Amanda Iglesias

Low-dose theophylline enhances the anti- inflammatory effects of steroids during exacerbations of COPD

Background: Chronic obstructive pulmonary disease (COPD) is characterised by an abnormal inflammatory response mainly to cigarette smoke that flares up during exacerbations of the disease (ECOPD). Reduced activity of histone deacetylases (HDAC) contributes to enhanced inflammation in stable COPD. It was hypothesised that HDAC activity is further reduced during ECOPD and that theophylline, an HDAC activator, potentiates the anti-inflammatory effect of steroids in these patients. A study was performed to investigate HDAC activity during ECOPD and the effects of theophylline on the anti-inflammatory effects of steroids in a randomised single-blind controlled study. Methods: 35 patients hospitalised with ECOPD and treated according to international guidelines (including systemic steroids) were randomised to receive or not to receive low-dose oral theophylline (100 mg twice daily). Before treatment and 3 months after discharge, HDAC and nuclear factor-κB (NF-κB) activity in sputum macrophages, the concentration of nitric oxide in exhaled air (eNO) and total antioxidant status (TAS), tumour necrosis factor α (TNFα), interleukin (IL)-6 and IL8 levels in sputum supernatants were measured. Results: Patients receiving standard therapy showed decreased NF-κB activity, eNO concentration and sputum levels of TNFα, IL6 and IL8, as well as increased TAS during recovery of ECOPD, but HDAC activity did not change. The addition of low-dose theophylline increased HDAC activity and further reduced IL8 and TNFα concentrations. Conclusions: During ECOPD, low-dose theophylline increases HDAC activity and improves the anti-inflammatory effects of steroids. Trial registration number: NCT00671151

Molecular Mechanisms of Inflammation During Exacerbations of Chronic Obstructive Pulmonary Disease

Abstract Introduction Exacerbations of chronic obstructive pulmonary disease (COPD) are characterised by an inflammatory and systemic response that persists for some time after their clinical resolution. The mechanisms of this inflammatory process are not well known. Objectives To explore the inflammatory changes and possible mechanisms during COPD exacerbation. Methods We determined the inflammatory cell concentrations in blood and sputum, nitric oxide in exhaled air (FeNO), C-reactive protein (CRP) in plasma, cytokines (IL-6, 8, 1β, 10, 12, TNF-α) and SLPI (leukocyte protease inhibitor) and total antioxidant status (TAS) in blood and sputum, the activity of nuclear kappa B factor (NF-κ B) and of the histone deacetylase enzyme (HDAC) in 17 patients during COPD exacerbation and in stable phase, as well as in 17 smoker and 11 non-smoker controls. Results COPD exacerbations are characterised by high levels of FeNO (p Conclusions Changes were observed in different pulmonary and systemic inflammatory markers during COPD exacerbation, which did not completely resolve during stable phase. However, current treatment does not allow for HDAC activity to be modified, which limits its anti-inflammatory effects.

Prevalence of and risk factors for pulmonary abnormalities in HIV‐infected patients treated with antiretroviral therapy

Pulmonary abnormalities are often present in patients infected with the human immunodeficiency virus (HIV).

Mecanismos moleculares de inflamación durante las agudizaciones de la enfermedad pulmonar obstructiva crónica

