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Biomedical subjects

Peter J Barnes

Publications and source records attributed to Peter J Barnes.

At least 91 records · Page 5Linked to original sources
PubMed2004

Defective glucocorticoid receptor nuclear translocation and altered histone acetylation patterns in glucocorticoid-resistant patients.

BACKGROUND: Most chronic inflammatory diseases are well controlled by glucocorticoids. However, a minority of patients fails to respond adequately to this treatment. OBJECTIVE: We wished to determine whether glucocorticoid insensitivity in a group of steroid-resistant (SR) and steroid-dependent (SD) asthmatic subjects resulted from an inability of the glucocorticoid receptor (GR) to translocate into the nucleus. METHODS: Glucocorticoid receptor nuclear translocation was determined in PBMCs by immunocytochemistry and GR function measured by suppression of TNF-alpha-induced GM-CSF release and effects of dexamethasone on histone acetylation. RESULTS: Glucocorticoid repression of TNF-alpha-induced GM-CSF release was reduced in PBMCs from SD and SR patients. This inhibition correlated with a failure of GR to translocate into the nucleus and induce histone acetylation in response to dexamethasone. In addition, dexamethasone failed to inhibit TNF-alpha-induced histone acetyltransferase activity, which predominantly targeted histone residues lysine (K)8 and K12. However, in a subset of patients, even high levels of GR nuclear translocation failed to produce histone acetylation in response to dexamethasone. Histone H4 K5 acetylation, a marker of dexamethasone transactivation, was specifically reduced in this group. However, cells from this subset of steroid-insensitive subjects were still capable of inhibiting TNF-alpha-induced histone acetylation. CONCLUSION: We have identified a novel mechanism of glucocorticoid insensitivity in a group of SR and SD subjects. These data suggest that most patients respond to glucocorticoids according to the degree of GR nuclear translocation occurring, but some subjects with steroid resistance have a reduced response because of a failure of steroids to transactivate, rather than transrepress.

Acetylation↗
PubMed2004

Effects of inhaled corticosteroids on exhaled leukotrienes and prostanoids in asthmatic children.

BACKGROUND: Lipid mediators play an important pathophysiologic role in atopic asthmatic children, but their role in the airways of atopic nonasthmatic children is unknown. OBJECTIVE: We sought (1) to measure leukotriene (LT) E 4 , LTB 4 , 8-isoprostane, prostaglandin E 2 , and thromboxane B 2 concentrations in exhaled breath condensate in atopic asthmatic and atopic nonasthmatic children; (2) to measure exhaled nitric oxide (NO) as an independent marker of airway inflammation; and (3) to study the effect of inhaled corticosteroids on exhaled eicosanoids. METHODS: Twenty healthy children, 20 atopic nonasthmatic children, 30 steroid-naive atopic asthmatic children, and 25 atopic asthmatic children receiving inhaled corticosteroids were included in a cross-sectional study. An open-label study with inhaled fluticasone (100 microg twice a day for 4 weeks) was undertaken in 14 steroid-naive atopic asthmatic children. RESULTS: Compared with control subjects, exhaled LTE 4 ( P <.001), LTB 4 ( P <.001), and 8-isoprostane ( P <.001) levels were increased in both steroid-naive and steroid-treated atopic asthmatic children but not in atopic nonasthmatic children (LTE 4 , P=.14; LTB 4 , P=.23; and 8-isoprostane, P=.52). Exhaled NO levels were increased in steroid-naive atopic asthmatic children ( P <.001) and, to a lesser extent, in atopic nonasthmatic children ( P <.01). Inhaled fluticasone reduced exhaled NO (53%, P <.0001) and, to a lesser extent, LTE 4 (18%, P <.01) levels but not LTB 4 , prostaglandin E 2 , or 8-isoprostane levels in steroid-naive asthmatic children. Conclusions Exhaled LTE 4 , LTB 4 , and 8-isoprostane levels are increased in atopic asthmatic children but not in atopic nonasthmatic children. In contrast to exhaled NO, these markers seem to be relatively resistant to inhaled corticosteroids.

Administration, Inhalation↗
PubMed2004

Asthma guidelines: recommendations versus reality.

