Comorbidities and COPD severity in a clinic-based cohort.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an important cause of morbidity and mortality around the world. The aim of our study was to determine the association between specific comorbidities and COPD severity. METHODS: Pulmonologists included patients with COPD using a web-site questionnaire. Diagnosis of COPD was made using spirometry post-bronchodilator FEV1/FVC < 70%. The questionnaire included the following domains: demographic criteria, clinical symptoms, functional tests, comorbidities and therapeutic management. COPD severity was classified according to GOLD 2011. First we performed a principal component analysis and a non-hierarchical cluster analysis to describe the cluster of comorbidities. RESULTS: One thousand, five hundred and eighty-four patients were included in the cohort during the first 2 years. The distribution of COPD severity was: 27.4% in group A, 24.7% in group B, 11.2% in group C, and 36.6% in group D. The mean age was 66.5 (sd: 11), with 35% of women. Management of COPD differed according to the comorbidities, with the same level of severity. Only 28.4% of patients had no comorbidities associated with COPD. The proportion of patients with two comorbidities was significantly higher (p < 0.001) in GOLD B (50.4%) and D patients (53.1%) than in GOLD A (35.4%) and GOLD C ones (34.3%). The cluster analysis showed five phenotypes of comorbidities: cluster 1 included cardiac profile; cluster 2 included less comorbidities; cluster 3 included metabolic syndrome, apnea and anxiety-depression; cluster 4 included denutrition and osteoporosis and cluster 5 included bronchiectasis. The clusters were mostly significantly associated with symptomatic patients i.e. GOLD B and GOLD D. CONCLUSIONS: This study in a large real-life cohort shows that multimorbidity is common in patients with COPD.

Bronchial Smooth Muscle Remodeling in Nonsevere Asthma.

RATIONALE: Increased bronchial smooth muscle (BSM) mass is a key feature of airway remodeling that classically distinguishes severe from nonsevere asthma. Proliferation of BSM cells involves a specific mitochondria-dependent pathway in individuals with severe asthma. However, BSM remodeling and mitochondrial biogenesis have not been examined in nonsevere asthma. OBJECTIVES: We aimed to assess whether an increase in BSM mass was also implicated in nonsevere asthma and its relationship with mitochondria and clinical outcomes. METHODS: We enrolled 34 never-smoker subjects with nonsevere asthma. In addition, we recruited 56 subjects with nonsevere asthma and 19 subjects with severe asthma as comparative groups (COBRA cohort [Cohorte Obstruction Bronchique et Asthme; Bronchial Obstruction and Asthma Cohort; sponsored by the French National Institute of Health and Medical Research, INSERM]). A phenotypic characterization was performed using questionnaires, atopy and pulmonary function testing, exhaled nitric oxide measurement, and blood collection. Bronchial biopsy specimens were processed for immunohistochemistry and electron microscopy analysis. After BSM remodeling assessment, subjects were monitored over a 12-month period. MEASUREMENTS AND MAIN RESULTS: We identified characteristic features of remodeling (BSM area >26.6%) and increased mitochondrial number within BSM in a subgroup of subjects with nonsevere asthma. The number of BSM mitochondria was positively correlated with BSM area (r = 0.78; P < 0.001). Follow-up analysis showed that subjects with asthma with high BSM had worse asthma control and a higher rate of exacerbations per year compared with subjects with low BSM. CONCLUSIONS: This study reveals that BSM remodeling and mitochondrial biogenesis may play a critical role in the natural history of nonsevere asthma (Mitasthme study). Clinical trial registered with www.clinicaltrials.gov (NCT00808730).

