Theophylline: new perspectives for an old drug.
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Apoptosis↗
Biomedical subjects
Peter J Barnes
Publications and source records attributed to Peter J Barnes.
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↗
High levels of interleukin-6 in the exhaled breath condensate of patients with COPD.
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by chronic inflammation of the respiratory tract. METHODS: We investigated the presence of interleukin-6 (IL-6: a cytokine secreted by monocytes/macrophages, T cells, B cells, fibroblasts, bone marrow stromal cells, keratinocytes and endothelial cells) in the exhaled breath condensate of 16 exsmokers with moderate COPD, 12 healthy non-smokers. IL-6 was measured by means of a specific enzyme immunoassay. RESULTS: IL-6 levels were detectable in all of the subjects, but were higher in the COPD patients (8.0 +/- 0.1 pg/ml; P < 0.0001) than in the healthy non-smokers (4.9 +/- 0.2 pg/ml) with a correlation in this group between age and IL-6 levels (r = 0.597; P < 0.05). CONCLUSIONS: The increased IL-6 levels in exhaled breath condensate may reflect airway inflammation in patients with COPD.
Adult↗
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↗
Cytokine-directed therapies for the treatment of chronic airway diseases.
Multiple cytokines play a critical role in orchestrating and perpetuating inflammation in asthma and chronic obstructive pulmonary disease (COPD) and several specific cytokine and chemokine inhibitors now in development as future therapy for these diseases. Anti-IL-5 antibody markedly reduces peripheral blood and airway eosinophils, but does not appear to be effective in symptomatic asthma. Inhibition of IL-4 despite promising early results in asthma has been discontinued and blocking IL-13 might be more effective. Inhibitory cytokines, such as IL-10, interferons and IL-12 are less promising, as systemic delivery produces side effects. Inhibition of TNF-alpha may be useful in severe asthma and for treating severe COPD with systemic features. Many chemokines are involved in the inflammatory response of asthma and COPD and several small molecule inhibitors of chemokine receptors (CCR) are in development. CCR3 antagonists (which block eosinophil chemotaxis) and CXCR2 antagonists (which block neutrophil and monocyte chemotaxis) are in clinical development for asthma and COPD, respectively. Because so many cytokines are involved in asthma, drugs that inhibit the synthesis of multiple cytokines may prove to be more useful; several such classes of drug are now in clinical development and any risk of side effects with these non-specific inhibitors may be reduced by the inhaled route.
Adrenal Cortex Hormones↗
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↗
Neutrophil chemotactic activity of sputum from patients with COPD: role of interleukin 8 and leukotriene B4.
STUDY OBJECTIVES: Neutrophilic inflammation is a major feature of COPD. Several factors in bronchial secretions have been identified as chemoattractants for neutrophils. The present study was designed to assess the contribution of interleukin (IL)-8 and leukotriene B(4) (LTB(4)) to neutrophil chemotaxis evoked by sputum obtained from patients with established COPD. DESIGN: Sputum supernatant of 20 patients with COPD was used as chemoattractant in a 96-well chemotaxis chamber, with subsequent quantification of migrated cells by a luminescence assay. The contribution of IL-8 and LTB(4) to chemotaxis was determined by addition of a neutralizing antibody and a selective receptor antagonist, respectively. MEASUREMENTS AND RESULTS: COPD sputum caused neutrophil chemotaxis in a concentration-dependent manner, with a maximum response evoked with a 10-fold dilution of the original sample. Pretreatment of sputum or neutrophils with either an anti-IL-8 antibody or the LTB(4) antagonist, SB 201146, led to a concentration-dependent inhibition of sputum-induced neutrophil chemotaxis, with a maximum suppression (mean +/- SEM) of 29.2 +/- 4.9% (p < 0.001) from baseline by 100 ng/mL of anti-IL-8 antibody, and 45.6 +/- 7% (p < 0.02) by 10 micro mol/L of SB 201146. The combination of the anti-IL-8 antibody and SB 201146 inhibited neutrophil chemotaxis, but this was not significantly greater than the effect of SB 201146 or anti-IL-8 alone. CONCLUSIONS: These data confirm the importance of IL-8 and LTB(4) as chemoattractants for neutrophils in bronchial secretions from patients with COPD, and suggest that specific inhibitors may have therapeutic potential in COPD.
Acrylates↗
Increased exhaled 8-isoprostane in childhood asthma.
STUDY OBJECTIVE: To quantify lung oxidative stress in asthmatic children by measuring concentrations of 8-isoprostane, a marker of oxidative stress, in exhaled breath condensate (EBC), which is a noninvasive method of sampling airway secretions. Secondary objectives were as follows: (1) to measure levels of exhaled prostaglandin (PG) E(2), since impaired PGE(2) production has been implicated in the pathogenesis of asthma in adults; and (2) to measure levels of fractional exhaled nitric oxide (FeNO), which is a marker of airway inflammation. DESIGN: Single-center, cross-sectional study. PATIENTS: Twelve healthy children, 12 steroid-naïve asthmatic children, and 30 children in stable condition with mild-to-moderate persistent asthma who were being treated with inhaled corticosteroids (ICSs) [average dose, 300 micro g per day] were studied. INTERVENTIONS: Subjects attended the outpatient clinic on one occasion for the collection of EBC and FeNO measurements. MEASUREMENTS AND RESULTS: 8-Isoprostane and PGE(2) concentrations in EBC were measured with specific radioimmunoassays. FeNO was measured online by a chemiluminescence analyzer. 8-Isoprostane was detectable in the EBC of healthy children (mean [+/- SEM], 34.2 +/- 4.5 pg/mL), and its concentrations were increased in both steroid-naïve asthmatic children (mean, 56.4 +/- 7.7 pg/mL; p < 0.01) and steroid-treated asthmatic children (mean, 47.2 +/- 2.3 pg/mL; p < 0.05). There was no difference in exhaled 8-isoprostane concentrations between the two groups of asthmatic children (p = 0.14). By contrast, exhaled PGE(2) concentrations were similar among the three study groups (p = 0.56). FeNO levels were higher in steroid-naïve children with asthma (49.2 +/- 9.6 parts per billion [ppb]; p < 0.05) and, to a lesser extent, in steroid-treated asthmatic children (37.8 +/- 6.6 ppb; p < 0.05) compared with healthy children (15.2 +/- 1.7 ppb). CONCLUSIONS: Lung oxidative stress is increased in children who are in stable condition with asthma, as reflected by increased exhaled 8-isoprostane concentrations. This increase seems to be relatively resistant to treatment with ICSs. Decreased PGE(2) lung production is unlikely to play a pathophysiologic role in childhood asthma.
