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.

[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.

Spontaneous pneumothorax associated with Pneumocystis carinii pneumonia. Successful treatment with talc pleurodesis.

Spontaneous pneumothoraces occur in patients with acquired immunodeficiency syndrome and Pneumocystis carinii pneumonia. However, treatment with tube insertion and tetracycline sclerosis often fails to prevent recurrence. We present a single case of such a patient successfully treated with talc sclerosis.

Selected contribution: tryptase-induced PAR-2-mediated Ca(2+) signaling in human airway smooth muscle cells.

Tryptase, the major mast cell product, is considered to play an important role in airway inflammation and hyperresponsiveness. Tryptase produces different, sometimes opposite, effects on airway responsiveness (bronchoprotection and/or airway contraction). This study was designed to examine the effect of human lung tryptase and activation of protease-activated receptor (PAR)-2 by synthetic activated peptide (AP) SLIGKV-NH(2) on Ca(2+) signaling in human airway smooth muscle (HASM) cells. Immunocytochemistry revealed that PAR-2 was expressed by HASM cells. Tryptase (7.5--30 mU/ml) induced a concentration-dependent transient relative rise in cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) that reached 207 +/- 32 nM (n = 10) measured by indo 1 spectrofluorometry. The protease inhibitors leupeptin or benzamidine (100 microM) abolished tryptase-induced [Ca(2+)](i) increase. Activation of PAR-2 by AP (1-100 microM) also induced a concentration-dependent transient rise in [Ca(2+)](i), whereas the reverse peptide produced no effect. There was a homologous desensitization of the [Ca(2+)](i) response on repeated stimulation with tryptase or AP. U-73122, a specific phospholipase C (PLC) antagonist, xestospongin, an inositol trisphosphate (IP(3))-receptor antagonist, or thapsigargin, a sarcoplamic Ca(2+)-ATPase inhibitor, abolished tryptase-induced [Ca(2+)](i) response, whereas Ca(2+) removal, in the additional presence of EGTA, had no effect. Calphostin C, a protein kinase C inhibitor, increased PAR-2 [Ca(2+)](i) response. Our results indicate that tryptase activates a [Ca(2+)](i) response, which appears as PAR-2 mediated in HASM cells. Signal transduction implicates the intracellular Ca(2+) store via PLC activation and thus via the IP(3) pathway. This study provides evidence that tryptase, which is increasingly recognized as an important mediator in airway inflammation and hyperresponsiveness, is also a potent direct agonist at the site of airway smooth muscle.

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.

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.

Practical evaluation of asthma exacerbation self-management in children and adolescents.

The objective of this study was to describe asthma exacerbation self-management in children and adolescents. We used a cross-sectional study population enrolled in the International Study of Asthma and Allergies in Childhood (ISAAC) in Bordeaux. Subjects answered an additional questionnaire on utilization of health services, self-evaluation of usual asthma exacerbation severity and home management of asthma exacerbation. Criteria used for selecting patients were both having asthma confirmed by a physician and having had suffered from symptoms during the past year. Children and adolescents attended similar health services for managing their asthma but compliance to anti-asthmatic treatment was better in children than in adolescents. Among the children 4.8% had asthma and 6.2% of adolescents had asthma, as diagnosed by a doctor. Of the children, 72.3% and of the adolescents 54.7% had less than one asthma attack per month. In cases of mild asthma exacerbation, 38.7% of adolescents and 9.3% of children waited until the end of exacerbation without taking any medication. The proportion of children not receiving any treatment was lower when symptoms were more severe but this was not the case in adolescents. Although most of the patients used were taking beta2-agonist, we found that 21-43% of children or adolescents did not receive appropriate medication in the event of asthma exacerbation. These results demonstrate that (i) asthma exacerbation self-management is related to self-assessed severity of symptoms and that (ii) a large proportion of asthmatic children in the community, and particularly adolescents, do not therefore receive appropriate treatment in the event of asthma exacerbation.

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.

[Immunoglobulins E and inflammatory cells]. / Immunoglobulines E et cellules de l'inflammation.

