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T J Williams

Publications and source records attributed to T J Williams.

At least 145 records · Page 8Linked to original sources
PubMed1995

Cooperation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo.

Experiments were designed to study the effect of systemically administered IL-5 on local eosinophil accumulation induced by the intradermal injection of the chemokine eotaxin in the guinea pig. Intravenous interleukin-5 (IL-5) stimulated a rapid and dramatic increase in the numbers of accumulating eosinophils induced by i.d.-injected eotaxin and, for comparison, leukotriene B4. The numbers of locally accumulating eosinophils correlated directly with a rapid increase in circulating eosinophils: circulating eosinophil numbers were 13-fold higher 1 h after intravenous IL-5 (18.3 pmol/kg). This increase in circulating cells corresponded with a reduction in the number of displaceable eosinophils recovered after flushing out the femur bone marrow cavity. Intradermal IL-5, at the doses tested, did not induce significant eosinophil accumulation. We propose that these experiments simulate important early features of the tissue response to local allergen exposure in a sensitized individual, with eosinophil chemoattractant chemokines having an important local role in eosinophil recruitment from blood microvessels, and IL-5 facilitating this process by acting remotely as a hormone to stimulate the release into the circulation of a rapidly mobilizable pool of bone marrow eosinophils. This action of IL-5 would be complementary to the other established activities of IL-5 that operate over a longer time course.

Animals↗
PubMed1995

Nitric oxide synthase activity is elevated in inflammatory lung disease in humans.

We have characterised nitric oxide (NO) synthase activity in lung samples from patients with inflammatory lung disease compared to that in normal donor lung. NO synthase activity was measured by the ability of tissue homogenates to convert L-arginine to L-citrulline. Higher levels of NO synthase activity were found in samples from patients with inflammatory lung disease (mild asthma, cystic fibrosis, obliterative bronchiolitis after lung transplantation) compared to samples from healthy donors. NO synthase activity in all samples was mainly dependent on the presence of extracellular Ca2+. The increased NO synthase activity in diseased-lung samples suggests a modulatory role for nitric oxide in lung inflammation.

Adolescent↗
PubMed1995

Interleukin-1-induced leukocyte extravasation across rat mesenteric microvessels is mediated by platelet-activating factor.

Although our understanding of the molecular interactions that mediate the adhesion of leukocytes to venular endothelial cells has greatly expanded, very little is known about the mechanisms that mediate the passage of leukocytes across the vessel wall in vivo. The aim of the present study was to investigate the role of endogenously formed platelet-activating factor (PAF) in the process of leukocyte extravasation induced by interleukin-1 (IL-1). To determine at which stage of emigration PAF was involved, we studied the behavior of leukocytes within rat mesenteric microvessels by intravital microscopy. Rats were injected intraperitoneally with saline, recombinant rat IL-1 beta (IL-1 beta), or the peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) 4 hours before the exteriorization of the mesenteric tissue. In animals treated with IL-1 beta there was a significant increase in the number of rolling and adherent leukocytes within venules (20- to 40-micron diameter) and in the number of extravasated leukocytes in the tissue. Pretreatment of rats with the PAF receptor antagonist UK-74,505 had no effect on the leukocyte responses of rolling and adhesion, but significantly inhibited the migration of the leukocytes across the vessel wall induced by IL-1 beta (76% inhibition). A structurally unrelated PAF antagonist, WEB-2170, produced the same effect (64% inhibition). However, in contrast, UK-74,505 had no effect on the leukocyte extravasation induced by FMLP, indicating selectivity for the response elicited by certain mediators. These results provide the first line of direct evidence for the involvement of endogenously formed PAF in the process of leukocyte extravasation induced by IL-1 in vivo.

Animals↗
PubMed1995

Cardiovascular responses to electrical stimulation of the bed nucleus of the stria terminalis.

