Publications
221 results found
Williams FM, Collins PD, Tannière-Zeller M, et al., 1990, The relationship between neutrophils and increased microvascular permeability in a model of myocardial ischaemia and reperfusion in the rabbit., Br J Pharmacol, Vol: 100, Pages: 729-734, ISSN: 0007-1188
1. 111In-labelled neutrophils and 125I-labelled albumin were used to measure neutrophil accumulation and microvascular plasma protein leakage in the ischaemic/reperfused myocardium of anaesthetized rabbits. 2. A period of 30 min coronary artery occlusion followed by 3 h reperfusion resulted in an increase in both 111In and 125I counts in the area at risk (AR) of the myocardium. 3. Pretreatment of 111In-neutrophils in vitro with monoclonal antibody 60.3 directed against the CD18 antigen on neutrophils, followed by intravenous administration, significantly suppressed their accumulation into the AR myocardium. 4. Depletion of circulating neutrophils by use of anti-neutrophil serum or mustine hydrochloride did not affect plasma protein leakage into the AR myocardium. 5. Administration of the platelet activating factor (PAF) antagonist WEB 2086 (10 mg kg-1, i.v.) had no effect on the accumulation of 111In-neutrophils or on plasma protein leakage in the AR myocardium.
Brain SD, Wimalawansa S, MacIntyre I, et al., 1990, The demonstration of vasodilator activity of pancreatic amylin amide in the rabbit., Am J Pathol, Vol: 136, Pages: 487-490, ISSN: 0002-9440
Amylin amide, a 37-amino acid peptide that is a major component of amyloid deposits in the diabetic pancreas, possesses vasodilator activity. Human synthetic amylin amide (30 to 300 pmol/site) stimulated a dose-dependent increase in blood flow after intradermal injection in rabbit skin. Amylin amide was 100 times less active than the structurally related potent vasodilator neuropeptide calcitonin gene-related peptide. Amylin amide did not induce edema formation; however, as a consequence of its vasodilator activity, amylin amide potentiated edema formation induced in rabbit skin by bradykinin. The intravenous injection of amylin amide (10 nmol) caused a systemic drop in blood pressure. This study demonstrates that amylin amide elicits vasodilator responses in vivo. It is possible that the release of amylin amide from the pancreas in type II diabetes could lead to changes in vascular tone.
WILLIAMS TJ, YARWOOD H, 1990, EFFECT OF GLUCOCORTICOSTEROIDS ON MICROVASCULAR PERMEABILITY, AMERICAN REVIEW OF RESPIRATORY DISEASE, Vol: 141, Pages: S39-S43, ISSN: 0003-0805
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- Citations: 51
Buckley TL, Brain SD, Williams TJ, 1990, Ruthenium red selectively inhibits oedema formation and increased blood flow induced by capsaicin in rabbit skin., Br J Pharmacol, Vol: 99, Pages: 7-8, ISSN: 0007-1188
It has been suggested that ruthenium red has a selective inhibitory effect on capsaicin-induced nociceptor stimulation. We have investigated the effect of ruthenium red on oedema formation and vasodilatation induced by intradermal (i.d.) injection of capsaicin in the rabbit in vivo. Responses induced by capsaicin were inhibited by ruthenium red, but responses induced by bradykinin, N-formyl-methionyl-leucyl-phenylalanine (FMLP), platelet activating factor (PAF), histamine and calcitonin gene-related peptide (CGRP) were not affected. These results suggest that ruthenium red selectively inhibits capsaicin-induced local plasma protein leakage and vasodilatation in the rabbit skin microvasculature.
Brain SD, Williams TJ, 1990, Leukotrienes and inflammation., Pharmacol Ther, Vol: 46, Pages: 57-66, ISSN: 0163-7258
The leukotrienes are synthesized from essential fatty acids via a 5-lipoxygenase enzyme. Most is known about the four-series leukotrienes derived from arachidonic acid. Leukotriene B4 is a potent chemotactic agent for leukocytes and it induces neutrophil-dependent increased microvascular permeability. Leukotrienes C4, D4 and E4 are bronchoconstrictors; and potent mediators of microvascular tone and permeability. The leukotrienes have been suggested to have a role in many inflammatory conditions in man in the skin (e.g. psoriasis), the lung (e.g. allergic asthma), joints (e.g. rheumatoid arthritis) and in the heart (e.g. myocardial infarction). Drugs which inhibit the generation and the actions of leukotrienes are under development and are being tested clinically as potential anti-inflammatory agents.