Highly effective treatments for asthma are now available, but many patients with asthma are still poorly controlled. Guidelines for asthma therapy are widely disseminated, but they may be considered too complex for general use, and clinical studies used to support the guidelines are not indicative of 'real life'. In the 'real' world, patients frequently cannot use their inhaler correctly, particularly pressurised metered-dose inhalers (pMDIs) which require good coordination between inhaler activation and patient inhalation. Breath-activated inhalers and dry powder inhalers (DPIs) are much easier to use and result in better lung deposition of the inhaled drug. Surprisingly, two recent Cochrane meta-analyses recommended that pMDIs should be preferentially prescribed, as they have similar efficacy to breath-activated inhalers and DPIs and are cheaper. In reality, DPIs are more cost-effective as they deposit more drug in the lungs, may improve compliance and result in more effective asthma control. Improvements in inhaled drug delivery will continue to be paramount in improving asthma management.

Asthma↗
PubMed2004

The size of the problem of managing asthma.

Asthma is now the commonest chronic disease in industrialised countries and its prevalence is rising throughout the world. However, despite the availability of very effective treatments many patients with asthma have poorly controlled symptoms and frequent exacerbations, some of which require hospital admission. Important factors contributing to poor asthma control are failure to recognise asthma as a diagnosis, non-implementation of asthma management guidelines and patient non-compliance with therapy. The guidelines themselves have many inherent limitations. Chief among these is that the evidence upon which they are based may be misleading. The evidence used to support recommendations in guidelines is derived from double-blind, placebo-controlled studies in very carefully selected patients who are usually compliant with therapy and instructed in the use of inhalers. In the 'real world' things are very different and patients frequently fail to understand how to use their therapy and are often non-compliant. Reasons for non-compliance are complex and include complicated drug and dosing regimens and inability to use inhaler devices correctly; particularly pressurised metered dose inhalers (pMDIs) due to difficulty co-ordinating device activation and inhalation. Dry powder inhalers (DPIs) preclude the need to co-ordinate inspiration with activation, are easy and convenient to use and are environmentally friendly. There is no doubt that the type of inhaler is just as important as the class of drug in the long-term management of asthma. Improvements in inhaled drug delivery will continue to be important in improving asthma management.

Adrenergic beta-Agonists↗
PubMed2004

Acidic mammalian chitinase--a potential target for asthma therapy.

Recently, inhibition of acidic mammalian chitinase in a murine asthmatic model was reported to have a profound anti-inflammatory effect, leading to the suggestion that this enzyme might be a novel therapeutic target for T helper 2-driven diseases such as asthma. The mechanism of action of such an enzyme in asthma pathology is unclear but the enzyme appears to mediate interleukin 13-dependent responses in a STAT6-independent manner. This observation has led to the proposal that chitinase family members are important mediators in allergic diseases including asthma.

Animals↗
PubMed2004

New drugs for asthma.

Asthma is a major and increasing global health problem and, despite major advances in therapy, many patients' symptoms are not adequately controlled. Treatment with combination inhalers, which contain a corticosteroid and long-acting beta(2) adrenoceptor agonist, is the most effective current therapy. There is therefore a search for new therapies, particularly safe and effective oral treatments and those that are more efficacious in severe asthma. New therapies in development include mediator antagonists and inhibitors of cytokines, although these therapies might be too specific to be very effective. New anti-inflammatory therapies include corticosteroids and inhibitors of phosphodiesterase-4, p38 mitogen-activated protein kinase and nuclear factor-kappaB. The prospects for a curative treatment are on the horizon.

Animals↗
PubMed2004

Alveolar macrophages as orchestrators of COPD.

Alveolar macrophages play a critical role in the pathophysiology of COPD and are a major target for future anti-inflammatory therapy. Macrophage numbers are markedly increased in the lung and alveolar space of patients with COPD and are localized to sites of alveolar destruction. The increased numbers of macrophages may result from increased recruitment of blood monocytes, prolonged survival in the lung and to a lesser extent to increased proliferation in the lung. Alveolar macrophages from COPD patients have an increased baseline and stimulated secretion of inflammatory proteins, including certain cytokines, chemokines, reactive oxygen species and elastolytic enzymes, which together could account for all of the pathophysiological features of COPD. Alveolar macrophages form COPD appear to be resistant to the anti-inflammatory effects of corticosteriods and this is linked to reduced activity and expression of histone deacetylase 2, a nuclear enzyme that switches off inflammatory genes activated through the transcription factor nuclear factor-KB. Alternative anti-inflammatory therapies that inhibit macrophages are therefore needed in the future to deal with the chronic inflammation of COPD. These drugs may include resveratrol, theophylline derivatives, MAP kinase inhibitors and phosphodiesterase-4 inhibitors.