Adolescent↗
Nitric oxide metabolites are not reduced in exhaled breath condensate of patients with primary ciliary dyskinesia.
STUDY OBJECTIVES: To investigate whether nitric oxide (NO) metabolites would be reduced in children affected by primary ciliary dyskinesia (PCD). DESIGN: Single-center observational study. PATIENTS: Fifteen children with PCD (seven boys; mean [+/- SEM] age, 10.3 +/- 0.7 years; mean FEV(1), 73 +/- 2.1% predicted) were recruited along with 14 healthy age-matched subjects (seven boys; mean age, 11.5 +/- 0.4 years; mean FEV(1), 103 +/- 5% predicted). INTERVENTIONS: We assessed the levels of nitrite (NO(2)(-)), NO(2)(-)/NO(3)(-) (NO(2)(-)/NO(3)(-)), and S-nitrosothiol in exhaled breath condensate, exhaled NO, and nasal NO from children with PCD compared to those in healthy children. MEASUREMENTS AND RESULTS: The mean exhaled and nasal NO levels were markedly decreased in children with PCD compared to those without PCD (3.2 +/- 0.2 vs 8.5 +/- 0.9 parts per billion [ppb], respectively [p < 0.0001]; 59.6 +/- 12.2 vs 505.5 +/- 66.8 ppb, respectively [p < 0.001]). Despite the lower levels of exhaled NO in children with PCD, no differences were found in the mean levels of NO(2)(-) (2.9 +/- 0.4 vs 3.5 +/- 0.3 microM, respectively), NO(2)(-)/NO(3)(-) (35.2 +/- 5.0 vs 34.3 +/- 4.5 microM, respectively), or S-nitrosothiol (1.0 +/- 0.2 vs 0.6 +/- 0.1 microM, respectively) between children with PCD and healthy subjects. CONCLUSION: These findings suggest that NO synthase activity may not be decreased as much as might be expected on the basis of low exhaled and nasal NO levels.
Breath Tests↗
8-Isoprostane, a marker of oxidative stress, is increased in exhaled breath condensate of patients with obstructive sleep apnea after night and is reduced by continuous positive airway pressure therapy.
STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is characterized by recurrent apnea during sleep that may compromise oxidative balance. Oxidative stress is increased in the blood and in the airways of OSA patients. DESIGN: The aim of this study was to investigate whether oxidative stress is determined by nocturnal apneas and could be reduced by CPAP therapy, and whether there is a relation between local and systemic oxidative stress in these patients. PATIENTS AND METHODS: Eighteen patients with OSA (13 men; mean [+/- SD] age, 48 +/- 3 years) and 12 healthy age-matched and weight-matched subjects (8 men; mean age, 46 +/- 7 years) were recruited. 8-Isoprostane was measured in exhaled breath condensate and blood by a specific enzyme immunoassay. MEASUREMENTS AND RESULTS: Higher concentrations of 8-isoprostane were found in the morning exhaled condensate (9.5 +/- 1.9 pg/mL) and plasma (9.7 +/- 1.5 pg/mL) of OSA patients compared to healthy obese subjects (6.7 +/- 0.2 and 7.1 +/- 0.3 pg/mL, respectively; p < 0.0001). Elevated mean concentrations of exhaled 8-isoprostane were observed in the OSA patients at 8:00 AM (9.5 +/- 1.9 pg/mL) but not at 8:00 PM (7.6 +/- 0.8 pg/mL; p < 0.0005), and a significant reduction was seen after continuous positive airway pressure (CPAP) therapy (7.7 +/- 0.9 pg/mL; before treatment, 9.6 +/- 1.7 pg/mL; p < 0.005). A positive correlation was found between morning exhaled 8-isoprostane levels and the apnea-hypopnea index (r = 0.8; p < 0.0001), and 8-isoprostane levels and neck circumference (r = 0.6; p < 0.0001). CONCLUSIONS: These findings suggest that systemic and local oxidative stress are increased in OSA patients, and that they are higher after nocturnal apnea and reduced by CPAP therapy.
Breath Tests↗
Update on asthma.
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Adrenal Cortex Hormones↗
New treatments for chronic obstructive pulmonary disease.
No currently available treatments reduce the progression of chronic obstructive pulmonary disease (COPD) or suppress the inflammation in small airways and lung parenchyma. However, several new treatments now in development for COPD are targeted at the inflammation process. Antagonists of mediators, such as leukotriene B4, interleukin-8, and tumour necrosis factor-alpha and inhibitors of oxidative and nitrative stress are in clinical development. Phosphodiesterase-4 inhibitors are in clinical trials and drugs that inhibit p38 MAP kinase, nuclear factor-kappaB and phosphoinositide-3 kinase-gamma are now in early development. There is also a search for elastase inhibitors to prevent the development of emphysema and drugs that may even reverse the lung destruction.
Anti-Inflammatory Agents↗