To determine whether the influence of the bed nucleus of the stria terminalis (BST) on cardiovascular function can be localized to specific cytoarchitectural areas within the BST, urethane (1.3 g/kg)-anesthetized male Sprague-Dawley rats were probed for cardiovascular reactive sites. Electrical stimuli (50 microA, 50 Hz, and a 0.5 ms pulse duration), delivered through stereotaxically placed glass semimicroelectrodes, were localized to the BST. Sham-stimulated animals served as controls. Stimulation sites were correlated with cytoarchitecturally distinct areas within the BST, and changes in mean arterial pressure (MAP) were subjected to statistical analysis. Systematically probing the BST for cardiovascular reactive sites showed a correlation between evoked responses and distinct cytoarchitectural areas. Stimulation of the medial BST produced increases in MAP; stimulation of the lateral aspect of the BST produced decreases in MAP. Both pressor and depressor responses were evoked from the area ventral to the anterior commissure. Pressor responses were elicited from the area immediately ventral to the anterior commissure, and depressor responses followed stimulation of an area more ventral. All subnuclei showed corroborating cardiovascular responses to 20-30 nl microinjection of sodium glutamate. Taken together, these data provide substantial evidence to indicate that the BST, particularly at more rostral areas, consists of a medial pressor area, a lateral depressor area, and a ventral area with both pressor and depressor zones.

Animals↗
PubMed1995

Anti-inflammatory effects of a short-acting and a long-acting beta 2-adrenoceptor agonist in guinea pig skin.

The pharmacological modulation of the accumulation and function of eosinophils in tissues may have a significant impact in the treatment of allergic diseases such as asthma, atopic dermatitis and rhinitis. In this study, we have investigated the acute anti-inflammatory effects of a short-acting (salbutamol) and a long-acting (salmeterol) beta 2-adrenoceptor agonist on 111In-accumulation and oedema formation in allergic and mediator-induced inflammation in guinea pig skin. Both salbutamol and salmeterol inhibited 111In-eosinophil accumulation induced by platelet-activating factor and in a passive cutaneous anaphylactic reaction when co-injected with the inflammatory stimuli or when given as a 30 min pretreatment. The inhibition was reversed by DL-propranolol, but not D-propranolol. Systemic treatment with salbutamol inhibited 111In-eosinophil accumulation and oedema formation when given as a 15 min, but not as a 3 h, pretreatment. In contrast, salmeterol was effective when given at both times. We conclude that a long duration of action of beta 2-adrenoceptor agonists is not necessary to demonstrate acute anti-inflammatory effects on eosinophil accumulation in guinea pig skin.

Adrenergic beta-2 Receptor Agonists↗
PubMed1995

Characterization of eosinophil homotypic aggregation.

Guinea pig peritoneal eosinophils stimulated by platelet-activating factor (PAF), leukotriene B4 (LTB4), and human recombinant C5a (C5a) undergo a rapid concentration-dependent and partially reversible homotypic aggregation as assessed by changes in light transmission. The phorbol ester phorbol myristate acetate similarly induces a concentration-dependent aggregation, which is, however, slower in onset, takes longer to reach maximal aggregation, and is irreversible. In addition, we confirmed, using light microscopy, that these agonist-induced changes in light transmission do indeed represent true homotypic aggregation. We further characterized the aggregation response and showed that there is homologous but little heterologous desensitization when PAF and LTB4 are used as stimuli. A requirement for both Ca2+ and Mg2+ for full manifestation of agonist-induced aggregation was observed. LTB4- and PAF-induced superoxide anion generation is enhanced by the diacyglycerol kinase inhibitor R59022, whereas aggregation induced by LTB4, but not PAF, is augmented. Lastly, we show that eosinophil aggregation is partially dependent on the adhesion glycoprotein CD18. In summary, therefore, we believe that eosinophil aggregation provides a useful and reliable measure of eosinophil activation.

Animals↗
PubMed1995

Eosinophil chemoattractants generated in vivo.

