Airflow Limitation In Asthma Research Articles

Severe asthma in horses is associated with increased airway innervation.

Altered innervation structure and function contribute to airway hyperresponsiveness in human asthma, yet the role of innervation in airflow limitation in asthma in horses remains unknown. To characterize peribronchial innervation in horses with asthma. We hypothesized that airway innervation increases in horses with asthma compared with controls. Formalin-fixed lung samples from 8 horses with severe asthma and 8 healthy horses from the Equine Respiratory Tissue Biobank. Ante-mortem lung function was recorded. Blinded case-control study. Immunohistochemistry was performed using rabbit anti-s100 antibody as a neuronal marker for myelinating and non-myelinating Schwann cells. The number and cumulative area of nerves in the peribronchial region and associated with airway smooth muscle were recorded using histomorphometry and corrected for airway size. Both the number (median [IQR]: 1.87 × 10-5 nerves/μm2 [1.28 × 10-5 ]) and the cumulative nerve area (CNA; 1.03 × 10-3 CNA/μm2 [1.57 × 10-3 ]) were higher in the peribronchial region of horses with asthma compared with controls (5.17 × 10-6 nerves/μm2 [3.76 × 10-6 ], 4.14 × 10-4 CNA/μm2 [2.54 × 10-4 ], Mann-Whitney, P = .01). The number of nerves within or lining airway smooth muscle was significantly higher in horses with asthma (4.47 × 10-6 nerves/μm2 [5.75 × 10-6 ]) compared with controls (2.26 × 10-6 nerves/μm2 [1.16 × 10-6 ], Mann-Whitney, P = .03). Asthma in horses is associated with greater airway innervation, possibly contributing to airway smooth muscle remodeling and exacerbating severity of the disease.

Дисфункція дрібних дихальних шляхів та можливості її корекції при астмі

Abstract. Background. Although randomized controlled trials have shown that asthma control is an achievable goal, real-life studies over the past 20 years have shown that asthma remains poorly controlled in a significant proportion of patients, even among those receiving treatment at asthma specialist, and in patients with mild asthma who regularly take inhaled corticosteroids. Even when asthma control is achieved, it is not optimal on all GINA steps. The small airways have been recognized as the primary site of airflow limitation in asthma. The aim of the work: to study, according to the literature, the peculiarities of the dysfunction of the small airways in asthma and to evaluate the possibilities of its treatment. Materials and methods. Scientific articles that covered the pathophysiology of small airways disorders, their impact on asthma control, diagnostic methods, and pharmacological treatment methods were analyzed. The results. Airways with an internal diameter < 2 mm, which do not contain cartilage in their walls and extend from the 8th generation of the airways to the periphery of the lung, are collectively called “small airways”. They are called the QUIET ZONE because they are difficult to assess and treat in patients with asthma who are not optimally controlled but have relatively normal FEV1 and disproportionate small airways dysfunction (SAD). Predominant in patients at all stages of treatment, associated with poor disease control. The ATLANTIS study showed that up to 91 % of patients with asthma have. The small airways have a high density of corticosteroid and β2-adrenoceptors, which means that they can be influenced. The main task is that the drugs should reach these small airways. Conventional inhalers that generate particles larger than 2 μm do not address the problem of SAD in patients with asthma. Inhaler devices that produce ultrafine particles of inhaled corticosteroids alone or in combination with long-acting β-agonists with a diameter of less than 2 μm have the potential to improve long-term asthma control along with a corresponding improvement in small airway function. The fixed combination of beclomethasone dipropionate with formoterol has optimal deposition in the respiratory tract — central pulmonary deposition accounts for 66 %, and peripheral — 34 % of the dose, thus the drug is delivered to both the central and peripheral respiratory tracts and affects inflammation and bronchoconstriction throughout the lungs. This is facilitated by MODULITE technology. The effectiveness and safety of the use of the BDP/F combination (Foster) in MART regimen is confirmed by a significant evidence base, which guaranteed its place in the Track1 treatment of asthma. Conclusions: Patients with asthma have a serious inflammatory process in the peripheral airways, which makes them the main site of obstruction in asthma; SAD predominates in patients at all stages of asthma, is associated with poor disease control, is responsible for air trapping, correlates with poor asthma control1, and predicts an increased risk of exacerbations in patients. The fixed combination of beclamethasone/formoterol in one inhaler (Foster) is the only extrafinely dispersed fixed combination of ICS/LABA that reaches the small airways; the fixed combination of BDP/Formoterol in the MART regimen provides a significant reduction in the frequency of severe complications, hospitalizations, emergency calls, and reduces the number of courses of systemic corticosteroids.