HASLETT C, JOSE PJ, GICLAS PC, et al., 1989, CESSATION OF NEUTROPHIL INFLUX IN C5A-INDUCED ACUTE EXPERIMENTAL ARTHRITIS IS ASSOCIATED WITH LOSS OF CHEMOATTRACTANT ACTIVITY FROM THE JOINT SPACE, JOURNAL OF IMMUNOLOGY, Vol: 142, Pages: 3510-3517, ISSN: 0022-1767
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- Citations: 20
Nourshargh S, Rampart M, Hellewell PG, et al., 1989, Accumulation of 111In-neutrophils in rabbit skin in allergic and non-allergic inflammatory reactions in vivo. Inhibition by neutrophil pretreatment in vitro with a monoclonal antibody recognizing the CD18 antigen., J Immunol, Vol: 142, Pages: 3193-3198, ISSN: 0022-1767
The mAb 60.3 recognizes the neutrophil CD18 Ag. We have investigated the effect of in vitro pretreatment of radiolabeled neutrophils with mAb 60.3 on their accumulation in vivo. Further, we have compared the in vivo effects of mAb 60.3 with its effects on neutrophil adherence in vitro. Neutrophil accumulation in vivo was measured in response to: 1) exogenous mediators FMLP, C5a des Arg, LTB4 and IL-1; 2) endogenous mediators generated in a non-allergic inflammatory reaction induced by zymosan; and 3) endogenous mediators generated in two allergic inflammatory reactions, a passive cutaneous anaphylactic reaction and a reversed passive Arthus reaction in rabbit skin. Pretreatment of neutrophils with mAb 60.3 inhibited their accumulation in all the responses. The results demonstrate that there is a common mechanism mediating neutrophil accumulation in these inflammatory reactions. Neutrophils pretreated with mAb 60.3 were also unresponsive to chemoattractants in in vitro adherence assays. However, the antibody-treated neutrophils responded normally to FMLP and C5a with respect to granular enzyme release. These results suggest that the basal expression of CD18 Ag is important for the adherence of neutrophils to microvascular endothelial cells stimulated by the local generation, or administration, of chemical mediators in vivo. Despite the fact that mediators such as FMLP can increase CD18 expression in vitro, it appears more likely that such mediators act in vivo by inducing a conformational change in the basally expressed neutrophil adhesive molecules.
Hellewell PG, Williams TJ, 1989, An anti-inflammatory steroid inhibits tissue sensitization by IgE in vivo., Br J Pharmacol, Vol: 96, Pages: 5-7, ISSN: 0007-1188
An anti-inflammatory corticosteroid, dexamethasone, was found to be a potent suppressor of cell sensitization induced by IgE antibody in a model of type I allergic inflammation in vivo. Low doses (approximately less than 10(-10) mol) of dexamethasone, administered intradermally to rabbits 90 min before injection of IgE into the same sites, suppressed local oedema induced by a local challenge with antigen 72 h later. The effect was not due to anti-inflammatory activity persisting in the skin site for the 3 day period. This novel potent activity of the corticosteroid may be an important component of its anti-allergic effect in diseases such as asthma.
Brain SD, Crossman DC, Buckley TL, et al., 1989, Endothelin-1: demonstration of potent effects on the microcirculation of humans and other species., J Cardiovasc Pharmacol, Vol: 13 Suppl 5, Pages: S147-S149, ISSN: 0160-2446
The effect of endothelin-1 (ET-1) on microvessels was investigated by use of intravital microscopy and by measuring microvascular blood flow changes. ET-1 caused a selective constriction of arterioles in the hamster cheek pouch, without affecting venules. A decrease in blood flow was observed at the site of intradermal injection of ET-1 in rabbit and human skin. ET-1, as a consequence of its vasoconstrictor activity, acted in an anti-inflammatory manner to inhibit edema formation and neutrophil accumulation induced by chemotactic agents in rabbit skin. In human skin, a flare, due to increased blood flow, spread for several centimeters around a central constricted area. The flare, the result of an axon reflex, reveals an alternative mechanism through which ET-1 can act to modulate vascular tone.