INTRODUCTION Exacerbations of chronic obstructive pulmonary disease (COPD) are characterised by an inflammatory and systemic response that persists for some time after their clinical resolution. The mechanisms of this inflammatory process are not well known. OBJECTIVES To explore the inflammatory changes and possible mechanisms during COPD exacerbation. METHODS We determined the inflammatory cell concentrations in blood and sputum, nitric oxide in exhaled air (FeNO), C-reactive protein (CRP) in plasma, cytokines (IL-6, 8, 1β, 10, 12, TNF-α) and SLPI (leukocyte protease inhibitor) and total antioxidant status (TAS) in blood and sputum, the activity of nuclear kappa B factor (NF-κ B) and of the histone deacetylase enzyme (HDAC) in 17 patients during COPD exacerbation and in stable phase, as well as in 17 smoker and 11 non-smoker controls. RESULTS COPD exacerbations are characterised by high levels of FeNO (p<0.05), plasma CRP (p<0.001) and IL-8, IL-1B, IL-10 in sputum (p<0.05) greater activation of NF-κ appaB in sputum macrophages compared with stable COPD and controls. During the stable phase, there continue to be high levels of oxidative stress, SLPI, IL-8, IL-6 and TNF-alfa, with no observed changes in either HDAC activity or in the amount of neutrophils in sputum, despite presenting a significant improvement (p<0.05) in lung function. CONCLUSIONS Changes were observed in different pulmonary and systemic inflammatory markers during COPD exacerbation, which did not completely resolve during stable phase. However, current treatment does not allow for HDAC activity to be modified, which limits its anti-inflammatory effects.

B Cell–Activating Factor. An Orchestrator of Lymphoid Follicles in Severe Chronic Obstructive Pulmonary Disease

RATIONALE Patients with chronic obstructive pulmonary disease (COPD) have increased pulmonary lymphoid follicle (LF) counts. B cell-activating factor of tumor necrosis factor family (BAFF) regulates B cells in health, but its role in COPD pathogenesis is unclear. OBJECTIVES To determine whether BAFF expression in pulmonary LFs correlates with COPD severity, LF size or number, and/or readouts of B-cell function in LFs. METHODS We correlated BAFF immunostaining in LFs in lung explants or biopsies from nonsmoking control subjects (NSC), smokers without COPD (SC), and patients with COPD with the number and size of LFs, and LF B-cell apoptosis, activation, and proliferation. We analyzed serum BAFF levels and BAFF expression in B cells in blood and bronchoalveolar lavage samples from the same subject groups. We assessed whether: (1) cigarette smoke extract (CSE) increases B-cell BAFF expression and (2) recombinant BAFF (rBAFF) rescues B cells from CSE-induced apoptosis by inhibiting activation of nuclear factor-κB (NF-κB). MEASUREMENTS AND MAIN RESULTS Patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage IV COPD had increased numbers and larger pulmonary LFs than patients with GOLD stages I-II COPD and SC. We identified two main types of pulmonary LFs: (1) type A, the predominant type in GOLD stages I-II COPD and SC, characterized by abundant apoptotic but few BAFF-positive cells (mostly B cells); and (2) type B, the main type in GOLD stage IV COPD, characterized by abundant BAFF-positive cells but few apoptotic cells (mostly B cells). BAFF levels were also higher in blood and bronchoalveolar lavage B cells in patients with COPD versus NSC and SC. Surprisingly, rBAFF blocked CSE-induced B-cell apoptosis by inhibiting CSE-induced NF-κB activation. CONCLUSIONS Our data support the hypothesis that B-cell BAFF expression creates a self-perpetuating loop contributing to COPD progression by promoting pulmonary B-cell survival and LF expansion.

Differential effects of smoking and COPD upon circulating myeloid derived suppressor cells

BACKGROUND Chronic obstructive pulmonary disease (COPD) is characterized by an enhanced and persistent innate and acquired immune response to tobacco smoking. Myeloid-derived suppressor cells (MDSCs) modulate T-cell responses by down-modulating the T cell receptor ζ chain (TCR ζ) through the catabolism of l-arginine. The effects of smoking on MDSCs and their potential participation in COPD immunopathogenesis have not been explored so far. METHODS To investigate it, we compared the level of circulating Lineage-/HLA-DR-/CD33+/CD11b+ MDSCs, the serum concentration of arginase I (ARG I) and the expression of peripheral T-cell receptor ζ chain (TCR ζ) in never smokers, smokers with normal spirometry and COPD patients. Flow cytometry was used to quantify circulating MDSCs and TCR ζ expression. Serum ARG I levels were determined by ELISA. RESULTS The main findings of this study were that: (1) current smoking upregulates and activates circulating MDSCs both in smoker controls and COPD patients; and, (2) at variance with the smokers with normal spirometry, in patients with COPD this effect persists after quitting smoking and is accompanied by a significant and specific down-regulation of the TCR ζ chain expression in circulating T lymphocytes. CONCLUSION Smoking modulates circulating MDSCs. Their regulation appears altered in patients with COPD.

