Richard Russell

British guideline on the management of asthma: A national clinical guideline

These guidelines have been replaced by British Guideline on the Management of Asthma. A national clinical guideline. Superseded By 2012 Revision Of 2008 Guideline: British Guideline on the Management of Asthma. Thorax 2008 May; 63(Suppl 4): 1–121.

Increased levels of the chemokines GROα and MCP-1 in sputum samples from patients with COPD

Background: Patients with chronic obstructive pulmonary disease (COPD) have increased numbers of neutrophils and macrophages in their lungs. Growth related oncogene-α (GROα) attracts neutrophils, whereas monocyte chemoattractant protein-1 (MCP-1) attracts monocytes that can differentiate into macrophages. The aim of this study was to determine the concentration of GROα and MCP-1 in bronchoalveolar lavage (BAL) fluid and sputum from non-smokers, healthy smokers and patients with COPD, and to see if there was a correlation between the concentrations of these chemokines, lung function, and numbers of inflammatory cells. Methods: BAL fluid and sputum from non-smokers (n=32), healthy smokers (n=36), and patients with COPD (n=40) were analysed for the presence of GROα and MCP-1 using ELISA. Cells counts were performed on the samples and correlations between the concentrations of these chemokines, lung function, and inflammatory cells observed. Results: Median (SE) GROα and MCP-1 levels were significantly increased in sputum from patients with COPD compared with non-smokers and healthy smokers (GROα: 31 (11) v 2 (2) v 3 (0.8) ng/ml; MCP-1: 0.8 (0.4) v 0.2 (0.1) v 0.1 (0.04) ng/ml, p<0.05), but not in BAL fluid. There were significant negative correlations between both GROα and MCP-1 levels in sputum and forced expiratory volume in 1 second (FEV1) % predicted (GROα: r=–0.5, p<0.001; MCP-1: r=–0.5, p<0.001), together with significant positive correlations between GROα and MCP-1 and neutrophil numbers in sputum (GROα: r=0.6, p<0.001; MCP-1: r=0.4, p<0.01). Conclusion: These results suggest that GROα and MCP-1 are involved in the migration of inflammatory cells, thus contributing to the inflammatory load associated with COPD.

Inhibition by red wine extract, resveratrol, of cytokine release by alveolar macrophages in COPD

Background: The pathophysiology of chronic obstructive pulmonary disease (COPD) features pulmonary inflammation with a predominant alveolar macrophage involvement. Bronchoalveolar macrophages from patients with COPD release increased amounts of inflammatory cytokines in vitro, an effect that is not inhibited by the glucocorticosteroid dexamethasone. Resveratrol (3,5,4′-trihydroxystilbene) is a component of red wine extract that has anti-inflammatory and antioxidant properties. A study was undertaken to determine whether or not resveratrol would inhibit cytokine release in vitro by alveolar macrophages from patients with COPD. Methods: Alveolar macrophages were isolated from bronchoalveolar lavage (BAL) fluid from cigarette smokers and from patients with COPD (n=15 per group). The macrophages were stimulated with either interleukin (IL)-1β or cigarette smoke media (CSM) to release IL-8 and granulocyte macrophage-colony stimulating factor (GM-CSF). The effect of resveratrol was examined on both basal and stimulated cytokine release. Results: Resveratrol inhibited basal release of IL-8 in smokers and patients with COPD by 94% and 88% respectively, and inhibited GM-CSF release by 79% and 76% respectively. Resveratrol also inhibited stimulated cytokine release. Resveratrol reduced IL-1β stimulated IL-8 and GM-CSF release in both smokers and COPD patients to below basal levels. In addition, resveratrol inhibited CSM stimulated IL-8 release by 61% and 51% respectively in smokers and COPD patients, and inhibited GM-CSF release by 49% for both subject groups. Conclusions: Resveratrol inhibits inflammatory cytokine release from alveolar macrophages in COPD. Resveratrol or similar compounds may be effective pharmacotherapy for macrophage pathophysiology in COPD.

Treatment Effects of Low-Dose Theophylline Combined With an Inhaled Corticosteroid in COPD

