Autoantibodies of IgM and IgG classes show differences in recognition of multiple autoantigens in chronic obstructive pulmonary disease.

Autoimmunity occurs in chronic obstructive pulmonary disease (COPD). We describe an antigen microarray for detecting serum autoantibodies (AAbs) to determine how IgM, as well as IgG, AAbs distinguish patients with COPD from controls with a history of smoking without COPD. All COPD patients' sera contained elevated levels of AAbs to some of 30 autoantigens. There were significant differences in the autoantigenic specificities of IgM AAbs compared to IgG AAbs in the COPD sera: for example, AAbs to histone and scl-70 were mainly IgG, whereas AAbs to CENP-B and La/ssB were mainly IgM; by contrast, IgM and IgG AAbs to collagen-V were equally prevalent. Thus, a combination of IgM and IgG AAbs specific for multiple autoantigens are detected in all cases of COPD at a level at which all non-COPD controls are negative for AAbs. This highlights the importance of different classes of AAbs to a range of autoantigens in COPD.

Matrix Metalloproteinase-1 Activation Contributes to Airway Smooth Muscle Growth and Asthma Severity.

RATIONALE: Matrix metalloproteinase-1 (MMP-1) and mast cells are present in the airways of people with asthma. OBJECTIVES: To investigate whether MMP-1 could be activated by mast cells and increase asthma severity. METHODS: Patients with stable asthma and healthy control subjects underwent spirometry, methacholine challenge, and bronchoscopy, and their airway smooth muscle cells were grown in culture. A second asthma group and control subjects had symptom scores, spirometry, and bronchoalveolar lavage before and after rhinovirus-induced asthma exacerbations. Extracellular matrix was prepared from decellularized airway smooth muscle cultures. MMP-1 protein and activity were assessed. MEASUREMENTS AND MAIN RESULTS: Airway smooth muscle cells generated pro-MMP-1, which was proteolytically activated by mast cell tryptase. Airway smooth muscle treated with activated mast cell supernatants produced extracellular matrix, which enhanced subsequent airway smooth muscle growth by 1.5-fold (P < 0.05), which was dependent on MMP-1 activation. In asthma, airway pro-MMP-1 was 5.4-fold higher than control subjects (P = 0.002). Mast cell numbers were associated with airway smooth muscle proliferation and MMP-1 protein associated with bronchial hyperresponsiveness. During exacerbations, MMP-1 activity increased and was associated with fall in FEV1 and worsening asthma symptoms. CONCLUSIONS: MMP-1 is activated by mast cell tryptase resulting in a proproliferative extracellular matrix. In asthma, mast cells are associated with airway smooth muscle growth, MMP-1 levels are associated with bronchial hyperresponsiveness, and MMP-1 activation are associated with exacerbation severity. Our findings suggest that airway smooth muscle/mast cell interactions contribute to asthma severity by transiently increasing MMP activation, airway smooth muscle growth, and airway responsiveness.

Cardiovascular and inflammatory effects of simvastatin therapy in patients with COPD: a randomized controlled trial.

BACKGROUND: There is excess cardiovascular mortality in patients with chronic obstructive pulmonary disease. Aortic stiffness, an independent predictor of cardiovascular risk, and systemic and airway inflammation are increased in patients with the disease. Statins modulate aortic stiffness and have anti-inflammatory properties. A proof-of-principle, double-blind, randomized trial determined if 6 weeks of simvastatin 20 mg once daily reduced aortic stiffness and systemic and airway inflammation in patients with chronic obstructive pulmonary disease. METHODS: Stable patients (n=70) were randomized to simvastatin (active) or placebo. Pre-treatment and post-treatment aortic stiffness, blood pressure, spirometry, and circulating and airway inflammatory mediators and lipids were measured. A predefined subgroup analysis was performed where baseline aortic pulse wave velocity (PWV) was >10 m/sec. RESULTS: Total cholesterol dropped in the active group. There was no significant change in aortic PWV between the active group and the placebo group (-0.7 m/sec, P=0.24). In those with aortic stiffness >10 m/sec (n=22), aortic PWV improved in the active group compared with the placebo group (-2.8 m/sec, P=0.03). Neither systemic nor airway inflammatory markers changed. CONCLUSION: There was a nonsignificant improvement in aortic PWV in those taking simvastatin 20 mg compared with placebo, but in those with higher baseline aortic stiffness (a higher risk group) a significant and clinically relevant reduction in PWV was shown.