The eosinophil is the predominant inflammatory cell which accumulates in the asthmatic lung. There is considerable circumstantial evidence linking these cells to lung dysfunction, but the precise cause and effect relationship is controversial. The defensive role of the eosinophil appears to be concerned largely with eliminating helminth parasites which do not normally present a constant threat. Thus, unlike the neutrophil whose defensive role against microbes is essential, the eosinophil presents a target for therapeutic intervention which is potentially applicable to long-term treatment. Several approaches to suppressing eosinophil accumulation are possible, based on the multiple steps involved in their appearance and activation in the lung (for review see [1]). One approach is to block the receptor(s) to the important endogenous eosinophil chemoattractants generated in the asthmatic lung, offering the potential for selective leukocyte-type suppression. A first step in this pursuit is the identification of such chemoattractants. This article describes recent attempts in this direction, with the long-term goal of producing chemoattractant receptor antagonists.

Amino Acid Sequence↗
PubMed1995

beta-Lactamase production and genetic location in Staphylococcus aureus: introduction of a beta-lactamase plasmid in strains of phage group II.

Staphylococcus aureus strains of phage group II have increased in frequency in hospital-acquired infections during recent years. A total of 184 penicillin resistant group II strains from bacteraemia cases in the years 1961-1990 were analysed for the amount of beta-lactamase produced and the location of the beta-lactamase gene. Until 1977 all strains investigated had a chromosomally located beta-lactamase gene, but since then a 21 kb beta-lactamase plasmid has increased in occurrence among group II strains, especially among those strains typable only at high phage concentrations [100 x Routine Test Dilution (RTD) and 1000 x RTD]. In 1990, 84% of the group II strains contained this plasmid. Plasmid-containing strains produced more beta-lactamase than strains without the plasmid. S. aureus strains of the 94,96 complex, which since 1984 have decreased in frequency from 18 to 9% in 1993, have remained high producers of beta-lactamase.

Bacteriophage Typing↗
PubMed1995

Mechanisms and pharmacological manipulation of eosinophil accumulation in vivo.

The presence of eosinophils and their products in tissues is frequently associated with the pathogenesis of allergic inflammation. A better understanding of how these cells are recruited from the microcirculation will help in the development of therapies targeted at allergic disorders. Here, Mauro Teixeira, Timothy Williams and Paul Hellewell describe the current concepts of eosinophil accumulation, examine the potential ways of modulating this process, and discuss whether antagonists of eosinophil-specific mediators or functional antagonists would be the preferred therapies.

Antibodies, Monoclonal↗
PubMed1995

Molecular and cellular interactions mediating granulocyte accumulation in vivo.

An inflammatory response, either beneficial in host defence or detrimental resulting in an inflammatory disease, is associated with alterations in vascular tone and blood flow, enhanced vascular permeability to macromolecules and the extravasation of leucocytes from the vascular lumen into extravascular tissue. The adhesive interaction of granulocytes with venular endothelial cells is an essential step in the process of granulocyte accumulation at sites of inflammation in vivo. Recent advances made in the field of chemokines and adhesion molecules have led to a better understanding of the molecular events mediating this important component of the inflammatory response. The defined molecular interactions that mediate and regulate these events, in the process of neutrophil accumulation, will be discussed in this article. Recently, the eosinophil has come into focus because of its prominence in allergic reactions. This cell will be discussed in comparison.

Animals↗
PubMed1995

Characterization of alpha 1-adrenoceptors mediating vasoconstriction to noradrenaline and nerve stimulation in the isolated perfused mesentery of rat.