BACKGROUND Inhaled corticosteroids (ICS) have proved disappointing at reducing airway inflammation in COPD. However, previous studies indicate that low doses of theophylline enhance the activity of a key corticosteroid-associated corepressor protein, histone deacetylase (HDAC)2, which is reduced in COPD. This may account, at least in part, for the relative corticosteroid resistance. Thus, combination therapy with an ICS and low-dose theophylline may be of benefit in the treatment of COPD. METHODS To test the hypothesis that ICS and theophylline have a greater therapeutic effect than theophylline alone, 30 patients with COPD were treated with placebo theophylline capsules and either inhaled fluticasone propionate (FP) (500 microg bid) or inhaled placebo for 4 weeks in a double-dummy, randomized, double-blind, parallel study. After a 2-week washout, patients were given active theophylline capsules (plasma level of 8.8-12.4 mg/L). RESULTS In an across-arm comparison, combination treatment with FP and theophylline did not reduce total sputum neutrophils but significantly reduced total sputum eosinophils (P < .05). Additional across-arm comparisons suggest a further reduction in percentage sputum neutrophils and sputum chemokine (C-X-C motif) ligand 8/IL-8 (P < .05). Furthermore, within-arm observational data also demonstrated increases in forced midexpiratory flow rate and FEV(1)% predicted (P < .05) following combination treatment only. In an open-label study, low-dose theophylline when added to inhaled FP increased total HDAC activity in peripheral blood monocytes ninefold (P < .01) compared with FP alone from the same patients with COPD. CONCLUSIONS Combination therapy with an inhaled corticosteroid and low-dose theophylline may attenuate airway inflammation in patients with COPD. TRIAL REGISTRATION clinicaltrials.gov; Identifier NCT00241631.

Expression of Transient Receptor Potential C6 Channels in Human Lung Macrophages

Chronic obstructive pulmonary disease (COPD) is associated with pulmonary inflammation with increased numbers of macrophages located in the parenchyma. These macrophages have the capacity to mediate the underlying pathophysiology of COPD; therefore, a better understanding of their function in chronic inflammation associated with this disease is vital. Ion channels regulate many cellular functions; however, their role in macrophages is unclear. This study examined the expression and function of transient receptor potential (TRP) channels in human macrophages. Human alveolar macrophages and lung tissue macrophages expressed increased mRNA and protein for TRPC6 when compared with monocytes and monocyte-derived macrophages. Moreover, TRPC6 mRNA expression was significantly elevated in alveolar macrophages from patients with COPD compared with control subjects. There were no differences in mRNA for TRPC3 or TRPC7. Although mRNA for TRPM2 and TRPV1 was detected in these cells, protein expression could not be determined. Fractionation of lung-derived macrophages demonstrated that TRPC6 protein was more highly expressed by smaller macrophages compared with larger macrophages. Using whole-cell patch clamp electrophysiology, TRPC6-like currents were measured in both macrophage subpopulations with appropriate biophysical and basic pharmacological profiles. These currents were active under basal conditions in the small macrophages. These data suggest that TRPC6-like channels are functional on human lung macrophages, and may be associated with COPD.

Eosinophils in COPD: just another biomarker?

Eosinophils are innate immune cells that, under certain conditions, can be recruited to the lungs, where they have an incompletely understood role in health and disease. Eosinophils have been found in the airways, tissues, and circulation of patients with COPD, during both stable disease and exacerbations. Epidemiological studies and post-hoc analyses of clinical trials of corticosteroid treatment for COPD have shown that the blood eosinophil count is associated with the risk of COPD exacerbations, mortality, decline in FEV1, and response to both inhaled and systemic corticosteroids. Further studies are urgently needed to explore the contribution of eosinophils to the mechanism of disease in COPD and to identify their association with levels of clinical risk. In this review, we explore the role of the eosinophil as a biomarker and mediator of disease in COPD.

Expression of muscarinic receptors by human macrophages

Macrophages increase in number and are highly activated in chronic obstructive pulmonary disease (COPD). Muscarinic receptor antagonists inhibit acetylcholine-stimulated release of neutrophilic chemoattractants, suggesting that acetylcholine may regulate macrophage responses. Therefore, expression and function of components of the non-neuronal cholinergic system in monocyte-macrophage cells was investigated. RNA was isolated from monocytes, monocyte-derived macrophages (MDMs), lung and alveolar macrophages from nonsmokers, smokers and COPD patients, and expression of the high-affinity choline transporter, choline acetyltransferase, vesicular acetylcholine transporter and muscarinic receptors (M1–M5) ascertained using real-time PCR. M2 and M3 receptor expression was confirmed using immunocytochemistry. Release of interleukin (IL)-8, IL-6 and leukotriene (LT)B4 were measured by ELISA or EIA. All monocyte-macrophage cells expressed mRNA for components of the non-neuronal cholinergic system. Lung macrophages expressed significantly more M1 mRNA compared with monocytes, and both lung macrophages and alveolar macrophages expressed the highest levels of M3 mRNA. Expression of M2 and M3 protein was confirmed in MDMs and lung macrophages. Carbachol stimulated release of LTB4 from lung macrophages (buffer 222.3±75.1 versus carbachol 1,118±622.4 pg·mL−1; n=15, p<0.05) but not IL-6 or IL-8. LTB4 release was attenuated by the M3 antagonist, 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP; half maximal effective concentration 5.2±2.2 nM; n=9). Stimulation of macrophage M3 receptors promotes release of LTB4, suggesting that anti-muscarinic agents may be anti-inflammatory.

