How do corticosteroids work in asthma?
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Adrenal Cortex Hormones↗
Biomedical subjects
Peter J Barnes
Publications and source records attributed to Peter J Barnes.
Inhibition of guinea-pig and human sensory nerve activity and the cough reflex in guinea-pigs by cannabinoid (CB2) receptor activation.
1. There is considerable interest in novel therapies for cough, since currently used agents such as codeine have limited beneficial value due to the associated side effects. Sensory nerves in the airways mediate the cough reflex via activation of C-fibres and RARs. Evidence suggests that cannabinoids may inhibit sensory nerve-mediated responses. 2. We have investigated the inhibitory actions of cannabinoids on sensory nerve depolarisation mediated by capsaicin, hypertonic saline and PGE2 on isolated guinea-pig and human vagus nerve preparations, and the cough reflex in conscious guinea-pigs. 3. The non-selective cannabinoid (CB) receptor agonist, CP 55940, and the selective CB2 agonist, JWH 133 inhibited sensory nerve depolarisations of the guinea-pig vagus nerve induced by hypertonic saline, capsaicin and PGE2. These responses were abolished by the CB2 receptor antagonist SR144528, and unaffected by the CB1 antagonist SR141716A. Similarly, JWH 133 inhibited capsaicin-evoked nerve depolarisations in the human vagus nerve, and was prevented by SR144528. 4. Using a guinea-pig in vivo model of cough, JWH 133 (10 mg kg-1, i.p., 20 min) significantly reduced citric acid-induced cough in conscious guinea pigs compared to those treated with the vehicle control. 5. These data show that activation of the CB2 receptor subtype inhibits sensory nerve activation of guinea-pig and human vagus nerve, and the cough reflex in guinea-pigs, suggesting that the development of CB2 agonists, devoid of CB1-mediated central effects, will provide a new and safe antitussive treatment for chronic cough.
Animals↗
Effects of bronchodilator particle size in asthmatic patients using monodisperse aerosols.
Aerosol particle size influences airway drug deposition. Current inhaler devices are inefficient, delivering a heterodisperse distribution of drug particle sizes where, at best, 20% reaches the lungs. Monodisperse aerosols are the appropriate research tools to investigate basic aerosol science concepts within the human airways. We hypothesized that engineering such aerosols of albuterol would identify the ideal bronchodilator particle size, thereby optimizing inhaled therapeutic drug delivery. Eighteen stable mildly to moderately asthmatic patients [mean forced expiratory volume in 1 s (FEV1) 74.3% of predicted] participated in a randomized, double-blind, crossover study design. A spinning-top aerosol generator was used to produce monodisperse albuterol aerosols that were 1.5, 3, and 6 microm in size, and also a placebo, which were inhaled at cumulative doses of 10, 20, 40, and 100 microg. Lung function changes and tolerability effects were determined. The larger particles, 6 and 3 microm, were significantly more potent bronchodilators than the 1.5-microm and placebo aerosols for FEV1 and for the forced expiratory flow between exhalation of 25 and 75% of forced vital capacity. A 20-microg dose of the 6- and 3-microm aerosols produced FEV1 bronchodilation comparable to that produced by 200 microg from a metered-dose inhaler. No adverse effects were observed in heart rate and plasma potassium. The data suggest that in mildly to moderately asthmatic patients there is more than one optimal beta2-agonist bronchodilator particle size and that these are larger particles in the higher part of the respirable range. Aerosols delivered in monodisperse form can enable large reductions of the inhaled dose without loss of clinical efficacy.
Administration, Inhalation↗
Mitogen-activated protein kinase modulation of nuclear factor-kappaB-induced granulocyte macrophage-colony-stimulating factor release from human alveolar macrophages.
