Paul Stoll

Extracellular Adenosine Triphosphate and Chronic Obstructive Pulmonary Disease

RATIONALE Extracellular ATP promotes inflammation, but its role in chronic obstructive pulmonary disease (COPD) is unknown. OBJECTIVES To analyze the expression of ATP and its functional consequences in never-smokers, asymptomatic smokers, and patients with COPD. METHODS ATP was quantified in bronchoalveolar lavage fluid (BALF) of never-smokers, asymptomatic smokers, and patients with COPD of different severity. The expression of specific ATP (purinergic) receptors was measured in airway macrophages and blood neutrophils from control subjects and patients with COPD. The release of mediators by macrophages and neutrophils and neutrophil chemotaxis was assessed after ATP stimulation. MEASUREMENTS AND MAIN RESULTS Chronic smokers had elevated ATP concentrations in BALF compared with never-smokers. Acute smoke exposure led to a further increase in endobronchial ATP concentrations. Highest ATP concentrations in BALF were present in smokers and ex-smokers with COPD. In patients with COPD, BALF ATP concentrations correlated negatively with lung function and positively with BALF neutrophil counts. ATP induced a stronger chemotaxis and a stronger elastase release in blood neutrophils from patients with COPD, as compared with control subjects. In addition, airway macrophages from patients with COPD responded with an increased secretion of proinflammatory and tissue-degrading mediators after ATP stimulation. These findings were accompanied by an up-regulation of specific purinergic receptors in blood neutrophils and airway macrophages of patients with COPD. CONCLUSIONS COPD is characterized by a strong and persistent up-regulation of extracellular ATP in the airways. Extracellular ATP appears to contribute to the pathogenesis of COPD by promoting inflammation and tissue degradation.

Acute effects of tobacco smoke on human airway dendritic cells in vivo

Airway dendritic cells (DCs) play a key role in smoke-related lung diseases; however, the acute effects of tobacco smoke on human airway DCs in vivo are unknown. A total of 16 smokers underwent bronchoalveolar lavage at two time-points: directly after a 4-h period of nonsmoking (no smoke exposure); and directly after a 4-h period during which eight cigarettes were smoked (acute smoke exposure). Using flow cytometry, myeloid DCs (mDCs) and plasmacytoid DCs (pDCs), as well as function-associated surface molecules on mDCs, were analysed in bronchoalveolar lavage fluid (BALF) and in blood. The numbers of macrophages, lymphocytes, neutrophils, eosinophils and pDCs were unchanged in BALF following acute smoke exposure, as compared to no smoke exposure. In contrast, there was a strong increase in mDC number in BALF and a concomitant decrease in mDC number in blood following acute smoke exposure. In addition, acute smoke exposure led to an increase in the expression of the surface molecules blood dendritic cell antigen 1 and 4 and a decrease in the expression of the lung homing receptor, CC chemokine receptor 5, on mDCs in BALF. Acute tobacco smoke inhalation results in an immediate and selective recruitment of mDCs into human airways, which might reflect the very early reaction of the adaptive immune system to smoke exposure.

Regulation of brain-derived neurotrophic factor (BDNF) during sleep apnoea treatment

Background: Patients with obstructive sleep apnoea syndrome (OSAS) often display persistent cognitive dysfunction despite effective treatment with continuous positive airway pressure (CPAP). Brain-derived neurotrophic factor (BDNF) is a key mediator of memory and cognition, but its regulation in OSAS and during CPAP treatment is unknown. Methods: Serum and plasma BDNF concentrations, BDNF secretion by peripheral blood mononuclear cells, and overnight polysomnography were evaluated in 17 men with newly diagnosed OSAS (as defined by a respiratory disturbance index of >10/hour with >70% obstructive events and corresponding daytime symptoms) and 12 healthy control men. In the patients all the parameters were monitored after 1 night and 3 months of CPAP treatment. Results: There was no significant difference in baseline serum BDNF, plasma BDNF, or spontaneous BDNF secretion by peripheral blood mononuclear cells between untreated patients and controls. After 1 night of CPAP treatment there was a steep fall in median serum BDNF (from 18.0 ng/ml to 4.1 ng/ml) and plasma BDNF (from 58.7 pg/ml to 22.0 pg/ml) concentrations. Following 3 months of treatment BDNF concentrations did not return to baseline. In contrast, BDNF secretion was not suppressed by CPAP treatment. Conclusions: Patients with untreated OSAS have normal serum and plasma BDNF levels. CPAP treatment is associated with a rapid decrease in serum and plasma BDNF levels which may reflect enhanced neuronal demand for BDNF in this condition.