Blood fibrocytes are recruited during acute exacerbations of chronic obstructive pulmonary disease through a CXCR4-dependent pathway.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by peribronchial fibrosis. The chronic course of COPD is worsened by recurrent acute exacerbations. OBJECTIVE: The aim of the study was to evaluate the recruitment of blood fibrocytes in patients with COPD during exacerbations and, subsequently, to identify potential mechanisms implicated in such recruitment. METHODS: Using flow cytometry, we quantified circulating fibrocytes and characterized their chemokine receptor expression in 54 patients with COPD examined during an acute exacerbation (V1) and 2 months afterward (V2) and in 40 control subjects. The role of the chemokines CXCL12 and CCL11 in fibrocyte migration was investigated by using a chemotaxis assay. Patients were followed for up to 3 years after V1. RESULTS: We demonstrated a significantly increased number of circulating fibrocytes at V1 compared with control subjects. The number of circulating fibrocytes decreased at V2. A high percentage of circulating fibrocytes during exacerbation was associated with increased risk of death. The percentage of fibrocytes at V2 was negatively correlated with FEV1, forced vital capacity, FEV1/forced vital capacity ratio, transfer lung capacity of carbon monoxide, and Pao2. Fibrocytes highly expressed CXCR4 and CCR3, the chemokine receptors for CXCL12 and CCL11, respectively. Fibrocytes collected from patients with COPD at V1 had increased chemotactic migration in response to CXCL12 but not to CCL11 compared with those from control subjects. Plerixafor, a CXCR4 antagonist, decreased fibrocyte migration to plasma from patients with exacerbating COPD. CONCLUSION: Blood fibrocytes are recruited during COPD exacerbations and related to mortality and low lung function. The CXCL12/CXCR4 axis is involved in such fibrocyte recruitment (Firebrob study; ClinicalTrials NCT01196832).

Selective dysfunction of p53 for mitochondrial biogenesis induces cellular proliferation in bronchial smooth muscle from asthmatic patients.

BACKGROUND: Increase of bronchial smooth muscle (BSM) mass is a crucial feature of asthma remodeling. The mechanisms of such an increased BSM mass are complex but involve enhanced mitochondrial biogenesis, leading to increased proliferation of BSM cells in asthmatic patients. The major tumor suppressor protein p53 is a key cell regulator involved in cell proliferation and has also been implicated in mitochondrial biogenesis. However, the role of p53 in BSM cell proliferation and mitochondrial biogenesis has not been investigated thus far. OBJECTIVE: We sought to evaluate the role of p53 in proliferation of BSM cells in asthmatic patients and mitochondrial biogenesis. METHODS: The expression of p53 was assessed both in vitro by using flow cytometry and Western blotting and ex vivo by using RT-PCR after laser microdissection. The role of p53 was assessed with small hairpin RNA lentivirus in both asthmatic patients and control subjects with BSM cell proliferation by using 5-bromo-2'-deoxyuridine and cell counting and in the expression of p21, BCL2-associated X protein, mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). RESULTS: Twenty-nine patients with moderate-to-severe asthma and 26 control subjects were enrolled in the study. p53 expression was increased in BSM from asthmatic patients both ex vivo and in vitro, with a decreased interaction with mouse double minute 2 homolog (Mdm2) and an increased phosphorylation of serine 20. p53 did not inhibit the transcription of both TFAM and PGC-1α in BSM cells from asthmatic patients. As a consequence, p53 is unable to slow the increased mitochondrial biogenesis and hence the subsequent increased proliferation of BSM cells in asthmatic patients. CONCLUSION: This study suggests that p53 might act as a new potential therapeutic target against BSM remodeling in asthmatic patients.

Calcium channel blocker reduces airway remodeling in severe asthma. A proof-of-concept study.