BRAIN SD, TIPPINS JR, WILLIAMS TJ, 1988, ENDOTHELIN INDUCES POTENT MICROVASCULAR CONSTRICTION, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 95, Pages: 1005-1007, ISSN: 0007-1188
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- Citations: 115
Fellows IW, Powell RJ, Toghill PJ, et al., 1988, Epoprostenol in systemic capillary leak syndrome., Lancet, Vol: 2, ISSN: 0140-6736
Brain SD, Williams TJ, 1988, Substance P regulates the vasodilator activity of calcitonin gene-related peptide., Nature, Vol: 335, Pages: 73-75, ISSN: 0028-0836
The 37-amino-acid calcitonin gene-related peptide (CGRP) occurs as a result of alternative processing of mRNA from the calcitonin gene. The potency of CGRP as a vasodilator and the occurrence of the peptide in nerves associated with blood vessels suggest an important role for CGRP in the regulation of blood flow. The finding that CGRP induces protracted vasodilatation when administered extra-vascularly, to mimic release from nerves, has led us to investigate how the vasodilator activity of CGRP is controlled in vivo. CGRP is often co-localized with substance P in C-fibre nerves. Here, we demonstrate that injection of CGRP with substance P into human skin converts the long-lasting vasodilatation induced by CGRP into a transient response. Experiments in animals reveal that the phenomenon is dependent on the action of proteases from mast cells stimulated by substance P. The results reveal a new regulatory interaction between two neuropeptides and provide evidence for an in vivo role for mast cell proteases.
Williams TJ, Brain SD, Hellewell PG, et al., 1988, Alteration in microvascular permeability induced by products released during inflammation., Prog Clin Biol Res, Vol: 263, Pages: 55-69, ISSN: 0361-7742
Forrest MJ, Jose PJ, Williams TJ, 1986, Kinetics of the generation and action of chemical mediators in zymosan-induced inflammation of the rabbit peritoneal cavity., Br J Pharmacol, Vol: 89, Pages: 719-730, ISSN: 0007-1188
Acute inflammation was induced by intraperitoneal injection of zymosan (yeast cell walls) in the rabbit. Peritoneal inflammation was monitored by the local accumulation of intravenously-injected Evans blue dye (which binds to plasma albumin) and of polymorphonuclear leukocytes (PMNLs). The zymosan-induced exudate fluid contained a microvascular permeability-increasing factor or factors which, unlike histamine and bradykinin, had a long duration of action when tested in rabbit skin and was dependent on circulating PMNLs. Using radioimmunoassay, high levels of rabbit C5a, or C5a des Arg, were detected in the exudate fluid and accounted for much of the permeability-increasing activity, as judged by skin bioassay after separation on Sephadex G-100. The vasodilator prostaglandin, prostaglandin I2 (PGI2), was generated in the inflammatory reaction, as judged by the presence of high levels of 6-oxo-PGF1 alpha detected in the exudate by radioimmunoassay. However, in contrast to observations in rabbit skin, inhibition of prostaglandin generation had a relatively small effect on peritoneal oedema formation. C5a and C5a des Arg increase microvascular permeability by a PMNL-dependent mechanism in the rabbit. However, in response to zymosan, protein leakage was detected considerably earlier than PMNL accumulation. A hypothesis to account for this difference is proposed.
Williams TJ, Hellewell PG, Jose PJ, 1986, Inflammatory mechanisms in the Arthus reaction., Agents Actions, Vol: 19, Pages: 66-72, ISSN: 0065-4299
BRAIN SD, TIPPINS JR, MORRIS HR, et al., 1986, POTENT VASODILATOR ACTIVITY OF CALCITONIN GENE-RELATED PEPTIDE IN HUMAN-SKIN, JOURNAL OF INVESTIGATIVE DERMATOLOGY, Vol: 87, Pages: 533-536, ISSN: 0022-202X
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- Citations: 166
Rampart M, Williams TJ, 1986, Suppression of inflammatory oedema by ibuprofen involving a mechanism independent of cyclo-oxygenase inhibition., Biochem Pharmacol, Vol: 35, Pages: 581-586, ISSN: 0006-2952
The effects of a non-steroidal anti-inflammatory compound, ibuprofen, on experimentally-induced local oedema responses in rabbit skin were investigated. The accumulation of intravenously-injected 125I-albumin was used to measure oedema. Two peptides were used to increase microvascular permeability: C5a des Arg, whose action is dependent on circulating polymorphonuclear leukocytes, and bradykinin which acts directly on vascular endothelial cells. The peptides were injected intradermally together with either arachidonic acid or PGE2 to potentiate oedema formation. To study the cyclooxygenase inhibitory activity of ibuprofen, the effects of the mediators were potentiated by addition of arachidonic acid. To investigate whether the drug had effects independent of cyclo-oxygenase inhibition, PGE2 was used to potentiate responses. Both local and intravenous ibuprofen suppressed oedema induced by bradykinin + arachidonic acid and C5a des Arg + arachidonic acid, which is consistent with suppression of cyclo-oxygenase in the skin. Local ibuprofen had no effect on responses to bradykinin + PGE2 or C5a des Arg + PGE2. Intravenous ibuprofen had no significant effect on responses to bradykinin + PGE2 but, in contrast, had a marked inhibitory effect on responses to C5a des Arg + PGE2. It is concluded that, in addition to its known cyclo-oxygenase inhibitory activity, ibuprofen can inhibit inflammatory oedema at clinically-relevant doses by an action on circulating poly-morphonuclear leukocytes. These observations in vivo appear to be related to other observations on the effects of ibuprofen on polymorphonuclear leukocyte function in vitro and ex vivo. The observations described may also relate to the protective effects of ibuprofen on experimentally-induced myocardial infarction.