Granulocyte macrophage-colony-stimulating factor (GM-CSF), released from alveolar macrophages (AM), is an important regulator of eosinophil, T cell, and macrophage function and survival. We determined the mechanisms of GM-CSF regulation in AM from normal volunteers activated by lipopolysaccharide (LPS) by examining the role of nuclear factor-kappaB (NF-kappaB), and of p38 mitogen-activated protein (MAP) kinase and MAP kinase kinase (MKK-1). PD 098059 (10 microM), an inhibitor of upstream activator of MKK-1, inhibited GM-CSF expression, but the expression of GM-CSF was not inhibited by SB 203580 (10 microM), an inhibitor of p38-MAP kinase. Phosphorylation of extracellular signal-regulated kinase-1 (ERK-1), ERK-2, and p38 MAP kinase by LPS were demonstrated on Western blot analysis. LPS increased NF-kappaB:DNA binding as examined by electrophoretic mobility shift assay, but this was not suppressed by PD 098059 or by SB 203580. LPS induced an increase in NF-kappaB activation as examined by p50 translocation assay without suppression by PD 098059 or by SB 203580. SN50 (100 microM), an inhibitor of NF-kappaB translocation and the specific IKK-2-Inhibitor (AS602868; 10 microM), also prevented GM-CSF expression and release induced by LPS, indicating that GM-CSF release is NF-kappaB-dependent. PD 098059, but not SB 203580, inhibited LPS-induced histone acetyltransferase (HAT) activity, indicating chromatin modification. Furthermore, AS602868 and SN 50 suppressed LPS-induced HAT activity. TSA (10 ng/ml), an inhibitor of histone deacetylase (HDAC), reversed the inhibitory effect of PD 098059, SB 203580, SN 50 and AS602868 on GM-CSF release. GM-CSF expression and release in AM is controlled by NF-kappaB activation, and this is modulated by phosphorylation of MKK-1 and p38 MAP kinase acting on histone acetylation.
Acetyltransferases↗
IL-1beta-dependent activation of NF-kappaB mediates PGE2 release via the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase.
Prostaglandin (PG) E2 release is induced in pulmonary A549 cells by the NF-kappaB-activating stimuli interleukin-1beta (IL-1beta) and phorbol 12-myristate 13-acetate (PMA). Adenoviral over-expression of IkappaBalphaDeltaN, a dominant NF-kappaB inhibitor, prevents NF-kappaB-dependent transcription and was used to qualify the role of NF-kappaB in the release of PGE2. IkappaBalphaDeltaN repressed IL-1beta-induced, but not PMA-induced, cycloxygenase-2 (COX-2) and microsomal prostaglandin E synthase (mPGES) expression. These data conclusively demonstrate a substantial role for NF-kappaB in the co-ordinate induction of COX-2, mPGES and in the corresponding release of PGE2 by IL-1beta. However, other pathways are primarily responsible for PGE2 release induced by PMA.
Adenoviridae↗
A selective inhibitor of inducible nitric oxide synthase inhibits exhaled breath nitric oxide in healthy volunteers and asthmatics.
The inducible isoenzyme of nitric oxide synthase (iNOS) generates nitric oxide (NO) in inflammatory diseases such as asthma. The prodrug L-N6-(1-iminoethyl)lysine 5-tetrazole amide (SC-51) is rapidly converted in vivo to the active metabolite L-N6-(1-iminoethyl)lysine (L-NIL). Initially, we performed in vitro experiments in human primary airway epithelial cells to demonstrate that L-NIL causes inhibition of iNOS. In a randomized double-blind placebo-controlled crossover trial, SC-51 was administered as a single oral dose (20 or 200 mg) in separate cohorts of healthy volunteers (two groups of n=12) and mild asthmatic patients (two groups of n=12). SC-51 (200 mg) reduced exhaled breath NO levels to <2 ppb in both healthy volunteers (P<0.001) and mild asthmatics (P<0.001) within 15 min, representing >90% inhibition of baseline levels of NO in asthmatic patients, with the effects lasting at least 72 h. There were no significant effects on blood pressure, pulse rate, or respiratory function (FEV1). This study demonstrates that an inhibitor of iNOS produces marked inhibition of exhaled breath NO in normal and asthmatic subjects without producing the side effects observed following the systemic administration of non-selective NOS inhibitors, and thus provides support for the potential use of iNOS inhibitors to treat a range of inflammatory clinical disorders.
Administration, Oral↗
Increased leukotriene B4 and interleukin-6 in exhaled breath condensate in cystic fibrosis.
