Targeted treatment in COPD: a multi-system approach for a multi-system disease

Chronic obstructive pulmonary disease is a varied condition when examined from a number of different perspectives including factors which influence disease development, pathological process and clinical features. There may be a complex interaction between the degree by which each of these processes influences the development of COPD and the subsequent clinical phenotype with which the patient presents. The varied host response and subsequent clinical phenotype has generated much interest in recent years. It is possible that failure of treatment to impact on mortality and reverse the disease process is because of the heterogeneous nature of the condition. Identification and targeted treatment of clinical and pathological phenotypes within the broad spectrum of COPD may therefore improve outcome. This article will review previous work which has attempted to phenotype COPD and identify if specific treatment for these phenotypes has been shown to be of benefit. It will examine the work on pathological processes and clinical manifestations, both pulmonary and systemic, and will focus on pharmacological therapies

Right ventricular function in chronic bronchitis and emphysema

A reproducible method of measuring right ventricular ejection fraction was devised using the technique of equilibrium radionuclide ventriculography. In an assessment of ventricular function, in a population of 100 patients with chronic bronchitis and emphysema, the right ventricular ejection fraction was, on average, lower than in normal subjects, but was still relatively well preserved in most, as was the left ventricular ejection fraction. However, the range of values of ejection fractions in patients with chronic bronchitis and emphysema was wide, and low values occurred mainly in patients with oedema, indicative of decompensated pulmonary heart disease. The right ventricular ejection fraction was lower in those patients with lower arterial oxygen and higher carbon dioxide tensions, but was not related to the level of simultaneous measurements of pulmonary arterial pressure. Right ventricular ejection fraction was, however, related to right ventricular afterload as measured by the pulmonary vascular resistance. Occult right ventricular dysfunction could be demonstrated during exercise in patients with chronic bronchitis and emphysema. The change in right ventricular ejection fraction was related to the fall in oxygen saturation which occurred in such patients during exercise. In 20 patients with chronic bronchitis and emphysema and pulmonary hypertension, the right ventricular end-systolic pressure/volume relation was calculated from combined measurements of right ventricular pressure, ejection fraction and cardiac output, in order to assess right ventricular contractility. Analysis of the pressure/volume relation indicated normal or enhanced right ventricular contractility in these patients, despite the presence of pulmonary hypertension. The right ventricular end-systolic pressure/volume ratio was unchanged when right ventricular systolic pressure was reduced by an infusion of sodium nitroprusside. Oxygen (3 litres/minute, nasal prongs) both when given acutely and over a period of 6 months (15 hours/24 hour day) to patients with chronic respiratory failure reduced pulmonary arterial pressure, but did not result in any change in right ventricular ejection fraction, nor in right ventricular contractility as assessed by the pressure/volume relation. From these results there was little to suggest that the effect of domiciliary oxygen in improving survival in patients with respiratory failure was mediated through a direct effect on the right ventricle. However, oxygen did improve right ventricular function during exercise in such patients although the mechanism remains obscure. The beta-agonist Pirbuterol produced pulmonary vasodilatation in patients with hypoxic chronic bronchitis and emphysema. Moreover, the right ventricular end-systolic pressure/volume ratio increased, suggesting that this drug had an additional inotropic effect. In order to determine if patients with acutely decompensated pulmonary heart disease truly had 'heart failure', haemodynamic measurements were made in 6 patients with respiratory failure and pulmonary hypertension, who presented acutely with oedema. Measurements of right ventricular ejection fraction and analysis of the right ventricular end-systolic pressure/volume relation, suggested that right ventricular contractility was depressed. However, right ventricular function, as measured by the cardiac index or stroke work index, was normal as a result of an adaptive mechanism involving large increases in right ventricular end-diastolic volume, as predicted by Starling's Law. In those patients who presented with oedema, these haemodynamic changes did not seem to result from an increase in pulmonary arterial pressure. Moreover, the relief of hypoxaemia by breathing oxygen had no consistent effect on right ventricular performance, despite a small reduction in pulmonary arterial pressure. The measurement of right ventricular ejection fraction in patients with chronic bronchitis and emphysema when measured in isolation, may give little information as to the cause of right ventricular dysfunction in such patients, but when combined with haemodynamic measurements obtained during right heart catheterisation, allows assessment of the right ventricular pressure/volume relation. This measurement is useful in assessing the mechanism of right ventricular dysfunction and in measuring the effects of therapeutic interventions in patients with pulmonary heart disease