RATIONALE: Severe asthma is a major public health issue throughout the world. Increased bronchial smooth muscle (BSM) mass, a characteristic feature of airway remodeling in severe asthma, is associated with resistance to high-intensity treatment and poor prognosis. In vitro, the Ca(2+)-channel blocker gallopamil decreased the proliferation of BSM cells from patients with severe asthma. OBJECTIVES: We conducted a double-blind, randomized, placebo-controlled study to evaluate the effect of gallopamil on airway remodeling in patients with severe asthma. METHODS: Subjects received either gallopamil (n = 16) or placebo (n = 15) for 1 year and were monitored for an additional 3-month period. Airway remodeling was analyzed at baseline and after treatment phase using both fiberoptic bronchoscopy and computed tomography scan. The primary end point was the BSM area. Secondary end points included normalized BSM thickness and frequency of asthma exacerbations. MEASUREMENTS AND MAIN RESULTS: BSM area was reduced in the gallopamil group (baseline vs. end of treatment) but was unchanged in the placebo group. Between-group differences in BSM area were not significantly different in gallopamil versus placebo groups. By contrast, between-group differences in normalized BSM thickness were significantly different between the two groups. The mean number of exacerbations per month was not different during the treatment phase in gallopamil versus placebo group but was significantly lower in patients previously treated with gallopamil during the follow-up period. There were no differences between the groups with respect to overall side effects. CONCLUSIONS: Gallopamil treatment for 12 months reduces BSM remodeling and prevents the occurrence of asthma exacerbations. Clinical trial registered with www.clinicaltrials.gov (NCT 00896428).

Breathing variability and brainstem serotonergic loss in a genetic model of multiple system atrophy.

Breathing disorders like sleep apnea, stridor, and dysrythmic breathing are frequent in patients with multiple system atrophy (MSA). These observations have been related to neurodegeneration in several pontomedullary respiratory nuclei and may explain the occurrence of sudden death. In this study, we sought to determine whether these functional and neuropathological characteristics could be replicated in a transgenic model of MSA. Mice expressing human wild-type α-synuclein under the control of the proteolipid promoter (PLP-αSYN) were compared with age-matched controls. Using whole-body, unrestrained plethysmography, the following breathing parameters were measured: inspiratory and expiratory times, tidal volume, expiratory volume, peak inspiratory and expiratory flows, and respiratory frequency. For each category, the mean, coefficient of variation, and irregularity score were analyzed. Brains were then processed for stereological cell counts of pontomedullary respiratory nuclei. A significant increase in the coefficient of variation and irregularity score was observed for inspiratory time, tidal volume, and expiratory volume in PLP-αSYN mice (P < 0.05). Glial cytoplasmic inclusions were found in the medullary raphe of PLP-αSYN mice, together with a loss of serotonergic immunoreactivity in the raphe obscurus (P < 0.001) and pallidus (P < 0.01). There was a negative correlation between α-synuclein burden and raphe pallidus cell counts (P < 0.05). There was no significant neuronal loss in the pre-Botzinger complex. The PLP-αSYN mouse model replicates the breathing variability and part of the neuronal depletion in pontomedullary respiratory nuclei observed in patients with MSA. Our findings support the use of this model for future candidate drugs in the breathing disorders observed in MSA.

Ca(2+)-activated K(+) channel-3.1 blocker TRAM-34 attenuates airway remodeling and eosinophilia in a murine asthma model.

Key features of asthma include bronchial hyperresponsiveness (BHR), eosinophilic airway inflammation, and bronchial remodeling, characterized by subepithelial collagen deposition, airway fibrosis, and increased bronchial smooth muscle (BSM) mass. The calcium-activated K(+) channel K(Ca)3.1 is expressed by many cells implicated in the pathogenesis of asthma, and is involved in both inflammatory and remodeling responses in a number of tissues. The specific K(Ca)3.1 blocker 5-[(2-chlorophenyl)(diphenyl)methyl]-1H-pyrazole (TRAM-34) attenuates BSM cell proliferation, and both mast cell and fibrocyte recruitment in vitro. We aimed to examine the effects of K(Ca)3.1 blockade on BSM remodeling, airway inflammation, and BHR in a murine model of chronic asthma. BALB/c mice were sensitized with intraperitoneal ovalbumin (OVA) on Days 0 and 14, and then challenged with intranasal OVA during Days 14-75. OVA-sensitized/challenged mice received TRAM-34 (120 mg/kg/day, subcutaneous) from Days -7 to 75 (combined treatment), Days -7 to 20 (preventive treatment), or Days 21 to 75 (curative treatment). Untreated mice received daily injections of vehicle (n = 8 per group). Bronchial remodeling was assessed by histological and immunohistochemical analyses. Inflammation was evaluated using bronchoalveolar lavage and flow cytometry. We also determined BHR in both conscious and anesthetized mice via plethysmography. We demonstrated that curative treatment with TRAM-34 abolishes BSM remodeling and subbasement collagen deposition, and attenuates airway eosinophilia. Although curative treatment alone did not significantly reduce BHR, the combined treatment attenuated nonspecific BHR to methacholine. This study indicates that K(Ca)3.1 blockade could provide a new therapeutic strategy in asthma.