BRAIN SD, MACINTYRE I, TIPPINS JR, et al., 1986, THE VASODILATOR ACTIVITY OF HUMAN ALPHA-CALCITONIN GENE-RELATED PEPTIDE AND RELATED STRUCTURES, ACTA PHARMACOLOGICA ET TOXICOLOGICA, Vol: 59, Pages: 147-147, ISSN: 0001-6683
BRAIN SD, MACINTYRE I, MORRIS HR, et al., 1985, COULD THE POTENT VASODILATOR CALCITONIN GENE-RELATED PEPTIDE BE THE MEDIATOR OF THE FLARE RESPONSE IN HUMAN-SKIN, REGULATORY PEPTIDES, Vol: 13, Pages: 92-92, ISSN: 0167-0115
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- Citations: 1
Brain SD, Williams TJ, 1985, Inflammatory oedema induced by synergism between calcitonin gene-related peptide (CGRP) and mediators of increased vascular permeability., Br J Pharmacol, Vol: 86, Pages: 855-860, ISSN: 0007-1188
The potent vasodilator calcitonin gene-related peptide (CGRP, human synthetic), when mixed with histamine and injected intradermally in the rabbit, induced a marked potentiation of local oedema. CGRP also potentiated oedema induced by other mediators of increased microvascular permeability in the rabbit; bradykinin, platelet-activating factor (Paf), C5a des Arg, N-formylmethionyl-leucyl-phenylalanine (FMLP) and leukotriene B4 (LTB4). Substance P alone, or mixtures of substance P and CGRP, failed to induce oedema in rabbit skin. In rat skin, however, substance P induced oedema and this was potentiated by CGRP. CGRP had a protracted potentiating action following intradermal injection in the rabbit. The time for half loss of activity for CGRP was 40.1 +/- 7.5 min compared to 18 +/- 1 min for prostaglandin E2 (PGE2). No loss of potentiating activity was detected after incubation of CGRP in rabbit plasma or blood for 60 min. We postulate that endogenous CGRP, if released locally from nerve endings, could have a marked enhancing effect on oedema induced by other mediators in an inflammatory reaction.
Jose PJ, Forrest MJ, Williams TJ, 1985, Generation of C5a and prostacyclin (PGI2) in an inflammatory response to zymosan and a reversed passive Arthus-type reaction in the peritoneal cavity of the rabbit., Agents Actions, Vol: 16, Pages: 39-40, ISSN: 0065-4299
Exudate fluids were removed from the rabbit peritoneal cavity 2 h after the injection of zymosan or the initiation of a reversed passive Arthus-type reaction. Inflammatory oedema was measured using Evans blue dye extravasation and the concentrations of C5a and the PGI2 metabolite, 6-oxo-PGF1 alpha, were measured by radioimmunoassay. High levels of C5a were found in these inflammatory exudates and we suggest that the extravascular generation of C5a is important in the induction of increased microvascular permeability. The presence of PGI2 may have an enhancing effect on plasma protein leakage.