Chronic neutrophilic airway inflammation is an important feature of cystic fibrosis (CF). Noninvasive inflammatory markers may be useful in monitoring CF. Leukotriene B4 (LTB4) and interleukin (IL)-6 are inflammatory mediators that are increased in chronic neutrophilic inflammation. The aim of this study was to assess whether LTB4 and IL-6 were increased in exhaled breath condensate of CF patients and whether they could be used to monitor inflammation. Twenty patients with CF (13 males, age of 28 +/- 9 years) were recruited together with 15 age-matched healthy subjects (8 males, age 35 +/- 7 years). LTB4 and IL-6 levels were markedly elevated in patients with acute exacerbations (28.8 +/- 4.3 and 8.7 +/- 0.4 pg/ml) compared with control subjects (6.8 +/- 0.7 and 2.6 +/- 0.1 pg/ml, p < 0.0001). We also observed a decrease of exhaled LTB4 and IL-6 concentrations after antibiotic treatment in six patients who were followed until clinically stable (31.1 +/- 4.4 and 9.5 +/- 0.4 pg/ml vs. 18.8 +/- 0.8 and 6.4 +/- 0.2 pg/ml, respectively) and an increase in 15 CF patients infected with Pseudomonas aeruginosa (34.3 +/- 5.0 and 9.3 +/- 0.3 pg/m) compared with those infected with other bacteria (18.3 +/- 0.7 and 6.9 +/- 0.5 pg/ml). These findings suggest that LTB4 and IL-6 levels are increased in exhaled breath condensate of patients with CF during exacerbation and could be used to monitor airway inflammation in these patients.
Adult↗
A system for the production and delivery of monodisperse salbutamol aerosols to the lungs.
An aerosol system is described for the generation and delivery of measured doses of monodisperse therapeutic drug particles to the human lungs. The system comprises a spinning top aerosol generator (STAG), aerosol chamber and inhalation control unit. Monodisperse aerosols allow drug particle size effects to be studied as the dose is within a narrow size distribution and when combined with controlled inhalation may lead to more precise targeting of therapeutic drug to the airways. Using the STAG, particles in the size range 1.5-12 microm were generated and their mass median aerodynamic diameter (MMAD) and concentration measured using an aerodynamic particle sizer (APS). The application and validation of the system with the bronchodilator drug salbutamol sulphate is described, and its potential use in the study of aerosol particle size effects is discussed.
Administration, Inhalation↗
Theophylline: new perspectives for an old drug.
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Apoptosis↗
Mitogen-activated protein kinases mediate peroxynitrite-induced cell death in human bronchial epithelial cells.
Peroxynitrite, formed by the reaction of nitric oxide (NO. ) with superoxide anions (O(2)(-).), may play a role in the pathophysiology of inflammation. The effects of 3-morpholinosydnonimine (SIN-1), a peroxynitrite generator, on the human bronchial epithelial cell line BEAS-2B, were examined. SIN-1 exposure resulted in cell death in a time- and dose-dependent manner. Depletion of intracellular glutathione increased the vulnerability of the cells. Pretreatment with Mn(III)tetrakis(N-methyl-4'-pyridyl)porphyrin (MnTMPyP) or hydroxocobalamin (HC), O(2)(-). and NO. scavengers, respectively, reduced significantly SIN-1-induced cell death (18.66 +/- 3.57 vs. 77.01 +/- 14.07 or 82.20 +/- 9.64, % cell viability SIN-1 vs. MnTMPyP or HC). Moreover, the mitogen-activated protein kinases (MAPK) p44/42 (ERK), p38, and p54/46 (JNK) were also activated in a time- and concentration-dependent manner. PD-98059 and SB-239063, specific inhibitors of ERK and p38 MAPK pathways, failed to protect cells against 1 mM SIN-1. However, PD-98059 partially inhibited (60% cell survival) SIN-1 effects at < or =0.25 mM, and this was increased with the inclusion of SB-239063. Therefore, MAPKs may mediate signal transduction pathways induced by peroxynitrite in lung epithelial cells leading to cell death.
Bronchi↗
Nitric oxide, nitrotyrosine, and nitric oxide modulators in asthma and chronic obstructive pulmonary disease.
Nitric oxide (NO), a simple free-radical gas, elicits a diverse range of physiologic and pathophysiologic effects, and plays an important role in pulmonary diseases. Nitrosative stress and nitration of proteins in airway epithelium may be responsible for steroid resistance in asthma and their ineffectiveness in chronic obstructive pulmonary disease (COPD), supporting the potential role of future therapeutic strategies aimed at regulating NO synthesis in asthma and COPD. In this article, we review the potential role of NO modulators (NO synthase inhibitors and NO donors), which, if given on a regular basis, may have clinical benefit in asthma and COPD.
