activities of diclofenac on carrageenan paw oedema and diclofenac and piroxicam on adjuvant arthritis in the rat. Combination with Phospholipon 100 offers a novel means for reducing the gastric side-effects of NSAID therapy.

Animals↗
PubMed1984

A novel biologically active seleno-organic compound--III. Effects of PZ 51 (Ebselen) on glutathione peroxidase and secretory activities of mouse macrophages.

PZ 51 (2-phenyl-1,2-benzisoselenazol-3(2H)-on), a selenium-containing compound with glutathione peroxidase (GSH-Px)-like activity, was administered to selenium-deficient mice for 5 days. A significant increase in peritoneal macrophage GSH-Px activity after treatment was only observed when basal GSH-Px activity was almost zero (i.e. in 19 weeks selenium-deficient animals), possibly due to binding of PZ 51 to the macrophages. This indicates that PZ 51 releases very little, if any, free selenium for incorporation into endogenous GSH-Px. The compound in vitro exerted a concentration-dependent inhibition of the generation of chemiluminescence by resident mouse peritoneal macrophages and a partial inhibition of the production of prostaglandin E2 by resident peritoneal macrophages. beta-Glucuronidase production by C. parvum-activated peritoneal macrophages was unaffected by PZ 51. These in vitro data can be explained on the basis of a selective peroxide scavenging and/or GSH-Px-like activity of PZ 51, offering a novel approach to anti-inflammatory therapy.

Animals↗
PubMed1984

Inflammatory pleuropulmonary fibrosis in essential fatty acid deficient rats and the lack of response to methysergide.

In view of the association between essential fatty acid (EFA) deficiency and human cystic fibrosis, we have investigated the possible occurrence of pulmonary disease in rats fed an EFA deficient (EFAD) diet for 40 weeks. In contrast to a few slight spontaneous lesions consisting of pleural membrane hyperplasia, which were found in the lungs of control rats, a much greater incidence of fibrotic lesions was observed in the lungs of EFAD rats. These pleuropulmonary fibroses extended from the hyperplastic pleural membrane into the alveoli and were characterized by collagen deposition and marked macrophage infiltration to the extent that, in some cases, the alveolar septa were completely obstructed by inflammatory exudate. These findings lend indirect support to the contention that EFA deficiency plays a role in the aetiology of cystic fibrosis, at least with regard to pulmonary lesions. Administration of methysergide (10 mg/kg/day, p.o.) for a total of 11 weeks, did not alter the incidence of fibrosis in the lungs of EFAD rats, despite the finding that a man who had developed pleuropulmonary fibrosis as a result of chronic methysergide treatment exhibited a relative serum EFA deficiency. While a relative EFA deficiency may be a predisposing factor for the induction of fibrosis by chronic methysergide treatment, our data are not sufficient to make a decision upon this hypothesis.

Adult↗
PubMed1984

Regulation of the oxidative burst of macrophages by lipid mediators.

Macrophages, on stimulation, generate both cyclo-oxygenase and lipoxygenase products of arachidonic acid as well as the acetylated phospholipid, PAF-acether. The latter induces the oxidative burst in C. parvum-activated macrophages, but has little activity on resident macrophages. Mouse macrophages are generally rather insensitive to PAF-acether. Prostaglandin (PG)E2, on the other hand is a potent inhibitor of the macrophage oxidative burst, though its activity is also dependent upon the source of the macrophages and the stimulus used. Several lipoxygenase inhibitors inhibit the oxidative burst of mouse peritoneal macrophages, while other authors have reported stimulatory effects of lipoxygenase products on different macrophage populations. The differential actions of lipoxygenase and cyclo-oxygenase products on the macrophage oxidative burst are reflected by the effect of arachidonic acid on the zymosan induced response of mouse resident peritoneal cells: initial enhancement, followed by prolonged inhibition, the latter being indomethacin-sensitive. While PAF-acether is probably an important initiator of the macrophage oxidative burst in vivo, arachidonic acid modulates the response by a "see-saw mechanism", lipoxygenase products being stimulatory and cyclo-oxygenase products (mainly PGE2) being inhibitory.

Animals↗
PubMed1983

Chemiluminescence from mouse resident macrophages: characterization and modulation by arachidonate metabolites.

Oxidative burst dependent chemiluminescence (CL), generated by mouse resident peritoneal and alveolar macrophages obtained by peritoneal and lung lavage, has been studied using a lumanol-dependent assay. Alveolar macrophages generated greater CL in response to opsonized zymosan (OpZ, 0.017-0.67 mg/ml) than did peritoneal cells, but the former were less sensitive to inhibition by joint cyclo-oxygenase/lipoxygenase inhibitors and superoxide dismutase. Responses of peritoneal macrophages to OpZ and calcium ionophore A23187 (0.1-0.5 microM) were small in comparison to responses of C. parvum-elicited cells, while FMLP (2-20 microM) was ineffective. Arachidonic acid alone (40-80 microM) generated slight CL from resident peritoneal macrophages. When added with OpZ (0.017 mg/ml), arachidonate (40 microM) initially enhanced, then inhibited CL, the inhibition being indomethacin (10 microM) sensitive. These data indicate that modulation of resident macrophage CL by arachidonate products differs somewhat from that reported for elicited macrophages.