BRAIN SD, WILLIAMS TJ, TIPPINS JR, et al., 1985, CALCITONIN GENE-RELATED PEPTIDE IS A POTENT VASODILATOR, NATURE, Vol: 313, Pages: 54-56, ISSN: 0028-0836
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- Citations: 2003
Williams TJ, Jose PJ, Forrest MJ, et al., 1984, Interactions between neutrophils and microvascular endothelial cells leading to cell emigration and plasma protein leakage., Kroc Found Ser, Vol: 16, Pages: 195-208, ISSN: 0361-0489
Jose PJ, Forrest MJ, Williams TJ, 1983, Detection of the complement fragment C5a in inflammatory exudates from the rabbit peritoneal cavity using radioimmunoassay., Journal of Experimental Medicine, Vol: 158, Pages: 2177-2182, ISSN: 1540-9538
We describe a radioimmunoassay for rabbit C5a and its use to obtain evidence of extravascular C5a generation in two inflammatory reactions in the peritoneal cavity. These observations, together with the potent activity of C5a in inducing increased microvascular permeability involving circulating PMN leukocytes, strengthen the case for considering C5a an important inflammatory mediator. These findings offer an explanation for the many different experimental inflammatory reactions where oedema formation can be suppressed either by systemic depletion of complement or by depletion of circulating PMN leukocytes.
Williams TJ, 1983, Interactions between prostaglandins, leukotrienes and other mediators of inflammation., Br Med Bull, Vol: 39, Pages: 239-242, ISSN: 0007-1420
Williams TJ, Jose PJ, Wedmore CV, et al., 1983, Mechanisms underlying inflammatory edema: the importance of synergism between prostaglandins, leukotrienes, and complement-derived peptides., Adv Prostaglandin Thromboxane Leukot Res, Vol: 11, Pages: 33-37, ISSN: 0732-8141
Williams TJ, Jose PJ, Wedmore CV, et al., 1982, Blood flow, vascular permeability and the role of neutrophils., Agents Actions Suppl, Vol: 11, Pages: 39-49, ISSN: 0379-0363
Jose PJ, Page DA, Wolstenholme BE, et al., 1981, Bradykinin-stimulated prostaglandin E2 production by endothelial cells and its modulation by antiinflammatory compounds., Inflammation, Vol: 5, Pages: 363-378, ISSN: 0360-3997
Prostaglandin production was studied in cultures of pig aorta endothelial cells using radioimmunoassay, radiochromatography, and smooth muscle bioassay. PGE2 was produced in higher concentrations than other prostaglandins. Bradykinin produced a rapid dose-related stimulation of PGE2 production. These results provided the basis for establishment of a simplified test system for investigating new compounds which alter prostaglandin synthesis and might therefore affect inflammatory response. It was also observed that these endothelial cells do not metabolize prostaglandins via 15-hydroxyprostaglandin dehydrogenase.
Williams TJ, Westwick J, Williamson EM, et al., 1981, Vascular changes in rabbit skin induced by proinflammatory phorbol and 12-deoxyphorbol esters., Inflammation, Vol: 5, Pages: 29-36, ISSN: 0360-3997
The effects of proinflammatory phorbol and 12-deoxyphorbol esters were determined on blood flow changes and plasma exudation in rabbit skin. Blood flow changes were measured by means of 133Xe washout over that in control-treated sites, while plasma exudation was measured by 131I-labeled human serum albumin leakage from skin blood vessels. 12-Deoxyphorbol-13-phenylacetate, 12-deoxyphorbol-13-angelate, and their C-20 acetates induced vasoconstriction in rabbit skin in doses of 100 ng/site. Tetradecanoyl phorbol acetate indiced vasoconstriction to a far lower degree, while the parent alcohol phorbol and 9,13,14-orthophenylacetyl-resiniferonol had no significant effects on rabbit microvasculature. The ability of tigliane esters to contract rabbit blood vessels was confirmed in vitro in that each of these esters induced a prolonged contraction of superfused rabbit aorta in doses of 1-5 microgram. Plasma exudation in rabbit skin was not significantly increased by the phorbol and 12-deoxyphorbol esters, but in a second determination using 100 ng of PGE1 together with 100 ng of ester, plasma exudations of up to 40 microliter per site were recorded.
Wedmore CV, Williams TJ, 1981, Control of vascular permeability by polymorphonuclear leukocytes in inflammation., Nature, Vol: 289, Pages: 646-650, ISSN: 0028-0836
Polymorphonuclear leukocytes infiltrate tissues in response to an inflammatory stimulus to remove invading microorganisms and cell debris. We present eivdence that these scaveging cells have another, more sophisticated role in that they are involved in the control of fluid efflux through the blood vessel wall which leads to tissue oedema.
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