Asthma↗
Therapy of chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease is one of the commonest causes of morbidity and mortality in the world, and is increasing in prevalence. Current therapies are not very effective, and no current treatment prevents the relentless progression of airflow limitation that characterizes this disease. Smoking cessation is the only strategy that reduces this decline in lung function, and although bupropion is the most effective aid to quitting, more effective treatments of nicotine addiction are needed. The mainstay of treatment is bronchodilators for symptom relief, and inhaled anticholinergics and beta(2)-agonists are useful by reducing hyperinflation of the lungs. A new once-daily inhaled anticholinergic is the most effective bronchodilator, but long-acting inhaled beta(2)-agonists are also useful. Theophylline is used as an additional bronchodilator in more severe patients, and may have some anti-inflammatory action. In contrast, inhaled corticosteroids are poorly effective and do not reduce disease progression, although recent studies with combination inhalers (corticosteroid + long-acting beta(2)-agonist) have shown better effects. Long-term oxygen therapy is needed by patients with pulmonary hypertension and right heart failure. There is a pressing need to develop new classes of therapy, and several new drugs are current in development, including interleukin-8 antagonists, phosphodiesterase-4 inhibitors, protease inhibitors, and antioxidants.
Acute Disease↗
The relationship between age and production of tumour necrosis factor-alpha in healthy volunteers and patients with chronic heart failure.
BACKGROUND: Ageing is associated with an altered immune response. Elevated plasma levels of tumour necrosis factor-alpha (TNF-alpha) are present in patients with advanced chronic heart failure (CHF). However, the relationship between age and the immune response in CHF is unknown. METHODS: We investigated the relationship between age and the TNF-alpha generating capacity of lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cells (PBMC) in nine healthy control subjects (mean age 51.6+/-3.6 years, age range 39-75 years) and 22 stable patients with CHF (mean age 68.3+/-1.5 years, age range 52-78 years, NYHA class 3.0+/-0.2). We also tested the TNF-alpha generating capacity of all control subjects and 18 CHF patients in whole blood cultures. RESULTS: Subjects were subgrouped according to baseline TNF-alpha secretion in PBMC cultures into low- and high-responders, with the latter producing TNF-alpha even without LPS stimulation. High-responders produced more TNF-alpha than low-responders at all LPS doses (0.001-10 ng/ml, P<0.0001, repeated measures ANOVA), and high-responders were significantly older than low-responders (controls: 65.8+/-9.2 vs. 47.5+/-2.5 years; patients: 71.9+/-1.9 vs. 65.9+/-1.9 years, both P<0.05). Age correlated with TNF-alpha production in both patients and controls. This effect was independent of NYHA class. CONCLUSIONS: LPS-responsiveness appears to relate to age in both healthy controls and CHF patients. When assessing the immune status of CHF patients, age should therefore be considered an important confounding factor. In whole blood these findings could only be confirmed at the highest LPS concentration used, thus suggesting that certain factors in the blood may be able to abolish LPS activity at lower concentrations.
Adult↗
Anti-leukotrienes: here to stay?
Anti-leukotrienes, which are competitive antagonists of cysteinyl-leukotriene-1 receptors, are the first new class of anti-asthmatics introduced in over 30 years. There is a strong scientific rationale for their use, as cysteinyl-leukotrienes are increased in asthma and can mimic several of the pathophysiological features of asthma. In addition, there is often increased tissue responsiveness to these mediators. Anti-leukotrienes inhibit several bronchoconstrictor challenges, including allergens, exercise, irritants and aspirin. In clinical trials, they have significant benefit compared with placebo, but are less effective compared with low doses of inhaled corticosteroids. As an add-on therapy to inhaled corticosteroids, they are also disappointing and less effective than long-acting beta(2)-receptor agonists. In clinical practice, they have not proved to be very useful, and they are less cost-effective than other treatments. It is unlikely that this class of drug will be improved greatly in the future, and so will remain as a weak second-line therapy.
Adrenal Cortex Hormones↗
Long-acting beta 2-adrenoceptor agonists or tiotropium bromide for patients with COPD: is combination therapy justified?
Bronchodilators are the mainstay of therapy for patients with established chronic obstructive pulmonary disease (COPD) but, at present, the majority of patients use short-acting agents. There is increasing evidence that long-acting agents, such as the beta(2)-adrenoceptor agonists salmeterol and formeterol, and the new anticholinergic tiotropium bromide provide a better therapeutic option. In the treatment of COPD, long-acting beta(2)-adrenoceptor agonists (LABAs) given twice daily cause the same degree of bronchodilation as tiotropium bromide given once daily. Combined use of an inhaled LABA with tiotropium bromide should provide important therapeutic benefits, as these drugs have distinct and complementary pharmacological actions in the airways. Although clinical trials of this combination have not been performed, clinical experience with Combivent, a combination of a short-acting beta(2)-adrenoceptor agonist (salbutamol) and a short-acting anticholinergic (ipratropium bromide), in COPD is encouraging because the bronchodilation produced is of a magnitude greater than that of either component alone. However, because LABAs are given twice daily but tiotropium bromide is required only once daily, the challenge is to develop a combined inhaler that can be employed on a daily basis.