Histamine activates an intracellular Ca2+ signal in normal human lung fibroblast WI-38 cells.

Histamine is an inflammatory mediator that can be released from mast cells to induce airway remodeling and cause persistent airflow limitation in asthma. In addition to stimulating airway smooth muscle cell constriction and hyperplasia, histamine promotes pulmonary remodeling by inducing fibroblast proliferation, contraction, and migration. It has long been known that histamine receptor 1 (H1R) mediates the effects of histamine on human pulmonary fibroblasts through an increase in intracellular Ca2+ concentration ([Ca2+]i), but the underlying signaling mechanisms are still unknown. Herein, we exploited single-cell Ca2+ imaging to assess the signal transduction pathways whereby histamine generates intracellular Ca2+ signals in the human fetal lung fibroblast cell line, WI-38. WI-38 fibroblasts were loaded with the Ca2+-sensitive fluorophore, FURA-2/AM, and challenged with histamine in the absence and presence of specific pharmacological inhibitors to dissect the Ca2+ release/entry pathways responsible for the onset of the Ca2+ response. Histamine elicited complex intracellular Ca2+ signatures in WI-38 fibroblasts throughout a concentration range spanning between 1 µM and 1 mM. In accord, the Ca2+ response to histamine adopted four main temporal patterns, which were, respectively, termed peak, peak-oscillations, peak-plateau-oscillations, and peak-plateau. Histamine-evoked intracellular Ca2+ signals were abolished by pyrilamine, which selectively blocks H1R, and significantly reduced by ranitidine, which selectively inhibits H2R. Conversely, the pharmacological blockade of H3R and H4R did not affect the complex increase in [Ca2+]i evoked by histamine in WI-38 fibroblasts. In agreement with these findings, histamine-induced intracellular Ca2+ signals were initiated by intracellular Ca2+ release from the endoplasmic reticulum through inositol-1,4,5-trisphosphate (InsP3) receptors (InsP3R) and sustained by store-operated Ca2+ channels (SOCs). Conversely, L-type voltage-operated Ca2+ channels did not support histamine-induced extracellular Ca2+ entry. A preliminary transcriptomic analysis confirmed that WI-38 human lung fibroblasts express all the three InsP3R isoforms as well as STIM2 and Orai3, which represent the molecular components of SOCs. The pharmacological blockade of InsP3 and SOC, therefore, could represent an alternative strategy to prevent the pernicious effects of histamine on lung fibroblasts in asthmatic patients.

The Impact of Insulin Resistance on Loss of Lung Function and Response to Treatment in Asthma.

Rationale: The role of obesity-associated insulin resistance (IR) in airflow limitation in asthma is uncertain. Objectives: Using data in the Severe Asthma Research Program 3 (SARP-3), we evaluated relationships between homeostatic measure of IR (HOMA-IR), lung function (cross-sectional and longitudinal analyses), and treatment responses to bronchodilators and corticosteroids. Methods: HOMA-IR values were categorized as without (<3.0), moderate (3.0-5.0), or severe (>5.0). Lung function included FEV1 and FVC measured before and after treatment with inhaled albuterol and intramuscular triamcinolone acetonide and yearly for 5 years. Measurements and Main Results: Among 307 participants in SARP-3, 170 (55%) were obese and 140 (46%) had IR. Compared with patients without IR, those with IR had significantly lower values for FEV1 and FVC, and these lower values were not attributable to obesity effects. Compared with patients without IR, those with IR had lower FEV1 responses to β-adrenergic agonists and systemic corticosteroids. The annualized decline in FEV1 was significantly greater in patients with moderate IR (-41 ml/year) and severe IR (-32 ml/year,) than in patients without IR (-13 ml/year, P < 0.001 for both comparisons). Conclusions: IR is common in asthma and is associated with lower lung function, accelerated loss of lung function, and suboptimal lung function responses to bronchodilator and corticosteroid treatments. Clinical trials in patients with asthma and IR are needed to determine if improving IR might also improve lung function.