1. The objective of this study was to investigate the alpha 1-adrenoceptor subtype(s) mediating vasoconstrictor responses to perfused and neuronally-released noradrenaline (NA) in the isolated perfused mesentery preparation of rat. 2. Isolated mesenteric preparations (with gut attached) from male Sprague Dawley rats (250-300g) were perfused via the superior mesenteric artery with oxygenated Krebs solution at approximately 6 ml min-1. The effects of antagonists on vasoconstrictor responses to either perfused (+/-)-NA or periarterial nerve stimulation (70 V, 2 ms pulse width, 10 s train) were determined. 3. Vasoconstrictor responses to perfused NA were antagonized by prazosin (pA2 = 9.3 +/- 0.1), WB4101 (pA2 = 9.6 +/- 0.1), 5-methyl urapidil (5-MU: pA2 = 9.0 +/- 0.1), (+)-niguldipine (insurmountable) and spiperone (pA2 = 7.7 +/- 0.1). The insurmountable nature of the antagonism by (+)-niguldipine (0.1 nM) was greatly reduced by co-perfusion with prazosin (10 nM). Chloroethylclonidine (CEC: 100 microM for 20 min, followed by 40 min washout) caused an approximate twofold increase in the EC50 for (+/-)-NA and reduced the maximum response by approximately 25%. Pre-treatment of tissues with CEC (100 microM as above) did not significantly alter affinity estimates for prazosin (pA2 = 9.2 +/- 0.1), WB4101 (pA2 = 9.3 +/- 0.1) or 5-MU (pA2 = 8.7 +/- 0.2). Vasoconstrictor responses to periarterial nerve stimulation were antagonized by WB4101 > 5-MU > prazosin >> spiperone. CEC (100 microM as above) reduced nerve-stimulated responses by approximately 50%. 4. The affinity estimates for the various antagonists studied suggest that vasoconstrictor responses to both exogenous and neuronally-released NA are mediated via the same a,-adrenoceptor subtype. The pharmacological profile most resembles the 'classical' alpha l A-adrenoceptor, which, in turn, appears to be a rat homologue of the cloned bovine alpha lc-adrenoceptor.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1995

Substance P-induced inflammatory responses in guinea-pig skin: the effect of specific NK1 receptor antagonists and the role of endogenous mediators.

1. The sensory neuropeptide substance P (SP), when released from sensory nerves, has been implicated in the development of neurogenic inflammation. In the present study, using an in vivo model system, we have characterized and investigated the mechanisms underlying SP-induced leukocyte accumulation and oedema formation in the guinea-pig. 2. Intradermally injected SP (i.d., 10(-13) - 10(-9) mol per site), induced a dose- and time-dependent accumulation of 111In-neutrophils, 111In-eosinophils and oedema formation as measured by the local accumulation of i.v. injected 125I-albumin. The leukocyte accumulation evoked by SP was significant at 10(-10) and 10(-9) mol per site, whereas oedema formation was significant at the lowest dose tested (10(-13) mol per site). 3. The NK1 receptor antagonists, CP-96,345 (1 mg kg-1, i.v.) and RP-67,580 (10 micrograms per site, i.d.), significantly attenuated the oedema formation induced by the lower doses of SP. Oedema formation and leukocyte accumulation induced by 10(-9) mol per site SP were unaffected by either antagonist. 4. SP-elicited responses were not significantly affected by the platelet activating factor (PAF) receptor antagonist, UK-74,505 (2.5 mg kg-1, i.v.) or the H1 histamine receptor antagonist, chlorpheniramine (10(-8) mol per site, i.d.). However, the 111In-eosinophil accumulation, but not the 111In-neutrophil accumulation or oedema formation, induced by SP was significantly inhibited by the specific 5-lipoxygenase (5-LO) inhibitor, ZM-230,487 (10(-8) mol per site, i.d.). 5. The accumulation of both 111 In-neutrophils and 111 In-eosinophils induced by SP was abolished in guinea-pigs treated i.v. with an anti-CD18 monoclonal antibody 6.5E F(ab')2 (2.5 mg kg-1). The oedema response was unaffected in these animals.6. These results suggest that SP-induced inflammatory events may be mediated via two mechanisms involving NK1 receptor-dependent and independent pathways. Oedema formation induced by the lower doses of SP may be mediated via the direct activation of NK1 receptors whilst, at higher doses, oedema formation and leukocyte accumulation may be mediated via the release of secondary mediators, possibly mast cell derived, with 5-LO products playing an important role in the leukocyte infiltration. The leukocyte accumulation, but not the oedema induced by SP, is dependent on the expression of the CD18antigen on leukocytes.

Animals↗
PubMed1995

Functional evidence equating the pharmacologically-defined alpha 1A- and cloned alpha 1C-adrenoceptor: studies in the isolated perfused kidney of rat.

