Pathophysiology of bronchial smooth muscle remodelling in asthma.

Whereas the role of bronchial smooth muscle remains controversial in healthy subjects its role is well established in asthmatics. Bronchial smooth muscle contraction induces airway narrowing. The smooth muscle also contributes to bronchial inflammation by secreting a range of inflammatory mediators, recruiting and activating inflammatory cells, such as mast cells or T-lymphocytes. In addition, bronchial smooth muscle mass is significantly increased in asthma. Such an increase has been related to a deposition of extracellular matrix proteins, and an increase in both cell size and number. However, the mechanisms of this smooth muscle remodelling are complex and not completely understood. The article will review recent data regarding the pathophysiology of bronchial smooth muscle remodelling in asthma.

Mast cell adhesion to bronchial smooth muscle in asthma specifically depends on CD51 and CD44 variant 6.

BACKGROUND: Mast cells infiltrate the bronchial smooth muscle (BSM) in asthmatic patients, but the mechanism of mast cell adhesion is still unknown. The adhesion molecules CD44 (i.e. hyaluronate receptor) and CD51 (i.e. vitronectin receptor) are widely expressed and bind to many extracellular matrix (ECM) proteins. The aims of the study are (i) to identify the role of ECM in mast cell adhesion to BSM and (ii) to examine the role of CD51 and CD44 in this adhesion. METHODS: Human lung mast cells, human mast cell line (HMC-1), and BSM cells from control donors or asthmatic patients were cultured in the presence/absence of various cytokines. Mast cell-BSM interaction was assessed using (3)H-thymidine-pulsed mast cells, confocal immunofluorescence, or electron microscopy. Adhesion molecules expression and collagen production on both cell types were evaluated by quantitative RT-PCR, western blot, and flow cytometry. RESULTS: Mast cell adhesion to BSM cells mostly involved type I collagen of the ECM. Such an adhesion was increased in normal BSM cells under inflammatory condition, whereas it was maximal in asthmatic BSM cells. Blockade of either CD51 or CD44 significantly decreased mast cell adhesion to BSM. At the molecular level, protein and the transcriptional expression of type I collagen, CD51 or CD44 remained unchanged in asthmatic BSM cells or in mast cells/BSM cells under inflammatory conditions, whereas that of CD44 variant isoform 6 (v6) was increased. CONCLUSIONS: Mast cell-BSM cell adhesion involved collagen, CD44, and CD51, particularly under inflammatory conditions. CD44v6 expression is increased in asthmatic BSM cells.

Masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid-dependent asthmatics.

BACKGROUND: Masitinib is a tyrosine kinase inhibitor targeting stem cell factor receptor (c-kit) and platelet-derived growth factor (PDGF) receptor, which are expressed on several cell types including mast cells and bronchial structural cells, respectively. We hypothesized that c-kit and PDGF receptor inhibition may decrease bronchial inflammation and interfere with airway remodeling, which are crucial features of severe asthma. OBJECTIVES: The primary endpoint was the percent change from baseline in oral corticosteroids after 16 weeks of treatment. Change in asthma control (asthma control questionnaire), exacerbation rate, pulmonary function tests, rescue medication requirement and safety were secondary endpoints. METHODS: A 16-week randomized, dose-ranging (3, 4.5, and 6 mg/kg/day), placebo-controlled study was undertaken in 44 patients with severe corticosteroid-dependent asthma who remained poorly controlled despite optimal asthma management. RESULTS: At 16 weeks of treatment, a comparable reduction in oral corticosteroids was achieved with masitinib and placebo (median reduction of -78% and -57% in the masitinib and placebo arms, respectively). Despite this similar reduction, the Asthma Control Questionnaire score was significantly better in the masitinib arm as compared to placebo with a reduction by 0.99 unit at week 16 (P < 0.001) vs 0.43 unit in the placebo arm. Masitinib therapy was associated with more transient skin rash and edema. CONCLUSIONS: Masitinib, a c-kit and PDGF-receptor tyrosine kinase inhibitor, may represent an innovative avenue of treatment in corticosteroid-dependent asthma. These preliminary results warrant further long-term clinical studies in severe asthma

[Atopic dermatitis aggravates the allergic airways inflammation in acute viral bronchiolitis]. / La dermatite atopique aggrave l'inflammation allergique dans la bronchiolite aiguë virale.