Differential effect of clopidogrel and aspirin on the release of BDNF from platelets.

Anti-platelet treatment is a key therapeutic intervention in patients with cerebrovascular diseases. However, there is no information on its impact on the release of Brain-derived neurotrophic factor (BDNF), which is stored in large amounts in human platelets and essential for neuronal protection and repair. Here, we show that a single oral dose of clopidogrel, but not aspirin, significantly reduced the release of BDNF from platelets in healthy volunteers. These data point, for the first time, to possible differential effects of anti-platelet regimens on neuronal function in patients with cerebrovascular disorders.

Stage-dependent association of BDNF and TGF-β1 with lung function in stable COPD

BackgroundChronic Obstructive Pulmonary Disease (COPD) is characterised by complex inflammatory, neuronal and fibrotic changes. Brain-derived Neurotrophic Factor (BDNF) is a key regulator of neuronal plasticity, whereas Transforming Growth Factor-β1 (TGF-β1) plays a crucial role in tissue repair and emphysema pathogenesis. Both mediators are stored in platelets and released from platelets in inflammatory conditions and during serum preparation. In patients with asthma, it was previously shown that elevated serum BDNF concentrations correlate with disease severity, whereas TGF-β1 concentrations were normal.MethodsIn the present study, 63 patients with stable COPD (spirometric GOLD stages 2–4) and 17 age- and comorbidity-matched controls were studied. Lung function, smoking history, medication, platelet concentrations in peripheral blood and serum concentrations of BDNF, TGF-β1 and Serotonin (5-HT) were assessed in all participants.ResultsSerum levels of both BDNF and TGF-β1 (but not concentrations of platelets in peripheral blood) were significantly elevated in all stages of COPD as compared to controls. Highest BDNF concentrations were found in spirometric GOLD stage 3, whereas highest TGF-β1 serum levels were found in spirometric GOLD stage 4. There were specific, stage-dependent correlations of these mediators with lung function parameters of the patients.ConclusionsTaken together, we show that, in contrast to asthma, COPD is characterised by elevated concentrations of both BDNF and TGF-β1 in serum. The stage-dependent association with lung function supports the hypothesis that these platelet mediators may play a role in the pathogenesis of COPD.

Impact of smoking on dendritic cell phenotypes in the airway lumen of patients with COPD

BackgroundMyeloid dendritic cells (DCs) are increased in the airway wall of patients with chronic obstructive pulmonary disease (COPD), and postulated to play a crucial role in COPD. However, DC phenotypes in COPD are poorly understood.MethodsFunction-associated surface molecules on bronchoalveolar lavage fluid (BALF) DCs were analyzed using flow cytometry in current smokers with COPD, in former smokers with COPD and in never-smoking controls.ResultsMyeloid DCs of current smokers with COPD displayed a significantly increased expression of receptors for antigen recognition such as BDCA-1 or Langerin, as compared with never-smoking controls. In contrast, former smokers with COPD displayed a significantly decreased expression of these receptors, as compared with never-smoking controls. A significantly reduced expression of the maturation marker CD83 on myeloid DCs was found in current smokers with COPD, but not in former smokers with COPD. The chemokine receptor CCR5 on myeloid DCs, which is also important for the uptake and procession of microbial antigens, was strongly reduced in all patients with COPD, independently of the smoking status.ConclusionCOPD is characterized by a strongly reduced CCR5 expression on myeloid DCs in the airway lumen, which might hamper DC interactions with microbial antigens. Further studies are needed to better understand the role of CCR5 in the pathophysiology and microbiology of COPD.