Optimizing management of chronic obstructive pulmonary disease in the upcoming decade

Chronic obstructive pulmonary disease (COPD) is a leading cause of disability and mortality. Caring for patients with COPD, particularly those with advanced disease who experience frequent exacerbations, places a significant burden on health care budgets, and there is a global need to reduce the financial and personal burden of COPD. Evolving scientific evidence on the natural history and clinical course of COPD has fuelled a fundamental shift in our approach to the disease. The emergence of data highlighting the heterogeneity in rate of lung function decline has altered our perception of disease progression in COPD and our understanding of appropriate strategies for the management of stable disease. These data have demonstrated that early, effective, and prolonged bronchodilation has the potential to slow the rate of decline in lung function and to reduce the frequency of exacerbations that contribute to functional decline. The goals of therapy for COPD are no longer confined to controlling symptoms, reducing exacerbations, and maintaining quality of life, and slowing disease progression is now becoming an achievable aim. A challenge for the future will be to capitalize on these observations by improving the identification and diagnosis of patients with COPD early in the course of their disease, so that effective interventions can be introduced before the more advanced, disabling, and costly stages of the disease. Here we critically review emerging data that underpin the advances in our understanding of the clinical course and management of COPD, and evaluate both current and emerging pharmacologic options for effective maintenance treatment.

Impact factor and its role in academic promotion.

This statement was adopted unanimously at the May 17, 2009 meeting of the International Respiratory Journal Editors Roundtable. In our collective experience as editors of international peer-reviewed journals, we propose that the impact factor calculated for individual journals should not be used as a basis for evaluating the significance of an individual scientist’s past performance or scientific potential. There are several reasons not to equate the impact factor of a journal in which the scientist publishes with the quality of the scientist’s research. For example, as revealed by several recently published analyses of the impact factor:1–6 A journal’s impact factor is determined by a decided minority of its published manuscripts. Thus the impact factor correlates poorly with the citations of an individual manuscript. The impact factor does not consider the number of scientists actively producing research in a given specialty field. Indeed, some journals feel the need to serve constituencies with relatively small numbers of participants who continue to address important questions even though the number of scientists available for citations is limited. Citations of many articles may not peak until after the second year of publication, ie, beyond the brief period of time considered by the impact factor. A journal’s impact factor can be inflated by certain journal practices such as publication of many review articles, self-citation. The impact factor measures only the frequency of citations which cannot be assumed to always equate with quality. There are alternatives and we believe more valid measures of the quality and impact of an individual scientist’s published contributions. First, a citation record for the individual candidate is readily available via several types of Internet search engines. Second, the time-honored practice of soliciting evaluations concerning the significance of a candidate’s work from scientific peers who are carefully selected to be both highly qualified as well as clearly “arm’s-length” from the candidate should be rigorously applied.

Enhanced monocyte migration to CXCR3 and CCR5 chemokines in COPD.

Chronic obstructive pulmonary disease (COPD) patients exhibit chronic inflammation, both in the lung parenchyma and the airways, which is characterised by an increased infiltration of macrophages and T-lymphocytes, particularly CD8+ cells. Both cell types can express chemokine (C-X-C motif) receptor (CXCR)3 and C-C chemokine receptor 5 and the relevant chemokines for these receptors are elevated in COPD. The aim of this study was to compare chemotactic responses of lymphocytes and monocytes of nonsmokers, smokers and COPD patients towards CXCR3 ligands and chemokine (C-C motif) ligand (CCL)5. Migration of peripheral blood mononuclear cells, monocytes and lymphocytes from nonsmokers, smokers and COPD patients toward CXCR3 chemokines and CCL5 was analysed using chemotaxis assays. There was increased migration of peripheral blood mononuclear cells from COPD patients towards all chemokines studied when compared with nonsmokers and smokers. Both lymphocytes and monocytes contributed to this enhanced response, which was not explained by increased receptor expression. However, isolated lymphocytes failed to migrate and isolated monocytes from COPD patients lost their enhanced migratory capacity. Both monocytes and lymphocytes cooperate to enhance migration towards CXCR3 chemokines and CCL5. This may contribute to increased numbers of macrophages and T-cells in the lungs of COPD patients, and inhibition of recruitment using selective antagonists might be a treatment to reduce the inflammatory response in COPD. Peripheral blood mononuclear cells from COPD patients migrate in greater numbers towards CCL5 and CXCR3 chemokines http://ow.ly/X6iQw