INTRODUCTION: Exhaled nitric oxide (FeNO) is a putative non-invasive marker of eosinophilic airway inflammation with a good predictive value for allergic asthma in preschool children. The aim of the present study was to compare FeNO after acute viral bronchiolitis (AVB) in children aged less than 2 years without atopic dermatitis (AD) vs those with atopic dermatitis, as well as children with AD without any history of AVB. METHODS: Forty-two children (mean age +/- SD: 12.3 +/- 5.2 months; range 5.0-23.5; sex-ratio M: F=1.3: 1) were included in this prospective study, > 8 wks after an episode of AVB. The patients' atopic status was assessed both by clinical phenotype and IgE- mediated response to inhaled and/or food allergens. FeNO (ppb) was measured off-line by the chemoluminescence method on samples obtained from gas collected in a balloon during tidal breathing. RESULTS: There was a significant difference between the AVB/AD (23.4 +/- 14.3 ppb, n=15) vs the AVB without AD group (13.5 +/- 10. 1 ppb, n=13) or the AD without AVB group (11.0 +/- 8.3 ppb, n=14). Maternal feeding for more than 2 months decreased FeNO by 50%. CONCLUSION: Atopic children below 2 years with AD produce more NO after AVB than non-atopic children or atopic children without any history of AVB. Maternal feeding decreases FeNO.

Omalizumab decreases nonspecific airway hyperresponsiveness in vitro.

BACKGROUND: In asthmatic patients, both symptoms and hyperresponsiveness are related to immunoglobulin E (IgE) concentration in serum. The anti-IgE monoclonal antibody omalizumab improved the control of asthma, but its effect on airway hyperresponsiveness is controversial. Passive sensitization reproduced in vitro a bronchial hyperresponsiveness, an increase in IgE bearing cells, and a mast cell degranulation. This study was designed to examine the effect of omalizumab on passive sensitization-induced hyperresponsiveness, alterations in IgE positive inflammatory cells and mast cell degranulation within the bronchial wall. METHODS: Proximal (3-5 mm diameter) and distal (0.5-1.5 mm diameter) human bronchi dissected out from 10 lung specimens were incubated in normal or asthmatic serum containing various concentrations of omalizumab. Contractile responses to histamine or Dermatophagoides pteronyssinus (D. pter) were recorded using an organ bath system and expressed as percentage of maximal contractile response to acetylcholine (ACh). Immunohistochemistry was performed using monoclonal antibodies directed against IgE or tryptase. Mast cells were classified as fully granulated (type I), partly (type II) or largely degranulated (type III). RESULTS: The specific bronchial hyperresponsiveness to D. pter and the nonspecific bronchial hyperresponsiveness to histamine following passive sensitization were significantly inhibited by omalizumab in both distal and proximal airways. Passive sensitization-induced increase in IgE positive cells was also abolished by omalizumab in a concentration dependent manner. Mast cell degranulation which was inhibited by omalizumab was positively correlated with the contractile response to D. pter. CONCLUSIONS: Omalizumab blocks specific and nonspecific bronchial hyperresponsiveness. Anti-IgE also decreases IgE bearing cell number and mast cell degranulation.

Inflammation of bronchial smooth muscle in allergic asthma.