Normalisation of airflow limitation in asthma: Post-hoc analyses of TRIMARAN and TRIGGER.

BackgroundIn asthma, persistent airflow limitation (PAL) is associated with poorer control, lung function decline and exacerbations. Using post‐hoc analyses we evaluated: the relationship between post‐salbutamol PAL at screening, airflow limitation (AL) during 52 weeks treatment with extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/G) versus BDP/FF and the risk of moderate/severe asthma exacerbations.MethodsTRIMARAN and TRIGGER were double‐blind studies comparing BDP/FF/G with BDP/FF (TRIMARAN medium‐dose ICS; TRIGGER high‐dose) in adults with uncontrolled asthma. Patients were subgrouped according to post‐salbutamol PAL status at screening, and AL over the 52‐week treatment period.ResultsMost patients with post‐salbutamol PAL at screening had AL at all on‐treatment visits (TRIMARAN 62.8%; TRIGGER 66.8%). A significantly higher proportion of patients had normalised airflow on ≥1 follow‐up visit when receiving BDP/FF/G than BDP/FF (TRIMARAN 44.1 vs. 33.1% [p = 0.003]; TRIGGER 40.1 vs. 26.0% [p < 0.001]). In patients with post‐salbutamol PAL at screening and normalised AL at ≥1 follow‐up visit, exacerbation rates were 15% (p = 0.105) and 19% (p = 0.039) lower in TRIMARAN and TRIGGER versus those with AL on all visits. There was a trend to lower exacerbation rates in patients receiving BDP/FF/G than BDP/FF, particularly in patients in whom AL was normalised.ConclusionIn these analyses, AL in asthma was associated with an increased exacerbation incidence. Inhaled triple therapy with extrafine BDP/FF/G was more likely to normalise airflow, and was associated with a trend to a lower exacerbation rate than BDP/FF, particularly in the subgroup of patients in whom treatment was associated with airflow normalisation.ClinicalTrials.gov: TRIMARAN, NCT02676076; TRIGGER, NCT02676089.

Effect of treatment with inhaled corticosteroid on serum periostin levels in asthma

Periostin is a biomarker of eosinophilic airway inflammation and may contribute to airway remodeling in asthma. The anti-inflammatory activity of inhaled corticosteroids (ICS) for asthma control is widely recognized. The aim of this study was to assess the effects of ICS on serum periostin levels and its relationships to inflammation and airway geometry. Forty-two healthy controls and 20 patients with steroid-naïve asthma before and after treatment with fluticasone propionate (800 μg/day for 16 weeks) were examined. Serum periostin, lung function and inflammatory cell counts in sputum were measured. Airway dimensions were determined by quantitative computed tomography (total area of the airway (Ao), wall area (WA), wall thickness (T) and percentage wall area (WA%) ). Serum periostin concentrations were significantly higher in patients with asthma than in controls. Periostin levels were correlated with airway wall thickness and sputum eosinophilia and inversely correlated with airflow limitation in asthma. ICS significantly decreased serum periostin (P < 0.01), decreased WA corrected for body surface area (WA/BSA, P < 0.05), T/√BSA (P < 0.01) and WA% (P < 0.01), reduced the percentage of sputum eosinophils (P < 0.01) and improved airflow limitation. The decrease in serum periostin levels was associated with an increased per cent predicted forced expiratory volume in 1 s (r = -0.64, P < 0.01), decreased WA/BSA (r = 0.46, P < 0.05) and decreased sputum eosinophils (r = 0.71, P < 0.01). Serum periostin levels respond partially to ICS and may reflect a reduction in airway inflammation and wall thickening in asthma.