Asthma and PM10

PM(10) (the mass of particles present in the air having a 50% cutoff for particles with an aerodynamic diameter of 10 μm) is the standard measure of particulate air pollution used worldwide. Epidemiological studies suggest that asthma symptoms can be worsened by increases in the levels of PM(10). Epidemiological evidence at present indicates that PM(10) increases do not raise the chances of initial sensitisation and induction of disease, although further research is warranted. PM(10) is a complex mixture of particle types and has many components and there is no general agreement regarding which component(s) could lead to exacerbations of asthma. However pro-inflammatory effects of transition metals, hydrocarbons, ultrafine particles and endotoxin, all present to varying degrees in PM(10), could be important. An understanding of the role of the different components of PM(10) in exacerbating asthma is essential before proper risk assessment can be undertaken leading to advice on risk management for the many asthmatics who are exposed to air pollution particles

Airways inflammation and treatment during acute exacerbations of COPD

INTRODUCTION: Inflammation is a core feature of acute chronic obstructive pulmonary disease (COPD) exacerbations. It is important to focus on inflammation since it gives insight into the pathological changes causing an exacerbation, thereby possibly providing directions for future therapies which modify inflammation. OBJECTIVES: To provide a cell-by-cell overview of the inflammatory processes during COPD exacerbations. To evaluate cell activation, and cytokine production, cellular interactions, damaging effects of inflammatory mediators to tissue, and the relation to symptoms at the onset of COPD exacerbations. To speculate on future therapeutic options to modify inflammation during COPD exacerbations. RESULTS: During COPD exacerbations, there is increased airway wall inflammation, with pathophysiological influx of eosinophils, neutrophils, and lymphocytes. Although links have been suggested between the increase in eosinophils and lymphocytes and a viral etiology of the exacerbation, and between the increase in neutrophils and a bacterial aetiology, these increases in both inflammatory cell types are not limited to the respective aetiologies and the underlying mechanisms remain elusive. CONCLUSION: Further research is required to fully understand the inflammatory mechanisms in the onset and development of COPD exacerbations. This might make inflammatory pathway-specific intervention possible, resulting in a more effective treatment of COPD exacerbations with fewer side effects

Neurological and endocrinological disorders: orphans in chronic obstructive pulmonary disease

SummaryPatients with chronic obstructive pulmonary disease (COPD) are often characterised by a range of characteristic co-morbidities that interfere with their pulmonary disease. In addition to a mere association with co-morbidities, a complex pathophysiological interaction and mutual augmentation occurs between COPD and its co-morbidities that may result in disease progression and increased morbidity and mortality. An interdisciplinary approach is required both for diagnosis and treatment to target co-morbidities early in the course of the disease. This review summarizes the current knowledge of the interaction with cerebrovascular disease and endocrinological co-morbidities in COPD patients. There is growing evidence that COPD is an independent risk factor for ischemic stroke, increasing the risk about twofold. Stroke risk in COPD patients increases with the severity of the disease as measured by the degree of airflow limitation. The presence of cardiovascular risk factors is of particular importance for stroke prevention in COPD patients. Endocrinological co-morbidities are also important and many are associated with increased cardiovascular risk. Impaired glucose metabolism ranges from insulin resistance to overt diabetes mellitus, which is a frequent finding and is associated with worse outcome