BACKGROUND: Recent observations in asthma suggest that bronchial smooth muscle is infiltrated by inflammatory cells including mast cells. Such an infiltration may contribute to airway remodelling that is partly due to an increase in smooth muscle mass. Whether muscle increase is the result of smooth muscle cell hypertrophy remains controversial and has not been studied by ultrastructural analysis. A morphometric analysis of airway smooth muscle (ASM) was undertaken in asthmatic patients using electron microscopy to examine the interactions between ASM cells and inflammatory cells. METHODS: ASM specimens were obtained from 14 asthmatic subjects and nine non-asthmatic controls undergoing fibreoptic endoscopy. Inflammatory cell counts were assessed by immunohistochemistry, and ultrastructural parameters were measured using electron microscopy in a blinded fashion on smooth muscle cells and inflammatory cells. RESULTS: ASM from asthmatic patients was infiltrated by an increased number of mast cells and lymphocytes. Smooth muscle cells and their basal lamina were thicker in asthmatic patients (9.5 (0.8) and 1.4 (0.2) microm) than in controls (6.7 (0.4) and 0.7 (0.1) microm). In asthmatics the extracellular matrix was frequently organised in large amounts between ASM cells. Myofibroblasts within smooth muscle bundles were only observed in asthmatics, some of them displaying a close contact with ASM cells. CONCLUSION: In asthma, airway myositis is characterised by a direct interaction between ASM cells and mast cells and lymphocytes. Smooth muscle remodelling was present, including cell hypertrophy and abnormal extracellular matrix deposition moulding ASM cells.

[IgE and respiratory disease]. / Immunoglobuline E et maladies respiratoires.

INTRODUCTION: IgE is known to provide the biological basis for allergy and immediate hypersensitivity. However, recent data provide some evidence that IgE responses are involved in other inflammatory processes apart from allergy, including several respiratory diseases. STATE OF THE ART: IgE binds to mast cells and basophils but also to other inflammatory cells, which are involved in non-allergic processes. IgE has a role in antigen presentation and is implicated in a number of other immune mechanisms. In the airways, IgE plays an important role in bronchial hyperactivity, even in the absence of an allergen. Epidemiological studies have demonstrated that IgE response is related not only to allergy but also to asthma symptoms, in the presence or absence of atopy, as well as exposure to cigarette smoke. IgE response is altered in several respiratory diseases including extrinsic and intrinsic asthma and allergic bronchopulmonary aspergillosis. CONCLUSION AND PERSPECTIVES: Since anti-IgE monoclonal antibodies are now available for administration to humans, a better understanding of the IgE response may allow the identification of novel therapeutic targets in the field of respiratory disease.

[Development of a questionnaire concerning the knowledge of COPD]. / Développement d'un questionnaire de connaissances sur la BPCO.

INTRODUCTION: The level of a patient's knowledge about his disease and its treatment is an essential part of an educational assessment. It is useful therefore to make use of a rapid, easy and valid method to collect the information necessary to develop an educational programme adapted to the needs of the patient. The aim of this study is to validate, in a structured way, a knowledge questionnaire on chronic obstructive pulmonary disease (COPD). METHODS: Following a revue of the literature an initial questionnaire was constructed. It included of four domaines: biomedical aspects; symptoms and signs of severity; general knowledge and treatments. The questionnaire was tested on 35 subjects with COPD in order to assess its clarity and comprehensibility. It was reviewed and modified in both content and format by 11: French experts. The reproducibility was studied by repeat testing. RESULTS: The first version of the questionnaire developed by the working party consisted of 50 items. It was reduced to 41 items after interviews with 35 COPD patients and evaluation by 11 experts. The questionnaire appeared to be reproducible: mean concordance 79.5%; minimum 53.3%; maximum 100% and intra-class correlation coefficient 0.53. CONCLUSION: This study lead to the development of a French language COPD knowledge questionnaire.

How should nasal symptoms be investigated in asthma? A comparison of radiologic and endoscopic findings.

BACKGROUND: To improve asthma control, the management of rhinosinusitis often leads the physician to perform sinonasal imaging and/or nasal endoscopy, but their respective contributions are still insufficiently understood. OBJECTIVE: To evaluate the potential contribution of a symptoms questionnaire, sinus radiography (SR) and computed tomography (CT) scan to the diagnosis of nasal diseases in asthmatic patients when compared with ENT examination. METHODS: A total of 124 patients completed a questionnaire on nasal symptoms administered by the chest physician. Then, they underwent ENT examination. On the same day, SR and CT scans were performed independently. RESULTS: Patients (80.3%) had nasal symptoms during the month preceding the consultation. The ENT examination was normal in 8.1% (n = 10) and revealed rhinitis in 57.3% (n = 71), rhinosinusitis in 14.5% (n = 18) and nasal polyposis in 20.2% (n = 25). For rhinitis, the negative predictive value of bilateral nasal obstruction was 87.8%. Both SR and CT had low sensitivity and specificity. For rhinosinusitis, the negative predictive value of nasal symptoms varied from 85.4 to 95.2%. Sinus CT was at least as accurate as SR for the diagnosis of rhinosinusitis. In a multivariate analysis, only the CT scan (score > or =12) appeared to be significantly associated with the diagnosis of nasal polyposis. CONCLUSION: In asthmatic patients, physicians need to enquire systematically about the existence of nasal symptoms by using this simple questionnaire which is sensitive for rhinitis, and has good negative predictive value for excluding rhinosinusitis and nasal polyposis.