Ultrashort-TE MRI longitudinal study and characterization of a chronic model of asthma in mice: inflammation and bronchial remodeling assessment.

Asthma is a chronic disease characterized by bronchial hyperresponsiveness (BHR), bronchial inflammation and remodeling. The great improvements in (1)H MRI ultrashort-TE (UTE) sequences in the last decade have allowed lung images with high-resolution and good signal-to-noise ratio to be obtained in parenchymal tissues. In this article, we present a UTE (1)H MRI high-resolution study of a chronic model of asthma in mice with the aim to longitudinally assess the main features of asthma using a fully noninvasive approach. Balb/c mice (n = 6) were sensitized with ovalbumin over a period of 75 days. The control group (n = 3) received normal saline on the same days. MRI acquisitions were performed on days 0, 38 and 78 to study the inflammatory volumes and bronchial remodeling (peribronchial signal intensity index, PBSI). Plethysmographic studies were performed on days 0, 39 and 79 to assess BHR to methacholine using the enhanced pause (Penh) ratio. The average inflammatory volume measured by MRI in the ovalbumin group (15.6 ± 2.4 µL) was increased significantly relative to control mice (-0.3 ± 0.7 µL) on day 38. The inflammatory volume was larger (34.2 ± 3.1 µL) on day 78 in the ovalbumin group. PBSI was significantly higher in the ovalbumin group on day 78 (1.53 ± 0.08) relative to the control group (1.16 ± 0.10), but not on day 38. After sensitization, asthmatic mice presented BHR to methacholine on days 39 and 79. Penh ratios correlated significantly with the inflammatory volume on day 39 and with the PBSI on day 79. This study shows, for the first time, that high-resolution UTE (1)H MRI of the lungs may allow the noninvasive quantification of peribronchial eosinophilic inflammation with airways occlusion by mucus and of bronchial remodeling in a murine asthma model that correlates with functional parameters.

Role of YKL-40 in bronchial smooth muscle remodeling in asthma.

RATIONALE: Bronchial remodeling, including increased bronchial smooth muscle (BSM) mass, contributes to bronchial obstruction in asthma. However, its mechanisms are complex and remain controversial. Recently, a role of the chitinase 3-like 1 protein (YKL-40) has been evoked in asthma. Indeed, YKL-40 concentration was increased in asthmatic serum, and correlated with asthma severity and subepithelial membrane thickness. Nevertheless, the role of YKL-40 on BSM cells remains to be investigated. OBJECTIVES: To evaluate whether YKL-40 altered the physiologic properties of BSM cells in asthma in vitro and ex vivo. METHODS: We enrolled 40 subjects with asthma, 13 nonsmokers, and 16 smokers. BSM cells were derived from bronchial specimens obtained by either fiberoptic bronchoscopy or lobectomy. We assessed cell proliferation using BrdU, flow cytometry, and cell count; signaling intermediates using Western blot; cell migration using inserts, wound healing, and phalloidin staining; and cell synthesis using ELISA and Western blot. The involvement of protease activated receptor (PAR)-2 was evaluated using blocking antibody and dedicated lentiviral small hairpin RNA. We also determined the BSM area and the YKL-40 staining ex vivo using immunohistochemistry on biopsies from subjects with asthma and control subjects. MEASUREMENTS AND MAIN RESULTS: We demonstrated that YKL-40 increased BSM cell proliferation and migration through PAR-2-, AKT-, ERK-, and p38-dependent mechanisms. The increased cell migration was higher in BSM cells of subjects with asthma than that of control subjects. Furthermore, YKL-40 epithelial expression was positively correlated with BSM mass in asthma. CONCLUSIONS: This study indicates that YKL-40 promotes BSM cell proliferation and migration through a PAR-2-dependent mechanism.

