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Biomedical subjects

A D Sedgwick

Publications and source records attributed to A D Sedgwick.

At least 19 recordsLinked to original sources
PubMed1992

The monoclonal antibody MEL-14 can block lymphocyte migration into a site of chronic inflammation.

The effect of MEL-14, a monoclonal antibody which binds to the lymphocyte homing receptor (MEL-14 Ag) on lymphocytes for peripheral lymph node (PLN) high endothelial venules (HEV), was investigated on lymphocyte migration into a delayed-type hypersensitivity (DTH)-like lesion produced by sensitization and challenge to Bordetella pertussis vaccine (BPV). Pretreatment of lymphocytes with saturating concentrations of MEL-14 caused a highly significant inhibition of lymphocyte migration into the chronically inflamed site and PLN. This finding suggests that lymphocyte migration into the BPV-induced site of chronic inflammation may be regulated by the same mechanism as lymphocyte migration into the PLN. It further indicates that the ligand for the MEL-14 Ag adhesion molecule, recognized by lymphocyte which home to the PLN, may also be expressed on HEV-like vessels at sites of BPV-induced chronic inflammation.

Animals↗
PubMed1992

Oral, anti-inflammatory activity of a potent, selective, protein kinase C inhibitor.

The protein kinase C family of enzymes is thought to be important in mediating signal transduction. Ro 31-8830 is a novel, potent inhibitor of protein kinase C, derived from the non-selective protein kinase inhibitor staurosporine. In this paper we demonstrate the selectivity of Ro 31-8830 for protein kinase C over other protein kinases and its ability to inhibit protein kinase-C-mediated events in platelets and lymphocytes. In addition, we describe a novel system for the in vivo evaluation of inhibitors of protein kinase C, and we demonstrate the oral anti-inflammatory activity of Ro 31-8830. This finding has implications for the treatment of inflammatory disorders in the clinic.

Administration, Oral↗
PubMed1992

Lymphocyte migration in the mouse. I. Time course of cell accumulation and the effect of antigen sensitisation and challenge in a murine model of chronic inflammation.

The effect of time and of antigen sensitisation and challenge on lymphocyte migration into a site of chronic inflammation has been examined in the mouse. Enhanced lymphocyte migration occurred at sites of chronic inflammation after sensitisation and challenge to Bordetella pertussis vaccine (BPV). Biphasic migration was observed with time (5 min to 24 h), the initial very rapid but transient localisation at the inflamed site being followed by a second slower more sustained influx of cells. Increased localisation was also obtained with time in the lymphoid tissues and was accompanied by a parallel decrease in the number of cells present in the blood. The relative importance of antigen sensitisation and challenge for lymphocyte migration to a site of chronic inflammation has also been assessed. Lymphocyte migration into the inflamed site was partially dependent on the immunological status of the injected lymphocytes, but the presence or absence of antigen at the site of inflammation was the major factor which determined the degree of migration to the site.

Animals↗
PubMed1992

Lymphocyte migration in the mouse. II. Differential B and T-lymphocyte migration into a site of chronic inflammation.

Different patterns of B and T-lymphocyte migration were observed in normal mice and in animals with a site of chronic inflammation. The early migration of lymphocytes into a site of chronic inflammation, induced by sensitisation and challenge to Bordetella pertussis vaccine (BPV), comprised mainly B-cells. Subsequently, a greater influx of T-cells occurred as the inflammation progressed. The lymphocyte population in the inflammatory exudate was composed of equal numbers of B and T-cells throughout the 30 day time course. Preferential migration of B-cells to Peyer's patches (PP) and T-cells to peripheral lymph nodes (PLN) occurred in both normal mice and animals with a site of chronic inflammation. In contrast, B-cells migrated preferentially to the spleen in normal mice while in mice with chronic inflammation a greater migration of T-cell was observed. These findings indicate the presence of homing receptors for PP on B-cells and of PLN homing receptors on T-cells, with their distribution unaffected during the development of the inflammatory response. In contrast, the inflammatory process did alter the type of cell migrating into the spleen which may reflect an increase in antigen presentation in the mice challenged with BPV.