[Anti-IgE and future treatments for respiratory allergies]. / Les anti-IgE et les traitements du futur des allergies respiratoires.

Immediate hypersensitivity remains the fundamental mechanism of respiratory allergy, emphasizing the importance of the antigen-immunoglobulin (IgE) reaction. Development of innovating treatments has naturally centered on a search for compounds inhibiting the IgE response, in particular anti-IgE antibodies. Humanized anti-IgE antibodies have been recently developed for administration in humans. These antibodies are designed to form complexes with circulating IgE which can be eliminated. The first trials have demonstrated an efficacy in allergic asthma, expressed by a significant decrease in consumption of systemic steroids in severe asthma. Other work has also showed a lower number of hospitalizations for acute asthma. Other therapeutic approaches have focused on limiting the production of IgE by an effect on the auxiliary lymphocyte balance, or more generally, by inhibiting the Th2 response while favoring the Th1 response. Early results obtained with anti-IL-5 were disappointing since the decrease in the eosinophilic response was not associated with any alteration in bronchial hyperreactivity. Administration of IL-12 has given similar results but the first trials with nebulized anti-IL-4 are more promising.

Asthma phenotypes according to the timing of smoking onset in young adults.

SETTING: Whether and how cigarette smoking influences asthma are still matters of debate. OBJECTIVE: To identify risk factors associated with asthma according to whether individuals began active smoking before or after asthma onset. DESIGN: A sample of 544 individuals was examined using the protocol of the European Community Respiratory Health Status, Phase 1. RESULTS: Current active smoking (43.6%) was associated with wheezing during the past year (15.2%, OR 3.7; 95% CI 1.7-8.4), but not with asthma (17.6%, OR 0.78; 95% CI 0.48-1.26). However, active smoking modulated risk factors for asthma. Asthma that developed before smoking and asthma without smoking were both significantly related to nasal allergy, parental asthma and atopy (as assessed by skin prick test positivity and increased total and specific IgE levels). Only a lower FEV1 level was significantly associated with asthma that initiated after beginning smoking. CONCLUSIONS: Our data put forward different phenotypes of asthma according to the timing of smoking onset and suggest that asthma either never accompanied by smoking or followed by smoking onset might be characterised by an allergic pattern. Longitudinal studies are warranted to further clarify the relationships among asthma phenotypes according to the sequence of disease onset and smoking.

[Validation of an asthma knowledge questionnaire]. / Validation d'un questionnaire de connaissances sur l'asthme.

INTRODUCTION: A patient's knowledge of his disease and its treatment is an essential part of the evaluation of an educational process. It is useful therefore to use a rapid, easy and valid means of collecting the information necessary to produce an educational programme adapted to the needs of the patient. METHODS: Following a review of the literature an initial questionnaire was constructed. It included four domains: biomedical, signs and symptoms of severity, general knowledge and treatment. The questionnaire was administered to 73 asthmatics in order to assess its clarity and comprehensibility. It was then reviewed and modified in both format and content by 10 French experts. The revised questionnaire was completed by 108 asthmatics distributed throughout 10 French respiratory centres, a group of 83 non-asthmatic subjects and 203 sixth year medical students at the Bordeaux University School of Medicine. RESULTS: The mean scores were: 19 for the non-asthmatics (range 2-36), 25.7 for the asthmatics (range 4-38) and 32.9 for the students (range 17-40), p 0.0001. The questionnaire was shown to be discriminating with good reliability and reproducibility: alpha Cronbach coefficient=0.82; intra-class correlation coefficient=0.70. CONCLUSIONS: This study has validated a French language asthma knowledge questionnaire.