Inhaled corticosteroids and the risk of pneumonia in people with asthma: a case-control study.

BACKGROUND: In clinical trials, the use of inhaled corticosteroids is associated with an increased risk of pneumonia in people with COPD, but whether the same is true for people with asthma is not known. METHODS: With the use of primary care data from The Health Improvement Network, we identified people with asthma, and from this cohort, we identified patients with pneumonia or lower respiratory tract infection and age- and sex-matched control subjects. Conditional logistic regression was used to determine the association between the dose and type of inhaled corticosteroid and the risk of pneumonia or lower respiratory tract infection. RESULTS: A dose-response relationship was found between the strength of inhaled corticosteroid dose and risk of pneumonia or lower respiratory tract infection (P < .001 for trend) such that after adjusting for confounders, people receiving the highest strength of inhaled corticosteroid (≥ 1,000 µg) had a 2.04 (95% CI, 1.59-2.64) increased risk of pneumonia or lower respiratory tract infection compared with those with asthma who did not have a prescription for inhaled corticosteroids within the previous 90 days. CONCLUSIONS: People with asthma receiving inhaled corticosteroids are at an increased risk of pneumonia or lower respiratory infection, with those receiving higher doses being at greater risk. Pneumonia should be considered as a possible side effect of inhaled corticosteroids, and the lowest possible dose of inhaled corticosteroids should be used in the management of asthma.

Systemic and bronchodilator effects of inhaled rac-formoterol in subjects with chronic obstructive pulmonary disease: a dose-response study.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The long-acting inhaled beta(2)-agonist formoterol has systemic effects when taken in high doses. It can be used as relief medication in asthma and there is interest in this approach in chronic obstructive pulmonary disease (COPD). Relief medication can involve high doses, and in subjects with COPD who have limited ability to bronchodilate the adverse effects can outweigh the benefits. There are concerns with the overall safety of high-dose beta(2)-agonists in subjects with COPD, and this study looks at the balance of beneficial and adverse effects of a range of doses of inhaled formoterol. WHAT THIS STUDY ADDS: Among subjects with COPD, high-dose inhaled formoterol produced a dose-related increase in forced expiratory volume in 1 s without a corresponding reduction in dyspnoea or increase in walk distance. Systemic effects were modest, however, and high doses did not appear to reduce patient satisfaction. Although further safety data are needed, inhaled formoterol may have a role as relief medication in COPD. AIMS Rac-formoterol is effective as maintenance treatment for both asthma and chronic obstructive pulmonary disease (COPD) and is now used as relief therapy in asthma. Using rac-formoterol for relief and maintenance treatment could involve inhalation of high doses, and whether this is of benefit in COPD is uncertain. Our aim was to determine whether higher doses of inhaled rac-formoterol produce systemic adverse effects that outweigh the limited bronchodilator benefit seen in subjects with COPD. METHODS: We examined airway and systemic effects of 6, 12, 24 and 48 microg rac-formoterol and placebo on separate days in 20 subjects with symptomatic COPD [forced expiratory volume in 1 s (FEV(1)) 47% predicted]. FEV(1), oxygen saturation, dyspnoea, 6-min walk distance, patient satisfaction and systemic effects were measured and treatment was assessed against placebo and for dose-response effects. RESULTS: FEV(1)[area under the time-response curve (AUC)] and satisfaction scores increased with all formoterol doses compared with placebo, as did AUC tremor with the 24- and 48-microg doses and AUC heart rate with the 48-microg dose. A dose-response relationship was seen with FEV(1) and tremor, but not with satisfaction scores. There was no difference between placebo and rac-formoterol for other variables. CONCLUSIONS: Our results show that in patients with COPD rac-formoterol improves FEV(1) and patient satisfaction without a corresponding reduction in dyspnoea. Since the systemic effects from a relatively high dose were minimal, its use as relief medication in COPD merits further evaluation.