Animals↗
PubMed1991

Modulation of cellular processes by H7, a non-selective inhibitor of protein kinases.

H7 has been described as a potent inhibitor of protein kinase C (PKC) and has been widely used to investigate the regulatory role of this enzyme in intact cell systems. In this comparative study between H7 and the microbial alkaloid, staurosporine, we found that the former inhibited rat brain PKC and cAMP dependent protein kinase with IC50 values of 18 and 16 microM respectively whereas the latter was a much more potent inhibitor of both kinases with IC50 values of 9.5 nM and 42 nM respectively. H7, at concentrations up to 100 microM, failed to block cellular events induced by phorbol esters, agents which specifically stimulate PKC, yet was a potent inhibitor of IL-2 induced T cell proliferation with an IC50 value of 19 microM. In contrast, staurosporine was a potent inhibitor of both phorbol ester induced p47 phosphorylation in platelet (I50 value = 540 nM) and also CD3 and CD4 down-regulation in T cells (I50 values 200 nM and 50 nM respectively). Staurosporine was also a potent inhibitor of IL-2 induced T cell proliferation I50 value = 9 nM). These results provide a strong argument against the use of H7 to probe for PKC involvement in cellular processes.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

IL-1 alpha inhibits lymphocyte migration into a site of chronic inflammation.

The effects of murine recombinant IL-1 alpha (muIL-1 alpha) on lymphocyte migration in the mouse have been investigated. Continuous infusion of muIL-1 alpha had marked effects on patterns of lymphocyte migration into a site of chronic inflammation, inflammatory exudate and spleen; the numbers of lymphocytes migrating to the inflamed tissue and spleen were reduced in a dose-dependent manner. The number of lymphocytes in the blood of muIL-1 alpha-treated animals was increased in a dose-related manner. The decrease in numbers of lymphocytes present in the chronically inflamed site may either be due to a direct inhibitory action of muIL-1 alpha or reflect an increased rate of cell migration through the inflamed tissues accompanied by a more rapid return to the circulation. These findings suggest that IL-1 alpha may act not only as an inflammatory cytokine, but also as a modulator with anti-inflammatory activity during chronic inflammation.

Animals↗
PubMed1991

Potent collagenase inhibitors prevent interleukin-1-induced cartilage degradation in vitro.

The matrix metalloproteinases (MMPs) collagenase, gelatinase and stromelysin, contribute to the destruction of articular cartilage which occurs during rheumatoid and osteoarthritis. Ro 31-4724, a substrate analogue containing a hydroxamic acid function, is a potent but non-selective inhibitor of all three MMPs (I50, collagenase = 10 nM), whereas Ro 31-7467, a phosphinic acid transition-state analogue, shows 14-fold and 12-fold selectivity for collagenase (I50 = 17 nM) over gelatinase and caseinase (stromelysin) respectively. The effects of these inhibitors on interleukin-1-induced bovine nasal cartilage degradation were examined. The hydroxamate Ro 31-4724 inhibits proteoglycan and collagen loss, whereas the phosphinic acid Ro 31-7467 selectively inhibits collagen breakdown in this model. This represents the first demonstration of potent and selective inhibition of IL1-induced cartilage degradation in vitro by MMP inhibitors. These results suggest that collagenase is responsible for collagen loss and that a different enzyme, possibly stromelysin, is responsible for proteoglycan degradation in this model.

Animals↗
PubMed1991

A comparative study of the cellular, exudative and histological responses to carrageenan, dextran and zymosan in the mouse.