Acute asphyxia caused by Gerhardt's syndrome associated with asthma.

Vocal cord dysfunction (VCD) has been frequently discussed as confounding the diagnosis of asthma, and it is recommended to examine vocal cord function in cases of difficult asthma. However, there is also strong evidence that asthma may be associated with VCD, sometimes masquerading as exercise-induced asthma. Gerhardt's syndrome frequently induces severe acute respiratory distress requiring ventilatory support, and this condition might be mistaken for a severe acute asthma attack. Here, a case of bilateral paralysis of the vocal cords, which was associated with asthma, is described.

[Impact of smoking habits on the every day life of asthmatic adolescents]. / Influence du tabagisme sur la vie quotidienne des adolescents asthmatiques.

The impact of asthma on every day life is an important consideration in asthma management. Tobacco use often starts during adolescence, but little is known about its effect on the asthmatic process. The aim of this study is to describe the impact of smoking habits on the every day life of adolescents with asthma. A survey of respiratory symptoms in children aged 13-14 years was conducted in Bordeaux France as part of the International Study of Asthma and Allergies in Childhood (ISAAC). 494 out of the 3.302 adolescents surveyed had a diagnosis of asthma. They filled in a further questionnaire on smoking habits and on the impact asthma had on their every day life. Respiratory symptoms were more frequent among current smoking asthmatic adolescents than non-smoking asthmatic adolescents. The impact of asthma on daily life, with implications for performance at school, family life, psychological status and future job prospects were different for smokers and non-smokers, with problems more prevalent for active smoking asthmatic adolescents. In a multiple regression analysis with confounding factors adjustment, school absence was reported more often in active smokers. Active smoking has an important impact on the every day life of asthmatic adolescents.

Passive sensitization of human airways induces mast cell degranulation and release of tryptase.

BACKGROUND: This study was designed to examine the effect of passive sensitization (PS) on human bronchial mast cells. PS with asthmatic serum induces a hyper-responsiveness to nonspecific agonists, and immunoglobulin (Ig)E binding mainly on mast cells. METHODS: Bronchi dissected out from 19 lung specimens were incubated in normal or asthmatic serum. Immunohistochemistry was performed using monoclonal antibodies (MoAbs) directed against tryptase, chymase, or c-kit. Mast cells were classified as fully granulated (type I), partly (type II) or largely degranulated (type III). Tryptase was measured in supernatant using ELISA. Contractile response was recorded in a separated set of experiments using an organ bath system. RESULTS: PS decreased both tryptase positive cells (47.9 +/- 10.0 vs. 26.7 +/- 4.8 cell/mm2, P = 0.003) and chymase positive cells (26.1 +/- 3.3 vs. 14.9 +/- 1.8 cell/mm2, P = 0.01), but did not alter the number of c-kit positive cell. PS decreased the proportion of type I (55.4 vs. 28.9%, P < 0.0001) and, concomitantly increased that of types II (23.2 vs. 41.0%, P < 0.0001) and III (21.4 vs. 30.1%, P = 0.04). Following PS, tryptase concentration significantly increased and the magnitude of histamine response, was correlated with the amount of type II mast cells. CONCLUSION: PS of human isolated bronchi induces a mast cell degranulation related to in vitro hyper-responsiveness, along with a tryptase release.

[Does the presence of a pet at home influence the prevalence of asthma and rhinitis?]. / La prévalence de l'asthme et de la rhinite est-elle différente selon la présence d'un animal domestique?