Progression of Irreversible Airflow Limitation in Asthma: Correlation with Severe Exacerbations

Severe exacerbations of asthma are periods of excess functional and pathological changes in the airways that have been proposed to induce airway remodeling. The objective of this study was to explore whether severe exacerbations are correlated with the decline in post-bronchodilator forced expiratory volume in 1 second (FEV1) and loss of bronchodilator reversibility (BDR). We examined the changes in FEV1 and BDR in 140 nonsmoking patients with well-controlled asthma at baseline and correlated these changes with the frequency of severe asthma exacerbations. A 3-year follow-up assessment was completed in 128 patients. A total of 28 (21.9%) patients experienced at least 1 severe exacerbation with a mean rate of 0.16 year(-1). The exacerbation rate was significantly correlated with an annual rate of decline in FEV1 (ρ = 0.49, P < .0001). Both patients with 1 exacerbation and those with 2 or more exacerbations had greater declines in FEV1 than patients with no exacerbations (no exacerbation, 13.6 mL/year; 1 exacerbation, 41.3 mL/year; 2 or more exacerbations, 58.3 mL/year; P < .01 and P < .0001, respectively). The changes in BDR from baseline to the end of the study in patients who did or did not experience an exacerbation were -1.2% and 0.1%, respectively (P < .0005). The changes in BDR were significantly correlated with the annual rates of change in FEV1 (r = 0.40, P < .0001). The occurrence of severe exacerbations of asthma is correlated with the progression of irreversible airflow limitation over time. This suggests that asthma exacerbations could have the long-term adverse consequences of structural and functional changes in the airways.

Smooth Muscle Calcium Signaling and Contraction in the Small Airways of the House Dust Mite Asthma Mouse Model

The small intrapulmonary airways are the major contributors to reversible airflow limitation in asthma. However, the mechanisms responsible for the increased small‐airway responsiveness to bronchoconstrictors (airway hyperresponsiveness) that characterized asthma pathophysiology are not fully understood. We used precision‐cut lung slices and microscope imaging approaches to investigate the contraction and intracellular calcium signaling in the smooth muscle of small airways from mice chronically challenged with house dust mite extract (HDM) during 3 to 7 weeks. Mice challenged with HDM developed a significant airway inflammation characterized by the presence of eosinophils, lymphocytes, neutrophils, and monocytes that spread through the airway tree and reached the small airways. Superfusion of lung slices with methacholine (MCh) induced a concentration‐dependent airway contraction that was significantly increased in the small airways of the HDM‐challenge mice than in PBS‐challenged mice (controls). MCh stimulation induced intracellular Ca2+ oscillations in the smooth muscle cells on the small airways. The frequency of these Ca2+ oscillations increased with MCh concentration and was higher in airway smooth muscle cells from the HDM‐exposed mice than from controls. The results suggest that airway hyperresponsiveness in asthma is caused by an increased contractility of the airway smooth muscle cells in the small airways which is accompanied by an increased intracellular Ca2+ response to bronchoconstrictors

Bronchoconstriction Induces TGF-β Release and Airway Remodelling in Guinea Pig Lung Slices

Airway remodelling, including smooth muscle remodelling, is a primary cause of airflow limitation in asthma. Recent evidence links bronchoconstriction to airway remodelling in asthma. The mechanisms involved are poorly understood. A possible player is the multifunctional cytokine TGF-β, which plays an important role in airway remodelling. Guinea pig lung slices were used as an in vitro model to investigate mechanisms involved in bronchoconstriction-induced airway remodelling. To address this aim, mechanical effects of bronchoconstricting stimuli on contractile protein expression and TGF-β release were investigated. Lung slices were viable for at least 48 h. Both methacholine and TGF-β1 augmented the expression of contractile proteins (sm-α-actin, sm-myosin, calponin) after 48 h. Confocal fluorescence microscopy showed that increased sm-myosin expression was enhanced in the peripheral airways and the central airways. Mechanistic studies demonstrated that methacholine-induced bronchoconstriction mediated the release of biologically active TGF-β, which caused the increased contractile protein expression, as inhibition of actin polymerization (latrunculin A) or TGF-β receptor kinase (SB431542) prevented the methacholine effects, whereas other bronchoconstricting agents (histamine and KCl) mimicked the effects of methacholine. Collectively, bronchoconstriction promotes the release of TGF-β, which induces airway smooth muscle remodelling. This study shows that lung slices are a useful in vitro model to study mechanisms involved in airway remodelling.