A murine 6-day air-pouch model of inflammation has been developed and used to compare the patterns of acute and chronic inflammatory response to three irritants, carrageenan, dextran and zymosan, each injected into the cavity of the pre-formed pouch. The inflammation was assessed by measurement of exudate volume and numbers of infiltrating leucocytes over a 30-day time course. Histological changes in the inflamed air-pouch lining tissue were also investigated. The inflammatory response to carrageenan was acute with moderate exudate formation and cell numbers. Dextran produced a mild inflammatory reaction with low cell infiltration into exudate. In contrast, the inflammatory response to zymosan was greater in terms of cell migration, but smaller in terms of exudate volume and occurred later in the time course. Histological changes in the inflamed air-pouch tissue were also markedly different in response to the three irritants. Carrageenan induced a rapid, mainly polymorphonuclear leucocyte (PMN) infiltrate into the tissue and deposition of fibrin on the luminal surface. The response to dextran was characterized by a rapid resolution of the inflammatory response, with fewer leucocytes present in the lining and no fibrin deposition. In contrast, zymosan caused a marked but slower leucocyte influx, with greater numbers of monocytes, and clearance of the zymosan particles from the air-pouch lining by macrophages. This study indicates that by using different irritants to produce inflammation, it may be possible to dissect the roles played by various cells and inflammatory mediators during acute and chronic inflammation.

Animals↗
PubMed1990

The effect of new potent selective inhibitors of protein kinase C on the neutrophil respiratory burst.

New potent inhibitors of protein kinase C were found to inhibit protein kinase C isolated from rat brain and human neutrophils, with a large degree of selectivity over cAMP-dependent kinase and Ca2+/calmodulin-dependent kinase. These novel compounds were potent inhibitors of the fluoride, diC8- and formyl-methionyl-leucyl-phenylalanine-mediated respiratory bursts in intact neutrophils. The opsonized zymosan-stimulated burst was only marginally affected by the compounds. These results differ from those obtained in studies with H7 and CI, (which are less potent and less specific protein kinase C inhibitors) and are consistent with the hypothesis that protein kinase C has a role in the transduction mechanism for the neutrophil oxidative burst stimulated with fluoride, formyl-methionyl-leucyl-phenylalanine and diC8.

Alkaloids↗
PubMed1990

K252a is a potent and selective inhibitor of phosphorylase kinase.

The inhibition of phosphorylase kinase by a number of protein kinase inhibitors was examined. Both K252a and staurosporine are potent inhibitors of phosphorylase kinase with IC50 values of 1.7 nM and 0.5 nM respectively. K252a shows a 300-fold selectivity for this enzyme over protein kinase C whereas staurosporine shows only a 20-fold selectivity for phosphorylase kinase. In contrast, the Roche bis-indolyl maleimides inhibit phosphorylase kinase with IC50 values of approximately 1 microM and are highly selective for protein kinase C.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1989

Potent selective inhibitors of protein kinase C.

A series of potent, selective inhibitors of protein kinase C has been derived from the structural lead provided by the microbial broth products, staurosporine and K252a. Our inhibitors block PCK in intact cells (platelets and T cells), and prevent the proliferation of mononuclear cells in response to interleukin 2 (IL2).

Alkaloids↗
PubMed1989

Lymphocyte kinetics in a murine model of chronic inflammation.

A modification of the air pouch system [1], has been developed to investigate the role of lymphocytes in an inmmunologically driven model of chronic inflammation. Radiolabelled spleen and lymph node mononuclear cells from mice presensitised with Bordatella pertussis vaccine (BPV) were infused intravenously into mice also presensitised with BPV and challenged with BPV into 6 day old air pouches. Cell migration was monitored by gamma counting of tissues sampled 4 hours after infusion. The percentage increase in counts obtained in air pouch tissue compared to control skin, over a time course of 30 days, reached a peak at 10 days after BPV challenge. Vessels with features of high endothelial venules, and clusters of lymphocytes have been demonstrated histologically and immunohistochemically in air pouch tissue at this time.

Animals↗
PubMed1988

Platelet activating factor as a mediator of equine cell locomotion.

Equine polymorphonuclear (PMN) and mononuclear (MN) leucocytes were separated on Percoll gradients and used to study the chemoattractant properties of the polar ether-linked phospholipid, platelet activating factor (PAF). Six concentrations of PAF ranging from 1 ng/ml to 100 micrograms/ml were studied in each of two in vitro assay systems, the agarose microdroplet and a microfilter technique. Very significant (p less than 0.01) increases in the movement of both PMN and MN cells were obtained with most concentrations of PAF. In two instances there was no apparent concentration-response relationship, although the action of PAF was approximately bell-shaped in two others. The possible significance of these findings for equine inflammatory conditions is discussed.