INTRODUCTION: Recent epidemiological studies have shown an increase in the prevalence of asthma and allergic diseases. Among aetiological factors, the domestic environment and, in particular, pet ownership may be a part of it. The relationship between severity of asthma and pets is still unclear. The aim of this study was to evaluate the relationship of asthma and rhinitis prevalence in teenagers with pet ownership. PATIENTS AND METHODS: ISAAC I studied 3,303 teenagers (13-14 years old) in Bordeaux in 1994. They completed a written questionnaire about asthma, rhinitis, eczema and their domestic environment. Four groups (asthmatics, asthmatics with rhinitis, teenagers with only rhinitis and a control group without asthma and rhinitis) were studied. RESULTS: 4.6% had only asthma. 43.2% had only rhinitis. 10.3% had asthma and rhinitis, 41.7% had no allergic disease. 34.9% kept a cat and 79.4% allowed the cat to go inside. No difference was found between the four groups with regard cat, dog, bird or other pet ownership irrespective if the pet was kept in-doors or out doors. The prevalence of previous asthma was 45.8% and 50.3% for current asthma. No difference was found between the severity of asthma and pet ownership. CONCLUSIONS: This is an epidemiological study based on a written questionnaire. Furthermore there is no data on the presence of pets during the first year of life. However, our results suggest that pet ownership amongst asthma and rhinitis sufferers is not different to that in the group without allergic disease.

[The pathophysiological role of smooth muscle cells in bronchial inflammation]. / Physiopathologie de la cellule musculaire lisse dans l'inflammation bronchique.

Airway smooth muscle cells (SMC) have been implicated in the pathophysiology of bronchial inflammation. SMC can be considered a target of the inflammatory reaction. This cell-type is capable of contraction, proliferation and mediator synthesis in response to various stimuli, in particular those associated with the inflammatory reaction. SMC can also be considered as an inflammatory cell-type. Cytokines and adhesion molecules released by SMC have an autocrine action and paracrine action on other cell-types, particularly those involved in inflammation, inducing chemotactism and cell adhesion. This interaction allows SMC to directly act on cells such as the T-lymphocyte, the eosinophil and the mast cell. SMC could therefore be a potential target of anti-inflammatory treatment.

Spontaneous pneumothorax: pragmatic management and long-term outcome.

We prospectively considered 65 patients admitted for a spontaneous pneumothorax (SP) to describe the pragmatic management of SP, the first recurrence-free interval after medical therapeutic procedure and to specify the first recurrence risk factors over a 7-year period in these patients treated medically. The treatment options were observation alone (9%), needle aspiration (6%), small calibre chest tube (Pleurocatheter) drainage (28%) or thoracic tube drainage (49%), and pleurodesis with video-assisted thoracic surgery procedure (8%). Duration of the drainage and length of hospital stay were shorter in the Pleurocatheter group than in the thoracic tube group (P < 0.01). Among the 47 patients (72%) with a first SP and treated medically, nine patients (19%) had a first homolateral recurrence (FHR) during a mean follow-up of 84+/-13 months. Recurrence-free intervals ranged from 1 to 24 months (mean +/- SD: 9.3+/-8.4 months). FHR cases were more frequent in the Pleurocatheter group (P < 0 04). Analysis of potential risk factors showed that the patient's height and a previous homolateral SP episode are independent recurrence risk factors.

Tryptase and agonists of PAR-2 induce the proliferation of human airway smooth muscle cells.

Airway remodeling with smooth muscle cell (SMC) hyperplasia is a feature of chronic asthma. We investigated the potential for tryptase, the major secretory product of human mast cells, to act as a growth factor for human airway SMCs. Because this serine protease can activate proteinase-activated receptor-2 (PAR-2), we also examined the actions of SLIGKV, a peptide agonist of PAR-2. Incubation with lung tryptase provoked a twofold increase in [(3)H]thymidine incorporation; a similar increase in cell numbers was found when we used the MTS assay. The effect was catalytic site dependent, being abolished by the protease inhibitors leupeptin and benzamidine and by heat inactivation of the enzyme. Tryptase-induced DNA synthesis was inhibited by preincubation of the cells with pertussis toxin, calphostin C, or genistein. Transduction mechanisms are thus likely to involve a pertussis toxin-sensitive G protein, protein kinase C, and tyrosine kinase. SLIGKV elicited a response on SMCs similar to that of tryptase. Tryptase could provide an important stimulus for SMC proliferation in asthmatic airways, by acting on PAR-2.