Epidemiology of the Origins of Airflow Limitation in Asthma

There is now conclusive evidence that, as a group, subjects with asthma have lower levels of lung function as compared with their peers and that a significant proportion of subjects with persistent asthma are at risk of developing non-fully reversible airflow limitation, the clinical hallmark of chronic obstructive pulmonary disease. Although at the population level the most conspicuous form of airflow limitation in asthma seems to be that of subjects who wheeze during the first years of life and whose symptoms persist into adult life, asthma-related lung deficits can be related to both acquired deficits in growth of lung function in childhood and steeper decline of lung function in adult life. These trajectories of lung function are likely to differ across subgroups of individuals with asthma, suggesting that different windows of opportunity may exist to modify the natural course of the disease before irreversible deficits are established. These observations indicate the importance of identifying biomarkers that can be used to target children and adults with asthma at increased risk for airflow limitation and determining whether pharmacological interventions can protect these patients from the development of chronic obstructive pulmonary disease.

Bronchial Measurements in Patients with Asthma: Comparison of Quantitative Thin-Section CT Findings with Those in Healthy Subjects and Correlation with Pathologic Findings

To analyze and compare computed tomographic (CT) bronchial measurements in patients with asthma and healthy subjects and to correlate bronchial morphometric parameters with functional data and immunohistologic markers of airway remodeling and inflammation. This retrospective study was approved by the institutional review board; patient informed consent was not required. CT and pulmonary function tests were performed in 27 patients separated into two groups: 15 patients with asthma (three men; mean age, 43.1 years +/- 5.3 [standard error of mean]) and 12 healthy subjects (10 men; mean age, 45.0 years +/- 5.4). Endobronchial biopsies were performed in 11 subjects. Bronchial cross-sectional wall area (WA) and lumen area (LA) were measured by using validated software, and wall thickness (WT), total area (TA), WA/LA ratio, and WA/TA ratio were computed. Slope and maximal local slope of each parameter along bronchial generations were calculated. Patients with asthma demonstrated significantly lower LA, TA, and WA and higher WA/LA and WA/TA ratios than healthy subjects downward from the fourth bronchial generation. Correlations existed between slope and maximal local slope of WA/LA and/or WA/TA ratios and functional data reflecting bronchial obstruction (r = 0.46-0.58, P = .001-.025), subepithelial membrane thickness (r = 0.67-0.69, P = .019-.023), smooth muscle layer area (r = 0.75, P = .007), subepithelial layer area (r = 0.81, P = .002), and infiltration of the bronchial wall by inflammatory cells (r = 0.67-0.86, P = .049-.003). Axial reconstructions with orthogonal measurements along the airways enabled by three-dimensional segmentation methods are able to demonstrate significant changes in bronchial morphometry, predicting airflow limitation in asthma, and may have a role in the noninvasive measurement of airway remodeling.

Airflow limitation, asthma, and Chlamydia pneumoniae-specific heat shock protein 60

Chlamydia pneumoniae has been associated with asthma. It has also been suggested that C pneumoniae infection may lead to lung remodeling in a subset of asthmatic patients. Seroreactivity against Chlamydia trachomatis heat shock protein 60 (hsp60), a highly conserved, immunoreactive chaperone protein, is associated with immunopathologic abnormalities, leading to blinding trachoma and tubal infertility. This suggests that the host response to infection may affect chronic inflammatory damage to the eye and the fallopian tubes. The pathogenesis of C trachomatis disease associations is thought to include molecular mimicry (autoimmunity), direct activation of the innate immune response via the CD14/toll-like receptor 4 complex, or both. To study whether airflow limitation in asthma in C pneumoniae-exposed individuals is associated with a specific antibody response to the C pneumoniae hsp60 molecule and not with a genus-specific response to the hsp60 molecule. In a case-control study, we evaluated 138 C pneumoniae-exposed primary care patients (86 adult asthmatic cases and 52 nonasthmatic controls) for seroreactivity against a C pneumoniae-specific hsp60 fragment and against the C trachomatis hsp60 molecule. We analyzed associations with asthma and irreversible lung remodeling as measured by means of postbronchodilator forced expiratory volume in 1 second. Twenty-seven percent of asthmatic patients were C pneumoniae hsp60 seropositive vs 8% of controls (P < .01). Controlling for age, sex, and smoking, C pneumoniae hsp60 seropositivity was associated with lower postbronchodilator forced expiratory volume in 1 second in asthmatic patients (P < .05). No comparable associations were present for C trachomatis hsp60. In individuals with evidence of previous exposure to C pneumoniae infection, a host antibody response against a C pneumoniae hsp60 fragment but not against C trachomatis hsp60 was associated with airflow limitation in adults with asthma.