CT attenuation of the bronchial wall in patients with asthma: comparison with geometric parameters and correlation with function and histologic characteristics.

OBJECTIVE: The purposes of this study were to compare airway wall attenuation in subjects with asthma and subjects without asthma; to correlate this value with pulmonary function test results, standard bronchial CT parameters, and immunohistologic data; and to identify CT parameters that influence obstructive indexes. SUBJECTS AND METHODS: Bronchial airway wall attenuation was averaged over four bronchi in 27 subjects with asthma and 15 control subjects without asthma. The following five standard bronchial parameters also were assessed: lumen area, wall area, wall thickness, wall-to-lumen area ratio, and wall-to-total area ratio (wall area percentage). These parameters were compared between groups and correlated with functional data. Ability to predict patient group with these parameters was determined by comparison of receiver operating characteristic curves and areas under the curve. The influence of the parameters on obstructive indexes was assessed by multivariate analysis. Correlations between wall attenuation value and histologic data were studied in 11 patients with asthma. RESULTS: Wall attenuation value was greater in patients with asthma (-322 ± 79 HU) than in control subjects (-463 ± 69 HU). Correlation coefficients of wall attenuation value with functional obstructive parameters were significant and greater than those obtained for any other CT parameter. The area under the curve of wall attenuation value was greater than that of bronchial lumen area and bronchial wall area. In the model of multiple regression that included wall attenuation value and wall-to-total area ratio, wall attenuation value was the only measurement that significantly influenced obstructive indexes (R(2) = 0.39-0.43). Wall attenuation value correlated with mast cell infiltration. CONCLUSION: Compared with the usual bronchial CT parameters, airway wall attenuation better differentiates patients with asthma from control subjects and better correlates with obstruction.

[Pathophysiology of asthma]. / Physiopathologie de l'asthme.

Asthma pathophysiology involves bronchial hyperreactivity, inflammation and remodelling, these features being closely linked. Bronchial hyperreactivity is characterized by an excessive airway response to a wide range of stimuli. Bronchial inflammation is characterized by an infiltration of all layers of the bronchial wall by a variety of inflammatory cells, especially mast cells, lymphocytes and eosinophils. Bronchial remodelling is defined by various structural alterations of all components of the bronchial wall, which is responsible for a worsening of the disease.

Airway remodeling in a mouse asthma model assessed by in-vivo respiratory-gated micro-computed tomography.

The aim of our study was to evaluate the feasibility of non-invasive respiratory-gated micro-computed tomography (micro-CT) for assessment of airway remodelling in a mouse asthma model. Six female BALB/c mice were challenged intranasally with ovalbumin. A control group of six mice received saline inhalation. All mice underwent plethysmographic study and micro-CT. For each mouse, peribronchial attenuation values of 12 bronchi were measured, from which a peribronchial density index (PBDI) was computed. Mice were then sacrificed and lungs examined histologically. Final analysis involved 10 out of 12 mice. Agreement of measurements across observers and over time was very good (intraclass correlation coefficients: 0.94-0.98). There was a significant difference in PBDI between asthmatic and control mice (-210 vs. -338.9 HU, P = 0.008). PBDI values were correlated to bronchial muscle area (r = 0.72, P = 0.018). This study shows that respiratory-gated micro-CT may allow non-invasive monitoring of bronchial remodelling in asthmatic mice and evaluation of innovative treatment effects.

Susceptibility to frequent exacerbation in COPD patients: Impact of the exacerbations history, vaccinations and comorbidities?