Reduced Expression of the Sarcoplasmic Calcium Pump SERCA2 in Skeletal Muscle From Patients With Chronic Obstructive Pulmonary Disease and Low Body Weight

OBJECTIVE To compare the concentrations and extent of nitration of sarcoplasmic-endoplasmic reticulum Ca(2+) adenosine triphosphatase 2 (SERCA2) in biopsies of the quadriceps femoris from patients with chronic obstructive pulmonary disease (COPD) who have normal or low body mass index (BMI). PATIENTS AND METHODS The patients were divided into 2 groups (n=7, each group), one containing individuals with normal BMI (> 21 kg/m(2)) and the other with low BMI (< 21 kg/m(2)). Forced spirometry and blood gas analysis were performed in both groups and percutaneous needle biopsies of the lateral portion of the quadriceps femoris muscle were performed. Western blots were used to assess the concentration of SERCA2 in the biopsy material. To determine whether or not the protein was tyrosine-nitrated, immunoprecipitation of SERCA2 was performed with an antinitrotyrosine antibody followed by Western blotting to determine the concentration of the tyrosine-nitrated protein. RESULTS Expression of SERCA2 was significantly lower in patients with low BMI (4.2 [0.5] vs 8.1 [1.2] integrated optical density units, P < .05). SERCA2 was also tyrosine-nitrated in the patients with low BMI. Finally, a significant negative correlation was observed between the concentration of SERCA2 and that of inducible nitric oxide synthase (determined in a previous study using the same biopsy material) in patients with COPD and low BMI (r=-0.89, P=.007), while such a correlation was not observed in patients with COPD and normal BMI (r=0.35, P=.43). CONCLUSIONS In patients with COPD, SERCA2 concentration is reduced and the protein is tyrosine-nitrated in skeletal muscle from patients with low BMI compared to those with normal BMI. These results indicate the presence of a previously unrecognized cellular alteration in skeletal muscle from patients with COPD and low muscle weight.

Haemophilus influenzae induces steroid-resistant inflammatory responses in COPD.

BackgroundChronic obstructive pulmonary disease (COPD) is an inflammatory disorder partially resistant to glucocorticoids. A reduced histone deacetylase (HDAC) activity has been proposed to explain this resistance. Haemophilus influenzae frequently colonizes the airways of COPD patients, where it enhances inflammation. The effects of Haemophilus influenzae on HDAC activity have not been investigated before.MethodsThe effects of the presence or absence of Haemophilus influenzae ex-vivo and in vitro were studied. To this end, we determined: (1) cytokine release in alveolar macrophages (AM) from 7 patients with COPD, 5 healthy smokers, 6 healthy non-smokers and (2) HDAC activity, nuclear factor kappa B (NF-κB) activation in a macrophage-like cell line (PMA-transformed U937 cells) co-cultured with epithelial cells. Experiments were repeated with dexamethasone (1 μM) and/or the HDAC enhancer theophylline (10 μM).ResultsHaemophilus influenzae induced a steroid-resistant inflammatory response in AM from COPD and controls and decreased HDAC activity, activated NF-κB and induced the secretion of several cytokines (IL-6, IL-8, IL-1β, IL-10 and TNF-α) (p < 0.001 for all comparisons) in the macrophage-like cell line. Dexamethasone reduced NF-κB activation but it did not modify HDAC activity. The addition of theophylline to dexamethasone increased HDAC activity and suppressed cytokine release completely, without modifying NF-κB activation.ConclusionsThese results indicate that Haemophilus influenzae reduces HDAC activity and induces a NF-κB mediated inflammatory response that is only partially suppressed by glucocorticoids irrespective of having COPD. Yet, the latter can be fully restored by targeting HDAC activity.