Peroxynitrite augments fibroblast-mediated tissue remodeling via myofibroblast differentiation

Irreversible airflow limitation in asthma is associated with airway remodeling in which the differentiation of fibroblasts to myofibroblasts plays a pivotal role. In asthmatic airways, excessive production of reactive nitrogen species (RNS) has been observed. The aim of this study is to evaluate whether peroxynitrite, one of the RNS, can affect the differentiation of fibroblasts to myofibroblasts. Human fetal lung fibroblasts were treated with various concentrations of authentic peroxynitrite or a peroxynitrite donor 3-morpholinosydnonimine hydrochloride (SIN-1), and the expressions of alpha-smooth muscle actin (alpha-SMA) and desmin, markers of myofibroblast differentiation, were evaluated. The releases of transforming growth factor-beta(1) (TGF-beta(1)) and ECM proteins including fibronectin and collagen I were assessed. To clarify the mechanism in this differentiation, the effect of anti-TGF-beta antibody or NF-kappaB inhibitors on the alpha-SMA expression and ECM production was assessed. Peroxynitrite and SIN-1 significantly augmented the alpha-SMA expression compared with control in a concentration-dependent manner (P < 0.01 and P < 0.05, respectively). Peroxynitrite significantly increased desmin and TGF-beta(1) production (P < 0.01). Peroxynitrite enhanced the translocation of NF-kappaB into the nucleus confirmed by immunocytostaining and immunoblotting. Peroxynitrite-augmented alpha-SMA expression was blocked by NF-kappaB inhibitors, MG132 and caffeic acid phenethyl ester (CAPE), and anti-TGF-beta antibody. CAPE completely inhibited the peroxynitrite-augmented TGF-beta(1) release. The production of fibronectin and collagen I was significantly increased by peroxynitrite (P < 0.01) and inhibited by anti-TGF-beta antibody. These results suggest that RNS can affect the differentiation to myofibroblasts and excessive ECM production via a NF-kappaB-TGF-beta(1)-dependent pathway.

Oxidative and Nitrative Stress in Bronchial Asthma

There has been a marked increase in the global prevalence, morbidity, and mortality of asthma, and its associated economic burden has also grown over the last 40 years. Approximately 300 million people worldwide currently have asthma, and its prevalence increases by 50% every decade. Airway inflammation is the most proximate cause of the recurrent episodes of airflow limitation in asthma. Recent research has revealed that numerous biologically active proinflammatory mediators are responsible for the pathogenesis of asthma. Among these mediators, there is increasing evidence that endogenous or exogenous reactive oxygen species (ROS) and reactive nitrogen species (RNS) are responsible for the airway inflammation of asthma. Many reports have shown that there is an excessive production of ROS and RNS in the airways of asthmatic individuals compared with healthy subjects. Excessively produced ROS and RNS have been reported to lead to airway inflammation, airway hyper-responsiveness, airway microvascular hyperpermeability, tissue injury, and remodeling in animal models and human studies. Although human lungs have a potent antioxidant system, excessive oxidative and nitrative stress leads to an imbalance of oxidants/antioxidants. This review describes the rapidly accruing data linking oxidative and nitrative events to the pathogenesis of bronchial asthma.