Animals↗
PubMed1983

Platelet activating factor (PAF) induces the oxidative burst in macrophages.

The response of guinea pig peritoneal macrophages to platelet activating factor (1-O-octadecyl-2-acetyl-sn-glycero-3-phosphoryl-choline) was examined. In Corynebacterium parvum induced macrophages, platelet activating factor, over a wide dose range (3.8 X 10(-5) to 3.8 X 10(-9)M) triggered the oxidative burst as indicated by increased luminol-dependent chemiluminescence and hydrogen peroxide release into culture supernatants. This effect of PAF was inhibited by superoxide dismutase and catalase. Resident macrophages exhibited only slight respiratory activity in response to platelet activating factor which could be increased by adding 1% gelatine to the medium. Activation of macrophages is a new biological effect exerted by platelet activating factor. In immuno-inflammatory reactions, cells capable of generating platelet activating factor may come into close contact with macrophages and by liberating this mediator cause them to release highly toxic oxygen species known to be microbicidal and cytocidal and able to produce vascular endothelial injury. Our findings lend further support to the view that platelet activating factor is a potent and rapid activator of physiological defence mechanisms.

Animals↗
PubMed1983

Macrophage, lymphocyte and chronic inflammatory responses in selenium deficient rodents. Association with decreased glutathione peroxidase activity.

The influence of a selenium deficient diet in mice and rats has been studied on glutathione peroxidase (GSH-Px) and secretory activities of peritoneal macrophages, mitogenesis of spleen cells and adjuvant arthritis. Macrophage GSH-Px activity was significantly reduced from 9 weeks on the selenium deficient diet. This reduction was associated with enhanced macrophage H2O2 release on zymosan stimulation after 12 weeks on the diet, a similar trend in chemiluminescence and reduced mitogenesis of spleen cell cultures to T and B cell mitogens after 8 weeks on the diet. Macrophage beta-glucuronidase release was not significantly altered. Phorbol myristic acetate induced macrophage H2O2 generation was reduced by selenium deficiency, possibly due to increased cellular damage. Adjuvant arthritis of rats was significantly enhanced after 6 and 12 weeks on the selenium deficient diet. The enhanced release of H2O2 by macrophages after zymosan stimulation can be directly attributable to loss of GSH-Px activity leading to reduced peroxide breakdown. Peroxide-mediated cell injury would also account for the reduction in lymphocyte mitogenesis and enhancement of adjuvant arthritis. These data provide support for a role of selenium in immune and inflammatory responses.

Animals↗
PubMed1982

Collagen metabolism and phenotype after prostaglandin E2 treatment of granuloma: direct and macrophage-modulated effects.

Local administration of PGE2 (2 micrograms) to polyether sponges, implanted s.c. in rats, inhibited hydroxyproline and total protein accumulation, without altering relative amounts of collagen, when administered early during granuloma development. In contrast, while DNA as well as total protein accumulation was inhibited by local PGE2 treatment of established granuloma, hydroxyproline accumulation and the relative amounts of collagen were enhanced. This PGE2-induced collagen enhancement was associated with an increased type III : type I collagen ratio, possibly due to differential intracellular breakdown of newly synthesized collagen. The solubility of granuloma collagen was unaffected by PGE2. Impregnation of sponges with carrageenan before implantation, thereby giving macrophage-dominated granuloma, did not affect the changes in protein and DNA induced by later treatment with PGE2, but did reverse the PGE2-induced accumulation of hydroxyproline. This latter effect probably reflects macrophage-mediated, PGE2 enhancement of collagenolytic activity.

Animals↗
PubMed1981

Comparison of the effects of inhibitors of cytochrome P-450-mediated reactions on human platelet aggregation and arachidonic acid metabolism.

Metyrapone and SKF-525A, together with amphenone B, a structural analogue of metyrapone, which are all inhibitors of cytochrome P-450-mediated reactions, were shown to inhibit the arachidonic acid-induced aggregation of human platelets. Amphenone B, like metyrapone, exhibited a type II (ligand) binding spectrum with rat liver microsomal cytochrome P-450, in contrast to SKF 525A which is a type I (substrate) binding agent. Independently of their type of binding spectra and of their maximum spectral change, however, the affinity of the three compounds for rat liver cytochrome P-450 showed a close proportional correlation with their platelet aggregation inhibitory potency. All three compounds inhibited the formation of [1-14C]thromboxane B2 from [1-14C]arachidonic acid by human platelets aggregated with collagen. The effect of metyrapone on the remaining labelled products suggested that it is a selective thromboxane synthesis inhibitor, while amphenone B exhibited activity reminiscent of cyclo-oxygenase inhibitors. SKF 525A produced complex effects possibly attributable to cyclo-oxygenase inhibition and enhanced lipid peroxidation, since it also enhanced platelet malonaldehyde formation, which the other two compounds inhibited. These data provide further support for a role of cytochrome P-450 in thromboxane synthesis and platelet aggregation.

Animals↗