Humans↗
PubMed2004

The role of oxidative stress in chronic obstructive pulmonary disease.

Tobacco smoke is the number one risk factor for chronic obstructive pulmonary disease (COPD) and contains a high concentration of oxidants. The lung has a high concentration of antioxidants and antioxidant enzymes; however, COPD patients show evidence of increased oxidative stress suggesting that endogenous antioxidants may be insufficient to prevent oxidative damage from cigarette smoke. The consequences of increased oxidative stress in the lung include increased transcription of inflammatory genes, increased protease activity, and increased mucus secretion. Oxidative stress is often associated with impaired skeletal muscle function and may be one of the causes of glucocorticoid resistance. While current pharmacologic approaches to the treatment of chronic obstructive pulmonary disease do not commonly include antioxidants, preclinical studies involving animal models suggest that antioxidant superoxide dismutase mimetics offer a potential new therapeutic approach to the prevention and treatment of chronic obstructive pulmonary disease.

Antioxidants↗
PubMed2004

Isoprostanes: markers and mediators of oxidative stress.

Some years ago it was discovered that prostaglandin F2-like compounds are formed in vivo by nonenzymatic free radical-catalyzed peroxidation of arachidonic acid. Because these compounds are a series of isomers that contain the prostane ring of prostaglandins, they were termed F2-isoprostanes. Intermediates in the isoprostane pathway are prostaglandin H2-like compounds that become reduced to form F2-isoprostanes but also undergo rearrangement in vivo to form E2-, D2-, A2-, J2-isoprostanes, isothromboxanes, and highly reactive gamma-ketoaldehydes, termed isoketals. Analogous compounds have also been shown to be formed from free radical mediated oxidation of docosoahexaenoic acid. Because docosahexaenoic acid is highly enriched in neurons, these compounds have been termed neuroprostanes and neuroketals. An important aspect of the discovery of isoprostanes is that measurement of F2-isoprostanes has emerged as one of the most reliable approaches to assess oxidative stress status in vivo, providing an important tool to explore the role of oxidative stress in the pathogenesis of human disease. Measurement of F4-neuroprostanes has also proved of value in exploring the role of oxidative stress in neurodegenerative diseases. Products of the isoprostane pathway have been found to exert potent biological actions and therefore may participate as physiological mediators of disease.

Animals↗
PubMed2004

Nuclear factor-kappaB does not mediate the inhibitory effects of dexamethasone on granulocyte-macrophage colony-stimulating factor expression.

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) reporter constructs containing up to 3.3 kb of upstream promoter sequence were transiently transfected into both Jurkat and HUT78 human T-cell lines. In Jurkat cells, stimulation with phorbol 12-myristate 13-acetate (PMA) plus phytohemaglutinin (PHA) produced robust increases in reporter activity, whereas HUT78 cells showed low levels of reporter induction attributable to constitutive nuclear factor (NF)-kappaB activity. Following mutation of either the proximal NF-kappaB site (-85/-76) or the activator protein1 (AP-1) motif within the conserved lymphokine element 0 (CLE0) site (-54/-31), reporter activity was markedly reduced in both cell lines. Despite this dependence on NF-kappaB and CLE0/AP-1, GM-CSF reporter activity was unaffected by dexamethasone in either cell line. Similarly, an NF-kappaB-dependent reporter was also not repressed by dexamethasone, yet GM-CSF release from HUT78 T cells was inhibited. These data therefore confirm a critical role for both NF-kappaB and CLE0 sites in GM-CSF promoter activation and indicate that NF-kappaB may not mediate glucocorticoid-dependent repression of GM-CSF in these cells.

Anti-Inflammatory Agents↗
PubMed2004

ICAM-1 expression is highly NF-kappaB-dependent in A549 cells. No role for ERK and p38 MAPK.