INTRODUCTION: Exacerbations are key events in the natural history of COPD, but our understanding of their longitudinal determinants remains unclear. We used data from a large observational study to test the hypothesis that vaccination status and comorbidities could be associated with the occurrence of exacerbations profile. METHODS: Diagnosed COPD patients have been included by their pulmonologists, with up to 3 years of follow-up. Data were analyzed using the KmL method designed to cluster longitudinal data and receiver operating characteristic curve analysis to determine the best threshold to allocate patients to identified clusters. RESULTS: 932 COPD patients were included since January 2014, 446 patients (65.68% males, 35.59% current smokers) were followed over a period of 3 years with complete data. 239(28.15%) patients reported two or more exacerbations in the year before enrolment (frequent exacerbations). Among them 142(16.68%) also had frequent exacerbations in the first year of the study, and 69(8.10%) who remained frequent exacerbators in the second year. Based on our hypothesis, we were able to determine four phenotypes: A (infrequent), B (frequent in underweight patients), C (transient), and D (frequent in obese patients). Frequent exacerbators had more airflow limitation and symptoms. Irrespective of cut-offs set to define the optimal number of clusters, a history of exacerbations OR: 3.72[2.53-5.49], presence of anxiety OR: 2.03[1.24-3.31] and absence of the annual influenza vaccination OR: 1.97[1.20-3.24] remained associated with the frequent exacerbator phenotypes. CONCLUSIONS: The most important determinants of frequent exacerbations are a history of exacerbations, anxiety and unvaccinated against influenza.

Protease activated receptor-2 expression and function in asthmatic bronchial smooth muscle.

Asthmatic bronchial smooth muscle (BSM) is characterized by structural remodeling associated with mast cell infiltration displaying features of chronic degranulation. Mast cell-derived tryptase can activate protease activated receptor type-2 (PAR-2) of BSM cells. The aims of the present study were (i) to evaluate the expression of PAR-2 in both asthmatic and non asthmatic BSM cells and, (ii) to analyze the effect of prolonged stimulation of PAR-2 in asthmatic BSM cells on cell signaling and proliferation. BSM cells were obtained from both 33 control subjects and 22 asthmatic patients. PAR-2 expression was assessed by flow cytometry, western blot and quantitative RT-PCR. Calcium response, transduction pathways and proliferation were evaluated before and following PAR-2 stimulation by SLIGKV-NH2 or trypsin for 1 to 3 days. Asthmatic BSM cells expressed higher basal levels of functional PAR-2 compared to controls in terms of mRNA, protein expression and calcium response. When PAR-2 expression was increased by means of lentivirus in control BSM cells to a level similar to that of asthmatic cells, PAR-2-induced calcium response was then similar in both types of cell. However, repeated PAR-2 stimulations increased the proliferation of asthmatic BSM cells but not that of control BSM cells even following lentiviral over-expression of PAR-2. Such an increased proliferation was related to an increased phosphorylation of ERK in asthmatic BSM cells. In conclusion, we have demonstrated that asthmatic BSM cells express increased baseline levels of functional PAR-2. This higher basal level of PAR-2 accounts for the increased calcium response to PAR-2 stimulation, whereas the increased proliferation to repeated PAR-2 stimulation is related to increased ERK phosphorylation.

In vivo micro-CT assessment of airway remodeling in a flexible OVA-sensitized murine model of asthma.

Airway remodeling is a major pathological feature of asthma. Up to now, its quantification still requires invasive methods. In this study, we aimed at determining whether in vivo micro-computed tomography (micro-CT) is able to demonstrate allergen-induced airway remodeling in a flexible mouse model of asthma. Sixty Balb/c mice were challenged intranasally with ovalbumin or saline at 3 different endpoints (Days 35, 75, and 110). All mice underwent plethysmography at baseline and just prior to respiratory-gated micro-CT. Mice were then sacrificed to assess bronchoalveolar lavage and lung histology. From micro-CT images (voxel size = 46×46×46 µm), the numerical values of total lung attenuation, peribronchial attenuation (PBA), and PBA normalized by total lung attenuation were extracted. Each parameter was compared between OVA and control mice and correlation coefficients were calculated between micro-CT and histological data. As compared to control animals, ovalbumin-sensitized mice exhibited inflammation alone (Day 35), remodeling alone (Day 110) or both inflammation and remodeling (Day 75). Normalized PBA was significantly greater in mice exhibiting bronchial remodeling either alone or in combination with inflammation. Normalized PBA correlated with various remodeling markers such as bronchial smooth muscle size or peribronchial fibrosis. These findings suggest that micro-CT may help monitor remodeling non-invasively in asthmatic mice when testing new drugs targeting airway remodeling in pre-clinical studies.