1. The present study characterizes and classifies alpha 1-adrenoceptor-mediated vasoconstriction in the isolated perfused kidney of rat using quantitative receptor pharmacology and compares the results to radioligand binding studies (made in cloned alpha 1-adrenoceptor subtypes, native alpha 1A-adrenoceptors in submaxillary gland of rat, and alpha 1A-adrenoceptors in several other tissues of rat). 2. Concentration-effect curves to noradrenaline in the presence of 5-methyl-urapidil were biphasic, indicating alpha 1-adrenoceptor heterogeneity. The alpha 1-adrenoceptor subtype mediating the first phase (low affinity for 5-methyl-urapidil) could not be 'isolated' for detailed pharmacological characterization but was defined by a sensitivity to inhibition by chloroethylclonidine and an inability of methoxamine to activate the site. Additionally, vasoconstriction mediated by this alpha 1-adrenoceptor subtype or subtypes was abolished by nitrendipine (1 microM), thereby allowing characterization of the second, high affinity site for 5-methyl-urapidil. 3. The following antagonists interacted competitively with noradrenaline at the alpha 1-adrenoceptor for which 5-methyl-urapidil exhibits high affinity (pKB value): WB 4101 (10.3) > prazosin (9.5) approximately HV 723 (9.3) approximately 5-methyl-urapidil (9.2) > phenotolamine (8.6) > spiperone (pA2 = 8.1) approximately oxymetazoline (7.9). In contrast, insurmountable antagonism was seen with S(+)- and R(-)-niguldipine, the S(+)-isomer being approximately 30 fold more potent than the R(-)-isomer. Receptor protection experiments indicated that S(+)-niguldipine interacted directly with alpha 1-adrenoceptors. Dehydroniguldipine acted as a competitive antagonist (pKB = 9.0). Thus, the results with antagonists define the alpha 1-adrenoceptor as an alpha 1A-adrenoceptor. 4. An agonist 'fingerprint' was constructed in the presence of nitrendipine to define further the alpha 1A-adrenoceptor. The following order and relativity of agonist potency was obtained: cirazoline (1) approximately adrenaline (2) > noradrenaline (5) > phenylephrine (23) approximately amidephrine (31) > methoxamine (71) >> isoprenaline (1456) approximately dopamine (2210). 5. A high correlative association was shown between the affinity of antagonists obtained functionally in the isolated perfused kidney of rat and pKi values obtained from binding experiments with the cloned bovine alpha 1C-adrenoceptor (R2 = 0.85), native alpha 1A-adrenoceptors in submaxillary gland of rat (R2 = 0.79), and alpha 1A-adrenoceptors from several other tissues of rat (values taken from the literature, R2 = 0.89). 6. The present study demonstrates that the alpha 1A-adrenoceptor is the predominant alpha 1-adrenoceptor subtype mediating vasoconstrictor responses to exogenously administered noradrenaline in the isolated perfused kidney of rat. More importantly, alpha 1A-adrenoceptors mediating vasoconstrictor responses to noradrenaline exhibited a pharmacological equivalency to the cloned bovine alpha 1 c-adrenoceptor. Thus,definitive functional pharmacological data are provided for equating the two receptors and support results derived recently from molecular and radioligand binding studies.

Adrenergic alpha-Agonists↗
PubMed1995

Corticosteroid inhibition of macrophage inflammatory protein-1 alpha in human monocytes and alveolar macrophages.