Poor adherence with inhaled corticosteroids for asthma: can using a single inhaler containing budesonide and formoterol help?

BACKGROUND: Poor adherence with inhaled corticosteroids is an important problem in asthma management. Previous approaches to improving adherence have had limited success. AIM: To determine whether treatment with a single inhaler containing a long-acting beta(2)-agonist and a corticosteroid for maintenance treatment and symptom relief can overcome the problem of poor adherence with inhaled corticosteroids. DESIGN OF STUDY: Randomised, parallel group, open-label trial. SETTING: Forty-four general practices in Nottinghamshire. METHOD: Participants who used less than 70% of their prescribed dose of inhaled corticosteroid and had poorly controlled asthma were randomised to budesonide 200 microg one puff twice daily plus their own short-acting beta(2)-agonist as required (control group), or budesonide/formoterol 200/6 microg one puff once daily and as required (active group) for 6 months. The primary outcome was inhaled corticosteroid dose. RESULTS: Seventy-one participants (35 control, 36 active group) were randomised. Adherence with budesonide in the control group was approximately 60% of the prescribed dose. Participants in the active group used approximately 80% more budesonide than participants in the control group (448 versus 252 microg/day, mean difference 196 mug, 95% confidence interval 113 to 279; P<0.001) and were less likely to withdraw from the study (3 versus 13; P<0.01). No safety issues were identified. CONCLUSION: Using a single inhaler for both maintenance treatment and symptom relief approximately doubled the dose of inhaled corticosteroid taken, suggesting this could be a useful strategy to overcome the problems related to poor adherence with inhaled corticosteroids.

Effects of rac-albuterol on arterial blood gases in patients with stable hypercapnic chronic obstructive pulmonary disease.

AIMS: Many patients with chronic obstructive pulmonary disease (COPD) are treated with high dose beta(2)-adrenoceptor agonists, which can increase ventilation/perfusion mismatching, and tremor and cardiac output, thereby increasing oxygen uptake and carbon dioxide output (VCO(2)). Patients with severe COPD and hypercapnia may be unable to increase ventilation in response to increased VCO(2), in which case arterial carbon dioxide tension (P(a)CO(2)) may rise. Our aim was to determine whether high dose nebulized rac-albuterol could increase P(a)CO(2) in patients with COPD, limited bronchodilator reversibilty and hypercapnia. METHODS: We compared 10 mg and 400 microg rac-albuterol, given in two doses 1 h apart on nonconsecutive days, in a double-blind randomized crossover study in 14 patients with severe COPD. P(a)CO(2), arterial oxygen tension (P(a)O(2)) and heart rate were measured over 120 min and change from baseline was plotted against time to obtain an area under the curve. RESULTS: Mean P(a)CO(2) fell slightly over 120 min, with no difference between treatments (0.03 kPa h(-1) (95% confidence interval 0.02, 0.04)) and only three subjects had an increase in P(a)CO(2) after high dose rac-albuterol. High dose rac-albuterol caused a greater fall in P(a)O(2)[0.1 kPa h(-1) (95% confidence interval 0, 0.2)] and increase in heart rate than the low dose, although the differences were small. CONCLUSIONS: Under stable conditions most subjects with severe COPD and hypercapnia will have a fall in P(a)CO(2) and P(a)O(2) following 10 mg rac-albuterol, suggesting that they maintain capacity to respond to any increase in VCO(2) and prevent a rise in P(a)CO(2).