Control maintenance can be predicted by exhaled NO monitoring in asthmatic patients.

BACKGROUND: Fractional exhaled nitric oxide (F(E)NO) is a marker of airway inflammation in asthma. Monitoring of such inflammation is currently not included in asthma guidelines and remains controversial. The hypothesis underlying the present study was that, F(E)NO could help assessing asthma control and, therefore, improve its management, by predicting loss of control in asthmatics. METHODS: A total of 90 adult asthmatics were included in the study. Asthma control was evaluated according to ACQ. All patients underwent F(E)NO by chemiluminescent (EndoNO) and hand-held (MINO) devices, followed by lung function testing. RESULTS: MINO was accurate as compared to EndoNO. F(E)NO was significantly increased in uncontrolled as compared to controlled asthmatics using both devices. F(E)NO measurement was able to predict control maintenance in controlled asthmatics in the absence of any change in their treatment. Indeed, using cut-off values of 31 and 40 ppb, the negative predictive values were 95 and 97% for EndoNO and MINO, respectively. EndoNO and MINO were also able to assess asthma control, although to a lesser extent. CONCLUSIONS: These findings suggest that F(E)NO can predict the persistence of asthma control in controlled patients and may now be used in asthma management since it can accurately be measured by means of hand-held devices.

Airway remodeling in asthma: new mechanisms and potential for pharmacological intervention.

The chronic inflammatory response within the airways of asthmatics is associated with structural changes termed airway remodeling. This remodeling process is a key feature of severe asthma. The 5-10% of patients with a severe form of the disease account for the higher morbidity and health costs related to asthma. Among the histopathological characteristics of airway remodeling, recent reports indicate that the increased mass of airway smooth muscle (ASM) plays a critical role. ASM cell proliferation in severe asthma implicates a gallopamil-sensitive calcium influx and the activation of calcium-calmodulin kinase IV leading to enhanced mitochondrial biogenesis through the activation of various transcription factors (PGC-1α, NRF-1 and mt-TFA). The altered expression and function of sarco/endoplasmic reticulum Ca(2+) pump could play a role in ASM remodeling in moderate to severe asthma. Additionally, aberrant communication between an injured airway epithelium and ASM could also contribute to disease severity. Airway remodeling is insensitive to corticosteroids and anti-leukotrienes whereas the effect of monoclonal antibodies (the anti-IgE omalizumab, the anti-interleukin-5 mepolizumab or anti-tumor necrosis factor-alpha) remains to be investigated. This review focuses on potential new therapeutic strategies targeting ASM cells, especially Ca(2+) and mitochondria-dependent pathways.

The pivotal role of airway smooth muscle in asthma pathophysiology.

Asthma is characterized by the association of airway hyperresponsiveness (AHR), inflammation, and remodelling. The aim of the present article is to review the pivotal role of airway smooth muscle (ASM) in the pathophysiology of asthma. ASM is the main effector of AHR. The mechanisms of AHR in asthma may involve a larger release of contractile mediators and/or a lower release of relaxant mediators, an improved ASM cell excitation/contraction coupling, and/or an alteration in the contraction/load coupling. Beyond its contractile function, ASM is also involved in bronchial inflammation and remodelling. Whereas ASM is a target of the inflammatory process, it can also display proinflammatory and immunomodulatory functions, through its synthetic properties and the expression of a wide range of cell surface molecules. ASM remodelling represents a key feature of asthmatic bronchial remodelling. ASM also plays a role in promoting complementary airway structural alterations, in particular by its synthetic function.