One of the major inducible cytokines secreted by mononuclear phagocytes is macrophage inflammatory protein 1 (MIP-1), which consists of two homologous polypeptides, MIP-1 alpha and MIP-1 beta. MIP-1 alpha possesses chemotactic and stimulatory activities for lymphocytes, eosinophils, and monocytes and may play a role in various pulmonary inflammatory conditions. We investigated the expression and release of MIP-1 alpha from human peripheral blood monocytes (PBM) and alveolar macrophages (AM) after stimulation with lipopolysaccharide (LPS), interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha, and interferon-gamma and the inhibitory effects of corticosteroids. LPS and IL-1 beta only enhanced MIP-1 alpha mRNA and protein in a dose- and time-dependent fashion. Dexamethasone (10(-9) to 10(-4) M) inhibited the basal and induced production and expression of MIP-1 alpha. In PBM, dexamethasone (10(-6) M) reduced LPS- and IL-1 beta-stimulated production of MIP-1 alpha protein by 50 and 63%, respectively, maximally at 24 h, whereas the inhibition of mRNA expression occurred maximally at 4 h. Similar trends were observed for AM. MIP-1 alpha mRNA decay was only slightly decreased in the presence of dexamethasone. Inhibition of LPS-induced MIP-1 alpha mRNA by dexamethasone was attenuated by the protein synthesis inhibitor cycloheximide, indicating the involvement of a protein intermediate. Corticosteroids are a potent inhibitor of IL-1 beta- and LPS-induced expression of MIP-1 alpha through mechanisms involving mainly inhibition of transcription and to a minor degree by reducing mRNA stability. Corticosteroids may be effective anti-inflammatory agents by preventing the expression of chemokines such as MIP-1 alpha.

Base Sequence↗
PubMed1995

Inhaled nitric oxide used as a bridge to heart-lung transplantation in a patient with end-stage pulmonary hypertension.

We describe a 40-yr-old woman who received inhaled nitric oxide (NO) as a therapeutic bridge to heart-lung transplantation for end-stage primary pulmonary hypertension. After 10 yr of increasing disability, the patient presented in October 1993 with severe dyspnea, right ventricular angina, and syncope. As predicted by a prior vasodilator trial, prostacyclin produced as initial favorable clinical and hemodynamic response. With the recurrence of severe symptoms and hemodynamic compromise, inhaled NO was successfully tried at 40 ppm, initially via a face mask and later via a transtracheal Scoop catheter. The patient was "bridged" to heart-lung transplant after 68 d of therapy (mean dose of NO, 50.4 +/- 23 ppm). The explanted lungs revealed no evidence of significant NO toxicity, and the explanted heart was successfully transplanted into another patient. Inhalation of NO via a transtracheal catheter is a useful and practical treatment of refractory pulmonary hypertension. The limits of NO therapy in terms of duration and dosage have not been determined.

Administration, Inhalation↗
PubMed1995

Glucocorticoid inhibition of RANTES expression in human lung epithelial cells.

An influx of eosinophils into the lungs occurs in several pulmonary disorders. However, the mechanisms involved remain unknown. Lung epithelial cell release of eosinophil chemotactic factors such as RANTES or macrophage inflammatory protein-1 alpha (MIP-1 alpha) could account for the influx of eosinophils into the lungs. In order to demonstrate the potential role for lung epithelial cells to release RANTES and/or MIP-1 alpha, we investigated the mRNA expression and protein release in cultured A549 cells. Tumor necrosis factor-alpha (TNF alpha) and interleukin-1 beta (IL-1 beta) induced a time- and dose-dependent increase in RANTES mRNA expression and protein release. In contrast, MIP-alpha protein release was not detectable in these cells. As corticosteroids decrease the influx of eosinophils into the lungs in vivo, we also investigated the capacity of dexamethasone to decrease the TNF alpha-induced RANTES release and mRNA expression; both were decreased in a time- and concentration-dependent manner. Dexamethasone did not affect the TNF alpha-induced RANTES mRNA half-life and did not require protein synthesis to manifest an inhibitory effect. Supernatant from cells stimulated with TNF alpha and IL-1 beta increased eosinophil chemotaxis and this was also inhibited by dexamethasone. These findings suggest a role for RANTES release by lung epithelial cells in the recruitment of eosinophils into the lungs in pulmonary disorders such as interstitial lung diseases, idiopathic pulmonary fibrosis, or asthma and suggest that one beneficial effect of corticosteroids may be inhibition of lung epithelial cell RANTES mRNA expression and protein release.

Cell Line↗