The transcription factor nuclear factor kappaB (NF-kappaB) is an activator of multiple cytokines, chemokines and adhesion molecules, which are important in inflammatory diseases such as asthma, and is consequently considered as an attractive therapeutic target. In the present study, a constitutively active dominant version of IkappaBalpha, IkappaBalphaDN, was introduced into A549 pulmonary cells by adenovirus-mediated delivery. The dominant IkappaB, but not a null viral vector, prevented the induction of NF-kappaB-dependent transcription by both tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta). Similarly, both TNFalpha and IL-1beta strongly induced mRNA and protein expression of intercellular adhesion molecule (ICAM)-1 and in each case this was prevented by adenovirus expressing the dominant IkappaB, but not by the null virus, thereby establishing ICAM-1 as an NF-kappaB-dependent gene. Numerous studies have suggested key roles for the p38 and extracellular regulated kinase (ERK) mitogen-activated protein kinase (MAPK) cascades in the activation and transactivation of NF-kappaB. We show here that SB203580, a selective inhibitor of the p38 MAPK, and PD098059 and UO126, both selective inhibitors of the ERK MAPK cascade, have no effect on TNFalpha or IL-1beta-induced translocation and DNA binding of NF-kappaB. Furthermore, these inhibitors showed no pharmacologically relevant effect on NF-kappaB-dependent transcription nor was there any effect on expression of ICAM-1. Taken together these data highlight the potential use of inhibition of the NF-kappaB signalling pathway in pulmonary inflammatory diseases and suggest that inhibitors of the p38 and ERK MAPK pathways may be of lesser effect.

Adenoviridae↗
PubMed2004

Differential effects of RU486 reveal distinct mechanisms for glucocorticoid repression of prostaglandin E release.

In A549 pulmonary cells, the dexamethasone- and budesonide-dependent repression of interleukin-1beta-induced prostaglandin E2 release was mimicked by the steroid antagonist, RU486. Conversely, whereas dexamethasone and budesonide were highly effective inhibitors of interleukin-1beta-induced cyclooxygenase (COX)/prostaglandin E synthase (PGES) activity and COX-2 expression, RU486 (<1 microm) was a poor inhibitor, but was able to efficiently antagonize the effects of dexamethasone and budesonide. In addition, both dexamethasone and RU486 repressed [3H]arachidonate release, which is consistent with an effect at the level of phospholipase A2 activity. By contrast, glucocorticoid response element-dependent transcription was unaffected by RU486 but induced by dexamethasone and budesonide, whilst dexamethasone- and budesonide-dependent repression of nuclear factor-kappaB-dependent transcription was maximally 30-40% and RU486 (<1 microm) was without significant effect. Thus, two pharmacologically distinct mechanisms of glucocorticoid-dependent repression of prostaglandin E2 release are revealed. First, glucocorticoid-dependent repression of arachidonic acid is mimicked by RU486 and, second, repression of COX/PGES is antagonized by RU486. Finally, whilst all compounds induced glucocorticoid receptor translocation, no role for glucocorticoid response element-dependent transcription is supported in these inhibitory processes and only a limited role for glucocorticoid-dependent inhibition of nuclear factor-kappaB in the repression of COX-2 is indicated.

Arachidonic Acid↗
PubMed2004

Mediators of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a major and increasing global health problem that is now a leading cause of death. COPD is associated with a chronic inflammatory response, predominantly in small airways and lung parenchyma, which is characterized by increased numbers of macrophages, neutrophils, and T lymphocytes. The inflammatory mediators involved in COPD have not been clearly defined, in contrast to asthma, but it is now apparent that many lipid mediators, inflammatory peptides, reactive oxygen and nitrogen species, chemokines, cytokines, and growth factors are involved in orchestrating the complex inflammatory process that results in small airway fibrosis and alveolar destruction. Many proteases are also involved in the inflammatory process and are responsible for the destruction of elastin fibers in the lung parenchyma, which is the hallmark of emphysema. The identification of inflammatory mediators and understanding their interactions is important for the development of anti-inflammatory treatments for this important disease.

Animals↗
PubMed2004

Theophylline: mechanism of action and use in asthma and chronic obstructive pulmonary disease.

Despite having been recognized for a long time as a cheap and effective therapy for the treatment of asthma and chronic obstructive pulmonary disease (COPD), theophylline is relegated to third-line therapy in the treatment of airway diseases due to the drug's frequent side effects and relatively low efficacy. However, regardless of the current situation, there are reasons for thinking that the use of theophylline, in addition to inhaled steroids, may come back into fashion for the treatment of chronic asthma, as it may have an anti-inflammatory and immunomodulatory effect when given in low doses. At these low doses, the drug is easier to use, side effects are uncommon and the problems of drug interaction are less of an issue, thus making the clinical use of theophylline less complicated. In COPD, low-dose theophylline is the first drug to demonstrate clear anti-inflammatory effects, and thus it may even have a role in preventing progression of the disease. Furthermore, the reversal of the steroid resistance induced by oxidative stress suggests that theophylline may increase responsiveness to corticosteroids.

Asthma↗