Role of accelerated aging in limb muscle wasting of patients with COPD

Purpose: Skeletal muscle wasting is an independent predictor of health-related quality of life and survival in patients with COPD, but the complexity of molecular mechanisms associated with this process has not been fully elucidated. We aimed to determine whether an impaired ability to repair DNA damage contributes to muscle wasting and the accelerated aging phenotype in patients with COPD. Patients and methods: The levels of phosphorylated H2AX (γH2AX), a molecule that promotes DNA repair, were assessed in vastus lateralis biopsies from 10 COPD patients with low fat-free mass index (FFMI; COPDL), 10 with preserved FFMI and 10 age- and gender-matched healthy controls. A panel of selected markers for cellular aging processes (CDKN2A/p16ink4a, SIRT1, SIRT6, and telomere length) were also assessed. Markers of oxidative stress and cell damage and a panel of pro-inflammatory and anti-inflammatory cytokines were evaluated. Markers of muscle regeneration and apoptosis were also measured. Results: We observed a decrease in γH2AX expression in COPDL, which occurred in association with a tendency to increase in CDKN2A/p16ink4a, and a significant decrease in SIRT1 and SIRT6 protein levels. Cellular damage and muscle inflammatory markers were also increased in COPDL. Conclusion: These data are in keeping with an accelerated aging phenotype as a result of impaired DNA repair and dysregulation of cellular homeostasis in the muscle of COPDL. These data indicate cellular degeneration via stress-induced premature senescence and associated inflammatory responses abetted by the senescence-associated secretory phenotype and reflect an increased expression of markers of oxidative stress and inflammation

Cytotoxicity and Induction of Inflammation by Pepsin in Acid in Bronchial Epithelial Cells

Introduction. Gastroesophageal reflux has been associated with chronic inflammatory diseases and may be a cause of airway remodelling. Aspiration of gastric fluids may cause damage to airway epithelial cells, not only because acidity is toxic to bronchial epithelial cells, but also since it contains digestive enzymes, such as pepsin. Aim. To study whether pepsin enhances cytotoxicity and inflammation in airway epithelial cells, and whether this is pH-dependent. Methods. Human bronchial epithelial cells were exposed to increasing pepsin concentrations in varying acidic milieus, and cell proliferation and cytokine release were assessed. Results. Cell survival was decreased by pepsin exposure depending on its concentration (F = 17.4) and pH level of the medium (F = 6.5) (both P < 0.01). Pepsin-induced interleukin-8 release was greater at lower pH (F = 5.1; P < 0.01). Interleukin-6 induction by pepsin was greater at pH 1.5 compared to pH 2.5 (mean difference 434%; P = 0.03). Conclusion. Pepsin is cytotoxic to bronchial epithelial cells and induces inflammation in addition to acid alone, dependent on the level of acidity. Future studies should assess whether chronic aspiration causes airway remodelling in chronic inflammatory lung diseases

Living and dying with severe chronic obstructive pulmonary disease: multi-perspective longitudinal qualitative study

Objectives To understand the perspectives of people with severe chronic obstructive pulmonary disease (COPD) as their illness progresses, and of their informal and professional carers, to inform provision of care for people living and dying with COPD

Lack of systemic oxidative stress during PAF challenge in mild asthma

SummaryTo further establish the role of oxidative stress in the pathogenesis of acute bronchial asthma, we investigated the effects of platelet-activating factor (PAF) challenge on systemic oxidant–antioxidant balance in 12 asthmatic patients (age, 25±3[sem] yr; FEV1, 95±10% predicted), using a double blinded, controlled with Lyso-PAF (L-PAF), cross-over design.Respiratory system resistance (Rrs), arterial blood gases, peripheral blood neutrophils and oxidant–antioxidant balance, including thiobarbituric acid (TBA)-malondialdehyde (MDA) adducts, protein sulphydryls and Trolox equivalent antioxidant capacity (TEAC), were assessed at baseline and 5, 15 and 45min after PAF and L-PAF (18μg each) bronchoprovocation. Urinary leukotriene E4 (uLTE4) elimination was measured 120min after challenge.Compared with baseline, as expected, PAF increased significantly Rrs and AaPO2 and decreased PaO2 and peripheral blood neutrophils along with a rebound neutrophilia and increased uLTE4. By contrast, markers of systemic oxidative stress remained unaltered throughout the study. Unlike PAF, L-PAF-induced changes were negligible.We conclude that there is no systemic oxidant–antioxidant imbalance during acute bronchoconstriction induced by PAF in these patients with mild asthma