Mixed Th2 and non-Th2 inflammatory pattern in the asthma–COPD overlap: a network approach

Introduction The asthma–chronic obstructive pulmonary disease (COPD) overlap (ACO) is a clinical condition that combines features of those two diseases, and that is difficult to define due to the lack of understanding of the underlying mechanisms. Determining systemic mediators may help clarify the nature of inflammation in patients with ACO. Objectives We aimed at investigating the role and interaction of common markers of systemic inflammation (IL-6, IL-8, and tumor necrosis factor-α), Th2-related markers (periostin, IL-5, and IL-13), and IL-17 in asthma, COPD, and ACO. Methods This is a cross-sectional study of patients aged ≥40 years with a post-bronchodilator forced expiratory volume in the first second/forced vital capacity <0.70 recruited from outpatient clinics in tertiary hospitals with a clinical diagnosis of asthma, COPD, or ACO. ACO was defined by a history of smoking >10 pack-years in a patient with a previous diagnosis of asthma or by the presence of eosinophilia in a patient with a previous diagnosis of COPD. Clinical, functional, and inflammatory parameters were compared between categories using discriminant and network analysis. Results In total, 109 ACO, 89 COPD, and 94 asthma patients were included. Serum levels (median [interquartile range]) of IL-5 were higher in asthma patients than in COPD patients (2.09 [0.61–3.57] vs 1.11 [0.12–2.42] pg/mL, respectively; p=0.03), and IL-8 levels (median [interquartile range]) were higher in COPD patients than in asthma patients (9.45 [6.61–13.12] vs 7.03 [4.69–10.44] pg/mL, respectively; p<0.001). Their values in ACO were intermediate between those in asthma and in COPD. Principal component and network analysis showed a mixed inflammatory pattern in ACO in between asthma and COPD. IL-13 was the most connected node in the network, with different weights among the three conditions. Conclusion Asthma and COPD are two different inflammatory conditions that may overlap in some patients, leading to a mixed inflammatory pattern. IL-13 could be central to the regulation of inflammation in these conditions.

Effects of simvastatin in chronic obstructive pulmonary disease: Results of a pilot, randomized, placebo-controlled clinical trial

Introduction Statins may have pleiotropic effects in COPD, but mechanisms remain unclear. Objectives To assess the pleiotropic effect of statins in patients with stable COPD on (1): lung function (2); pulmonary and systemic inflammation (3); endothelial function (vascular stiffness) and circulating vascular growth factors; and (4), serum uric acid levels. Method Pilot, double-blind, randomized, placebo-controlled clinical trial in 24 patients with stable COPD, all statin-naïve, who were randomized (1:1) to receive simvastatin 40 mg/24 h during 12 weeks (n = 12; 69.0 ± 7.3 years; post-bd FEV1 53.4 ± 10.0% pred.) or placebo (n = 12; 66.4 ± 4.6 years; post-bd FEV1 48.2 ± 12.6% pred.). Nine patients per group (total n = 18) completed the study. Results Lung function, pulmonary and systemic inflammatory markers and the degree of vascular stiffness did not change significantly in any group. However, treatment with simvastatin increased the plasma levels of erythropoietin (Epo) (4.2 ± 2.2 mIU/mL to 6.8 ± 3.2 mlU/mL, p < 0.05) and reduced those of serum uric acid (7.1 ± 1.3 mg/dL to 6.5 ± 1.4 mg/dL, p < 0.01). Conclusions Short-term treatment with simvastatin in stable COPD patients did not modify lung function, pulmonary and systemic inflammation, or vascular stiffness, but it changed Epo and uric acid levels.