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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-kB (NF-kB). 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-kB 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.

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 antiinflammatory 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-kB (NF-kB) activity in sputum macrophages, the concentration of nitric oxide in exhaled air (eNO) and total antioxidant status (TAS), tumour necrosis factor a (TNFa), interleukin (IL)-6 and IL8 levels in sputum supernatants were measured. Results: Patients receiving standard therapy showed decreased NF-kB activity, eNO concentration and sputum levels of TNFa, 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 TNFa concentrations. Conclusions: During ECOPD, low-dose theophylline increases HDAC activity and improves the anti-inflammatory effects of steroids. Trial registration number: NCT00671151Chronic obstructive pulmonary disease (COPD) is characterised by an enhanced inflammatory response to inhaled particles and gases, mostly cigarette smoking. 1 We have previously shown that the activity of histone deacetylases (HDAC) is decreased in patients with stable COPD, and that this can contribute to the abnormal inflammatory response that characterises the disease. 2 3 Patients with COPD often experience acute episodes of exacerbation (ECOPD) during the course of their disease. These episodes are characterised by nuclear factor-kB (NF-kB) activation 4 5 and a burst of airway inflammation, with increased oxidative and nitrative stress, 6 7 increased neutrophil counts and raised levels of several proinflammatory cytokines such as tumour necrosis factor a (TNFa) and interleukin-8 (IL8) and IL6. [8][9][10] Because both oxidative 11 and nitrative stress 12 can impair HDAC function, we hypothesised that HDAC activity will be further reduced during ECOPD, thus contributing to amplify baseline inflammation.Current international guidelines recommend the use of high-dose oral or intravenous steroids (in combination with inhaled bronchodilators) for the treatment of ECOPD. 1 Low concentrations of theophylline enhance HDAC activity and have anti-inflammatory effects, both in asthma and COPD, [13][14][15] that have been shown to add clinical ...

BackgroundPulmonary abnormalities are often present in patients infected with the human immunodeficiency virus (HIV). ObjectivesThe aim of the study was to determine the prevalence and characteristics of, and risk factors for, pulmonary abnormalities in HIV-positive patients. MethodsA total of 275 HIV-positive patients [mean (± standard deviation) age 48.5 ± 6.6 years] were included in the study, of whom 95.6% had been receiving highly active antiretroviral therapy (HAART) for a mean (± standard deviation) duration of 11.9 ± 5.4 years. The median (interquartile range) CD4 lymphocyte count was 541 (392-813) cells/μL, and 92% of the patients had an undetectable viral load. We determined: (1) spirometry, static lung volumes, lung diffusing capacity, pulmonary gas exchange and exercise tolerance, and (2) the amount of emphysema via a computed tomography (CT) scan. ResultsChronic cough and expectoration (47%) and breathlessness during exercise (33.9%) were commonly reported. Airflow limitation (AL) was present in 17.2%, low pulmonary diffusing capacity in 52.2% and emphysema in 10.5−37.7% of patients, depending on the method used for quantification. Most of these abnormalities had not been diagnosed or treated previously. Smoking exposure and previous tuberculosis were the main risk factors for AL, whereas smoking exposure and several variables related to HIV infection appeared to contribute to the risk of emphysema and low diffusing capacity. ConclusionsDespite HAART, pulmonary structural and functional abnormalities are frequent in HIV-positive patients. They are probably attributable to both environmental (smoking and tuberculosis) and HIV-related factors. Most of these abnormalities remain unnoticed and untreated. Given the relatively young age of these patients, these results anticipate a significant health problem in the next few years as, thanks to the efficacy of HAART, patients survive longer and experience the effects of aging.Keywords: airflow limitation, chronic obstructive pulmonary disease, emphysema, HIV, tuberculosis, smoking IntroductionAIDS remains a challenge for health care systems around the world as a consequence of its health and also its social impact [1,2]. During the early years of the pandemic, Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia, tuberculosis, bacterial pneumonia and Kaposi's sarcoma were the major causes of morbidity and mortality [3]. The introduction of highly active antiretroviral therapy (HAART) considerably improved the prognosis and quality of life of HIV-infected patients [4,5]. Previous studies have identified a high prevalence of airflow limitation (AL) and pulmonary emphysema in patients infected with HIV [6][7][8][9][10][11][12][13][14][15]. Yet, lung function assessment has not been included in large multicentre studies aimed at characterizing events not directly related to HIV infection in these patients [16,17]. Lung function testing is also not normally considered part of the routine clinical assessment of these patients, despite the availabili...

Cardiovascular morbidity and mortality is increased in patients with chronic obstructive pulmonary disease (COPD). Reduced levels of circulating endothelial progenitor cells (EPCs) are associated with increased risk of death in patients with stable coronary artery disease (CAD). Likewise, during acute events of CAD, the number of circulating EPCs increases under the influence of vascular endothelial growth factor (VEGF) and systemic inflammation. Abnormal levels of circulating EPCs have been reported in patients with COPD. However, the response of EPCs to episodes of exacerbation of the disease (ECOPD) has not been investigated yet. We hypothesized that similar to what occurs during acute events of CAD, levels of circulating EPCs would increase during ECOPD. We compared levels of circulating EPCs (assessed by the % of CD34(+)KDR(+) cells determined by flow cytometry) in patients hospitalized because of ECOPD (n = 35; 65 +/- 9 years [mean +/- SD]; FEV(1) = 46 +/- 15% predicted), patients with stable COPD (n = 44; 68 +/- 8 years; FEV(1) = 49 +/- 17% predicted), smokers with normal lung function (n = 10; 60 +/- 9 years), and healthy never smokers (n = 10; 62 +/- 4 years). To investigate potential mechanisms of EPC regulation, we assessed both VEGF and high-sensitivity C-reactive protein (hsC-RP) in plasma. Our results show that EPC levels were higher (p < 0.05) in patients with ECOPD (1.46 +/- 1.63%) than in those with stable disease (0.68 +/- 0.83%), healthy smokers (0.65 +/- 1.11%), and healthy never smokers (1.05 +/- 1.36%). The percentage of circulating EPCs was positively related to VEGF plasma levels during ECOPD (r = 0.51, p = 0.003). In a subset of 12 patients who could be studied during both ECOPD and clinical stability, the EPCs levels increased during ECOPD. We conclude that EPC levels are increased during ECOPD, likely in relation to VEGF upregulation.