Animals↗
PubMed1988

In vitro and in vivo binding of phenylbutazone and related drugs to equine feeds and digesta.

In vitro and in vivo studies of phenylbutazone binding to equine ingesta and digesta were undertaken. In vitro binding to chopped hay and powdered pony nuts in buffer solutions at 37 degrees C was found to be time-, concentration- and pH-dependent. Percentage binding generally increased with time, decreased with concentration and varied with buffer pH in an unpredictable manner. Other non-steroidal anti-inflammatory drugs (NSAIDs) also bound to hay, the degree of binding being less for meclofenamate and least for flunixin in comparison with phenylbutazone. Phenylbutazone became bound to digesta collected from eight regions of the gastrointestinal tract when they were spiked with a concentration of 1 mg.10 g-1 digesta, the amounts ranging from 80.0 per cent (duodenum) to 99.6 per cent (stomach). Binding also occurred to equine digesta following the oral administration of phenylbutazone (4.4 mg.kg-1) to three ponies. It was concluded that drug uptake by and release from equine ingesta and digesta were probably adsorptive and desorptive processes. The clinical significance of the findings for the use of NSAIDs in equine medicine was considered.

Animal Feed↗
PubMed1987

Inflammation: a clinical perspective. The Ciba-Geigy Prize for Research in Animal Health.

The cardinal signs of acute inflammation have been recognised for almost 2000 years, but it is only in the last hundred years that significant progress has been made in understanding the underlying cellular response. Our knowledge of the chemical messengers which regulate and in some cases lead to persistence of the inflammatory process is, as yet, incomplete, but it is hoped that further research at this level will lead to the development of more effective therapeutic agents.

Acute Disease↗
PubMed1987

Development of equine models of inflammation. The Ciba-Geigy Prize for Research in Animal Health.

Two experimental models of acute non-immune inflammation have been developed to enable studies of the biochemical composition and cellular content of exudates to be undertaken. Both are based on the creation of a mild, reproducible and reversible inflammatory reaction, which is free from uncontrolled incidental factors and which causes minimal distress to the experimental animals. The polyester sponge model involves the insertion of small polyester sponge strips soaked in sterile carrageenan solution into subcutaneous neck pouches and their serial removal. The tissue-cage model is based on the initial insertion of a spherical tissue-cage subcutaneously in the neck and the subsequent stimulation with carrageenan of the granulation tissue which lines and permeates the cage. The acute inflammatory exudates have been shown to contain eicosanoids with prostaglandin E2 predominant. Polymorphonuclear leucocyte numbers increased progressively in the polyester sponge model, whereas cell numbers were maximal at 12 hours in the tissue-cage model. The relationships between eicosanoid formation at the site of inflammation and leucocyte accumulation, enzyme release, total protein content of exudates and the temperature of the lesions have been investigated.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Applications of equine models of acute inflammation. The Ciba-Geigy Prize for Research in Animal Health.

The development of reproducible models of acute inflammation in which inflammatory heat is easily quantified and from which inflammatory exudate is readily harvested has facilitated studies in the horse of the actions of steroids and non-steroidal anti-inflammatory drugs (NSAIDS). Blockade of the synthesis of eicosanoids and suppression of inflammatory heat by clinical dose rates of NSAIDS suggests a causal link between the two events and provides further evidence for a role of these compounds in acute equine inflammation. The tendency for enolic and carboxylic acids NSAIDS to accumulate in inflammatory exudate may account for the duration of action of these compounds in inhibiting exudate eicosanoid synthesis and the data confirm clinical experiences with these drugs. A novel NSAID which inhibits both cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism, BW540C, and two anti-inflammatory steroids, betamethasone and dexamethasone, have been evaluated in the models of equine inflammation with some interesting and unexpected findings. This paper emphasises the interrelationships between the inflammatory process and the actions and fate of anti-inflammatory drugs.

Acute Disease↗