Adrenergic beta-2 Receptor Agonists↗
Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma.
Atopic or immunoglobulin E (IgE)-mediated diseases include the common disorders of asthma, atopic dermatitis and allergic rhinitis. Chromosome 13q14 shows consistent linkage to atopy and the total serum IgE concentration. We previously identified association between total serum IgE levels and a novel 13q14 microsatellite (USAT24G1; ref. 7) and have now localized the underlying quantitative-trait locus (QTL) in a comprehensive single-nucleotide polymorphism (SNP) map. We found replicated association to IgE levels that was attributed to several alleles in a single gene, PHF11. We also found association with these variants to severe clinical asthma. The gene product (PHF11) contains two PHD zinc fingers and probably regulates transcription. Distinctive splice variants were expressed in immune tissues and cells.
Adult↗
Evidence for post-transcriptional regulation of interleukin-5 by dexamethasone.
Interleukin-5 (IL-5) is a T helper type 2 cytokine, which is implicated in the pathogenesis of eosinophilic diseases such as asthma. Both peripheral blood mononuclear cells (PBMC) and primary human T cells display similar patterns of IL-5 expression when stimulated with both phorbol-12-myristate 13-acetate and phytohaemagglutinin. The expression of IL-5 stimulated by these agents was shown to require de novo transcription and translation. However, although dexamethasone was a potent inhibitor of both IL-5 release and messenger RNA accumulation from PBMC and T cells, dexamethasone had no effect on the luciferase activity of a reporter construct under the control of an IL-5 promoter region transiently transfected into primary human T cells. Furthermore, dexamethasone appeared to decrease the stability of IL-5 messenger RNA and this effect was dependent upon de novo transcription. Taken together, the results presented here suggest that, whilst transcriptional processes predominantly regulate IL-5 release, the mechanism by which dexamethasone inhibits IL-5 is post-transcriptional.
Administration, Topical↗
Regulation of eosinophil apoptosis by nitric oxide: Role of c-Jun-N-terminal kinase and signal transducer and activator of transcription 5.
BACKGROUND: Reduced eosinophil apoptosis is considered to be a key mechanism for eosinophilia in allergic diseases such as asthma, rhinitis, and eczema. OBJECTIVE: The aim of our study was to investigate the possible modulatory effect of nitric oxide (NO) in human eosinophils. METHODS: Apoptosis in isolated eosinophils was assessed by relative DNA fragmentation assay, annexin-V binding, and morphologic analysis. The activation of c-Jun-N-terminal kinase (JNK) and signal transducer and activator of transcription 5 (STAT5) was assessed by immunoblot analysis. RESULTS: The NO donor S-nitroso-N -acetylpenicillamine (SNAP) reversed the survival-prolonging effect of IL-5 by inducing apoptosis. This effect was blocked by the NO scavenger (2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3 oxide.potassium salt), indicating that reversal of IL-5-mediated eosinophil survival was due to NO. The effect of NO on IL-5-afforded cell survival was not mediated by cyclic guanosine 3': 5'-monophosphate (cGMP), because neither an inhibitor of guanylyl cyclase nor inhibitors of phosphodiesterases had any effect on SNAP-induced eosinophil apoptosis in IL-5-treated cells. SNAP induced a time-dependent increase in the activity of JNK, and an inhibitor peptide specific for JNK, L-JNKI1, completely reversed SNAP-induced apoptosis in IL-5-treated eosinophils. In contrast, SNAP did not inhibit IL-5-induced STAT5 activation. Inhibition of the activity of caspases by Z-Asp-CH(2)-DCB reversed the effect of SNAP, suggesting that NO promotes apoptosis in IL-5-treated human eosinophils in a caspase-dependent manner. However, this effect of NO was not mediated by means of activation of caspases 3, 8, or 9. CONCLUSIONS: Our results suggest that exogenous NO reverses IL-5-mediated eosinophil survival by inducing apoptosis, and this is mediated by means of activation of JNK in a cGMP-independent manner.
Apoptosis↗