Cyclooxygenase-2: regulation and relevance in inflammation.
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Animals↗
Biomedical subjects
T J Williams
Publications and source records attributed to T J Williams.
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↗
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↗
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↗
Sedation in fibreoptic bronchoscopy. Doses that produce amnesia should be given.
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Amnesia↗
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↗
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↗
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↗
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↗
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↗
The role of fine needle aspiration in the diagnosis of palpable metastases from lung cancer.
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Adult↗
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↗
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↗
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↗
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↗
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↗
Neutrophil chemoattractants generated in two phases during reperfusion of ischemic myocardium in the rabbit. Evidence for a role for C5a and interleukin-8.
The neutrophil chemoattractants generated in a model of myocardial infarction in the anesthetized rabbit were investigated. Coronary artery occlusion was followed by reperfusion for periods from 5 min to 4.5 h. Extracts of myocardial tissue in normal and post-ischemic zones were tested for C5a and interleukin-8 (IL-8) using specific radioimmunoassays. In the post-ischemic zone, immunoreactive C5a was detected within 5 min and rose progressively to reach a plateau at 3-4.5 h. In contrast, immunoreactive IL-8 concentrations rose after a delay and were highest at the last time point tested, 4.5 h. Myeloperoxidase activity levels, an index of neutrophil accumulation, rose progressively as the concentrations of chemoattractants increased. Using cation exchange and reversed phase HPLC, immunoreactive C5a and IL-8 co-eluted with authentic standards. Fractions taken at the C5a and IL-8 peaks from reversed phase HPLC exhibited neutrophil aggregating activity which was neutralized by the respective antibody used in the radioimmunoassays. Depletion of circulating neutrophils virtually abolished immunoreactive IL-8 in the post-ischemic myocardial tissue. These observations suggest a sequential release of chemoattractants: the first, C5a is generated in interstitial fluid, followed by IL-8 generated by infiltrating neutrophils. Thus, over the time period studied, IL-8 generation would be expected to be indirectly dependent on C5a production.
Animals↗
Effect of a microaerosol barrier filter on the measurement of lung function.
STUDY OBJECTIVE: A disposable barrier filter (Pall Biomedical, United Kingdom) was developed to prevent the contamination of lung function equipment in clinical use. The aims of this study were to examine its resistance characteristics and to determine the effect of the filter on clinical measurements of lung function. MEASUREMENTS: Twenty-one randomly selected patients and four normal subjects had lung function measured with and without the filter between the mouth and measuring equipment. Measurements of ventilatory function were made with a pneumotachograph (Lilly; Hoechberg, Germany), total lung capacity and airway resistance by constant volume plethysmography, and diffusing capacity for carbon monoxide by the single breath method. Resistance was determined in five unused filters over the flow range 1 to 12 L/s and at a single flow rate (12 L/s) just after a normal subject expired 20 forced vital capacity (FVC) breaths through each of them. RESULTS: The resistance (mean +/- SD) of unused filters was 0.19 +/- 0.02 cm H2O/L/s at 1 L/s and increased linearly to 0.56 +/- 0.02 cm H2O/L/s at 12 L/s. There was no significant increase in resistance after use. The addition of the filter to the breathing circuit caused statistically significant decreases in forced expiratory volume in 1 s (FEV1) (0.044 +/- 0.08 L, p = 0.014) and peak expiratory flow rate (PEFR) (0.47 +/- 0.073 L/s, p = 0.004). The filter did not affect other indices of lung function. CONCLUSION: The filter caused a statistically significant reduction in FEV1 and PEFR; however, this difference was believed not to affect the clinical utility of routine lung function testing.
Adult↗