Novel strategies for the treatment of asthma

Novel treatment strategies are currently emerging for patients with inadequately controlled asthma despite good adherence and trigger avoidance. These strategies serve primarily to reduce or completely avoid long-term oral corticosteroid therapy. A number of these options have already been implemented in practice or will soon be authorized for the treatment of asthma, while others still need to prove their clinical practicability, safety and efficacy. The present article provides an overview of the broad spectrum of novel inhaled, oral, systemic, and invasive treatment strategies for asthma.

The dendritic cell high‐affinity IgE receptor is overexpressed in both asthma and severe COPD

The reduction of asthma exacerbations following omalizumab treatment has been related to the suppression of the high‐affinity IgE receptor (FcεRI) on plasmacytoid dendritic cells (DCs). However, the FcεRI expression on DCs in chronic obstructive pulmonary disease (COPD) is unknown.

Platelets in Asthma: Does Size Matter?

activation and an increased release of growth factors such as brain-derived neurotrophic factor (BDNF) [7–11] . On the other hand, platelets from patients with asthma have been postulated to be less responsive to various stimulants such as collagen, adenosine diphosphate (ADP) [12] , platelet-activating factor (PAF) [13] , and arachidonic acid [14] , suggesting that platelets might be ‘exhausted’ as a consequence of chronic activation [15] . Thus, the precise phenotype and role of platelets in patients with asthma are still incompletely understood. In this issue of Respiration, Sun et al. [16] investigate the mean platelet volume (MPV) of 85 patients with stable asthma and of 85 patients with exacerbated asthma and compare the results to those of a group of 85 healthy volunteers matched for age, gender, BMI, and smoking history. The authors show that patients with stable asthma display a significantly lower MPV (10.3 fl) compared to healthy controls (10.7 fl). In patients with an acute exacerbation of asthma, the MPV was even lower (9.8 fl) and correlated negatively with their serum levels of Creactive protein. These results add new evidence to the ongoing discussion on the role and phenotype of platelets in asthma. It might be speculated that ‘exhausted’ platelets are smaller in size due to chronic activation and chronic mediator release. However, the neurotrophin Platelets are anucleated cells which are small in size, simple in structure, and phylogenetically older than leukocytes. Therefore, these cells are often neglected and their function is thought to be limited to hemostasis. However, there is now a growing body of evidence that platelets play an essential role in various inflammatory diseases [1] . The overwhelming number and turnover of these cells in the human body (about 100 billion new platelets are released daily from bone marrow megakaryocytes), the unique ability of platelets to incorporate, store, and release mediators, and the multiple interactions of these cells with leukocytes and endothelial cells led to the concept that platelets are crucial players in the innate and adaptive immune responses of mammals [1] . It is therefore not surprising that there have been major efforts to elucidate the role of platelets in chronic inflammatory diseases such as asthma [2] . Data from animal models of asthma suggest that platelets infiltrate the airway wall after an allergen challenge, either by active migration [3] or by passive migration in platelet-leukocyte aggregates [4] , contributing to airway remodeling [5] and the development of airway hyperresponsiveness [6] . Clinical studies have shown a more complex picture of the platelet in asthma. On the one hand, platelets from patients with asthma are characterized by an increased Published online: May 28, 2014

Impact of an increase in the inhaled corticosteroid dose on blood eosinophils in asthma

Here, we report that increasing treatment with inhaled corticosteroids (ICS) in patients with not well-controlled asthma from a medium to a high dose results in a profound reduction of blood eosinophils (median fall in blood eosinophil concentrations from 560 to 320 cells/µL). Therefore, ‘normal values’ of blood eosinophils in patients with asthma need to be considered in view of the individual ICS doses of the patients. In addition, increases in the dose of ICS may result in blood eosinophil concentrations which would formally preclude treatment with biologics targeting the interleukin-5 pathway.