Risk factors associated with irreversible airflow limitation in asthma

Irreversible airflow limitation develops in some patients with asthma and is related to poorer prognosis. This paper reviews recent literature on natural course, risk factors, and potential mechanisms of persistent airflow limitation in asthma. The natural course of persistent airflow limitation in asthma is poorly known, but reduced lung function at disease onset and an increased rate of decline during adult life contribute to its development. Risk factors for progressive irreversible airway obstruction in asthma include adult onset, frequent exacerbations, smoking, occupational exposure, ongoing eosinophilic airway inflammation and airway hyperresponsiveness. Polymorphisms of the ADAM33 gene predict excess decline in lung function, in asthma as well as at population level. It is still not clear how different components of airway remodeling affect lung function in asthma. Airway epithelium and airway smooth muscle seem to be highly important, but the interrelationship between persistent airflow limitation, airway inflammation, remodeling and airway hyperresponsiveness has not been clearly defined. Whereas several factors have been implicated as being important in the development of fixed airway obstruction in asthma, we are just beginning to explore the different components of airway remodeling and their relevance, deleterious or beneficial, to clinical outcome.

Association Between Neutrophilic Airway Inflammation and Airflow Limitation in Adults With Asthma

There is debate about the mechanisms of persistent airflow limitation in patients with asthma. Chronic inflammation is assumed to be important, although there is limited and contradictory information about the relationship between airway inflammation and postbronchodilator FEV1. We have assessed the cross-sectional relationship between prebronchodilator and postbronchodilator FEV1 and measures of airway inflammation after allowing for the effects of potential confounding factors. Multivariate analysis was performed on data collected from 1,197 consecutive patients with asthma seen at the respiratory outpatient clinic at Glenfield Hospital between 1997 and 2004. Relationships between induced sputum total neutrophil and differential eosinophil cell counts, and prebronchodilator and postbronchodilator lung function were examined. Sputum total neutrophil but not differential eosinophil count was associated with lower postbronchodilator FEV1. Both differential eosinophil and total neutrophil count were associated with lower prebronchodilator FEV1. These effects were independent after adjustment for age, smoking, ethnicity, asthma duration, and inhaled corticosteroid use. A 10-fold increase in neutrophil count was associated with a 92 mL reduction (95% confidence interval, 29 to 158; p = 0.007) in postbronchodilator FEV1. In this large heterogeneous population of adults with asthma, we have shown that prebronchodilator FEV1 is associated with neutrophilic and eosinophilic airway inflammation, whereas sputum total neutrophil counts alone are associated with postbronchodilator FEV1. This supports the hypothesis that neutrophilic airway inflammation has a role in the progression of persistent airflow limitation in asthma and raises the possibility that this progression and the development of COPD share a common mechanism.

The systemic face of airway diseases: the role of C-reactive protein

Airway diseases, predominantly asthma and chronic obstructive pulmonary disease (COPD), are highly prevalent diseases, constituting a major financial burden to society. Both asthma and COPD are identified by the presence of characteristic symptoms and functional abnormalities. Airflow limitation is the dominant physiological characteristic of both diseases. The airflow limitation in asthma must be reversible to establish a diagnosis, whereas in COPD the airflow limitation does not change markedly over periods of several months and the disease is characterised by a steady downhill course over time. Asthma usually commences in childhood, whereas COPD is generally diagnosed at an older age. Lung inflammation induced by different initiating factors is now recognised as an important characteristic in both diseases. The airway inflammation in asthma is characterised by an increase in eosinophils, lymphocytes (predominantly of the CD4+ type) and mast cells. In contrast, inflammation in COPD can be described by a predominance of lymphocytes, in particular CD8+ lymphocytes, and large numbers of neutrophils in the airway lumen. While achievement of asthma control and suppression of airway inflammation are considered as important management goals in asthma, particularly as a consequence of the effects of inhaled steroids in this disease process, the focus of research in COPD has moved from the typical pulmonary pathology of COPD to the role of numerous abnormalities outside the lung. At present, COPD is considered as a multicomponent disease, including skeletal muscle dysfunction and cachexia, as well as cardiovascular and osteoskeletal alterations. Particularly in order to explain the process of muscle wasting, the presence of a chronic low-grade systemic inflammatory response has been identified as one of the catabolic factors, although the precise role, as well as the intracellular pathways, remain to be defined 1. In this issue of the European Respiratory Journal (ERJ) , two clinical papers focus attention …

The pathophysiology of airway dysfunction

Asthma and chronic obstructive pulmonary disease (COPD) are distinct inflammatory disorders with differing pathophysiologic mechanisms, different clinical courses, and, therefore, distinct treatment strategies. Whereas in asthma airflow limitation is typically episodic and reversible, airflow limitation in COPD is progressive and only partially reversible. In contrast to asthma, which is characterized by an elevated number of eosinophils in the blood and the accumulation of elevated numbers of activated eosinophils, mast cells, and CD4+ T(H)2-lymphocytes in the lungs, the primary inflammatory cells present in the lungs of patients with stable COPD are neutrophils, macrophages, and CD8+ lymphocytes. Bronchoconstriction in COPD is largely regulated by cholinergically mediated vagal tone, and the pathologic processes of COPD further reduce airway patency. Bronchodilators, most notably anticholinergics, are recommended as first-line pharmacologic therapy for COPD. Proper use of inhaled anticholinergic medications has been shown to lead to significant reversibility of acetylcholine-mediated bronchoconstriction during both stable disease and exacerbations of COPD. For patients with asthma, current guidelines recommend anti-inflammatory medications, specifically inhaled corticosteroids and leukotriene-modifiers, as first-line therapy, making these agents the mainstay of asthma therapy. In contrast, the current guidelines for COPD management recommend that inhaled anti-inflammatory agents be tried in patients with COPD only as second-line therapy for patients who have severe to very severe airflow obstruction with frequent exacerbations and who remain symptomatic despite maximized bronchodilation with multiple inhaled bronchodilators. Hence, it is extremely important to understand the differences between the underlying pathogenesis and pathophysiology of COPD and those of asthma, as these differences dictate the implementation of distinctly different treatment options for these 2 diseases.

Brain-derived Neurotrophic Factor in Platelets and Airflow Limitation in Asthma

Brain-derived neurotrophic factor (BDNF), a key mediator of neuronal plasticity, contributes to airway obstruction and hyperresponsiveness in a model of allergic asthma. BDNF is stored in human platelets and circulates in human plasma, but the significance of BDNF in this compartment is poorly understood. We investigated the relationship between platelet and plasma BDNF levels and pulmonary function in a cohort of 26 adult patients with recently diagnosed allergic asthma. BDNF levels in serum, platelets, and plasma were significantly increased in participants with asthma, as compared with 26 age- and sex-matched control subjects. In steroid-naive patients, but not in patients using inhaled corticosteroids, enhanced platelet BDNF levels correlated with parameters of airway obstruction and airway hyperresponsiveness to histamine. Experiments with activated peripheral blood mononuclear cells revealed that corticosteroids such as fluticasone effectively suppress BDNF secretion. In conclusion, we demonstrate that enhanced platelet BDNF is associated with airflow limitation and airway hyperresponsiveness in asthma. In addition, we provide evidence that corticosteroids suppress BDNF production by activated immune cells.

Oxidative and nitrosative events in asthma.

Asthma affects over 15 million individuals in the United States, with over 1.5 million emergency room visits, 500,000 hospitalizations, and 5500 deaths each year, many of which are children. Airway inflammation is the proximate cause of the recurrent episodes of airflow limitation in asthma. Research applying molecular biology, chemistry, and cell biology to human asthma and model systems of asthma over the last decade has revealed that numerous biologically active proinflammatory mediators lead to increased production of reactive oxygen species (ROS) and the gaseous molecule nitric oxide (NO). Persistently increased ROS and NO in asthma lead to reactive nitrogen species (RNS) formation and subsequent oxidation and nitration of proteins, which may cause alterations in protein function that are biologically relevant to airway injury/inflammation. Eosinophil peroxidase and myeloperoxidase, leukocyte-derived enzymes, amplify oxidative events and are another enzymatic source of NO-derived oxidants and nitrotyrosine formation in asthma. Concomitant with increased generation of oxidative and nitrosative molecules in asthma, loss of protective antioxidant defense, specifically superoxide dismutase (SOD), contributes to the overall toxic environment of the asthmatic airway. This review discusses the rapidly accruing data linking oxidative and nitrosative events as critical participants in the acute and chronic inflammation of asthmatic airways.