Immunoglobulins E (IgE) have a privileged relationship with inflammatory cells due to the fact that there are different receptors for their Fc fragment expressed on the cell's surface. Currently one recognises at least three types of receptor: high affinity receptors (Fc epsilon RI) which are present on the surface of mast cells, basophils, and Langerhans cells. The receptors of low affinity (Fc epsilon RII) are represented on the surface of numerous inflammatory cells (eosinophils, lymphocytes, platelets...) and some lectine type (epsilon BP) receptors which are present on polymorpho-nuclear neutrophils and activated macrophages. The IgE interaction in the presence of specific antigens on the receptor may lead to cellular activation by transduction mechanism which are becoming better understood. This sequence of events, combined with the mechanisms of immediate hypersensitivity lead to the liberation of mediators and cytokines which nature varies according to the cell type and its environment. Polymorpho-nuclear eosinophils, mast cells, basophils and many other cells comply with this type of activation. However, the relationship between IgE and cells is not limited to this type of activation response. In the absence of specific antigen, IgE may sometimes play an inhibitory role on cellular functions; it is the case of blood platelets and polymorpho-nuclear neutrophils. Finally, IgE also participates in normal mechanisms of immune defence and may perhaps, by their presence on the surface of the dentritic cells, be determining factors in the function of antigen presentation. The diversity of IgE action at cellular level may equally be observed at the level of the bronchus, on organ which is implicated in allergic pathology. Passive sensitisation of the human bronchus by IgE may have at least two types of effect on the contractile response observed in vivo: in the presence of specific antigen it enables the contraction of bronchial smooth muscles and in the absence of antigen it could change the contractile response to non-specific agonists as it is observed in vivo in bronchial hyper-reactivity.

[A new form of mushroom workers' lung]. / Une nouvelle forme du poumon des champignonnistes.

The authors describe a new form of mushroom workers' lung after assessing the clinical situation and also the results of an immunological study. The case was related to the mushroom Poria megalopora. A new antigen has been identified and also its domiciliary origin, thus the ubiquitous nature of the antigen contributes to the interest of the case reported.

[Response to IgE]. / La réponse à IgE.

Over the last three decades, a good deal of work has focused on the IgE response due to the implication of these antibodies in allergic diseases. IgE antibodies, mediators of immediate hypersensitivity reactions, bind to specific high or low affinity receptors which are distributed on cell surfaces throughout the organism. Activation of receptors contributes to the different aspects of allergic inflammation. Regulation of the IgE response is complex and involves different factors modulating isotype synthesis, low-affinity receptor FcERII:CD23 and its soluble portion, and the Th1/Th2 balance. Allergic diseases are characterized by a dysregulated IgE response, probably related to an imbalance favoring Th2 leading to exaggerated reaction. The advent of anti-IgE treatments can be seen as a notable progress in the management of atopic diseases. Their contribution will depend on the exact role of the IgE response in inflammatory allergic reactions.

[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.

[Diagnostic and therapeutic strategies in acute pneumopathies in urban practice]. / Stratégies diagnostiques et thérapeutiques devant les pneumopathies aiguës en pratique de ville.

The consensus conference of the French Language Society of Infectious Disease convened at Lille in 1991 stressed the fact that "in the management of pneumonia, neither the clinical features nor the bacteriological information would enable a prediction of the responsible and effective agent with sufficient accuracy" and that antibiotic therapy should be empirical, based on the probabilities linked to the epidemiology and locality. The object of this study was to ascertain the diagnosis and therapeutic attitude of the general practitioner (GP) dealing with an acute infectious pneumonia in a 40 year old adult, previously well without any critical signs, which was the model taken for the consensus conference. One hundred GPs were selected at random from the general medical list in the city of Bordeaux and registered with the local medical council in Gironde. They were invited to answer a questionnaire containing 69 questions. The results were analysed for the two phases of the enquiry. The strategy of first intention and the method of re-evaluating for treatment instituted. Secondly the strategy used when faced with a patient who did not improve with the initial treatment. Eighty eight GPs answered the questionnaire and thus we are able to give the following information: the differential diagnosis was not clearly made between bronchial and pulmonary pathology when faced with a lower respiratory tract infection; two thirds of the GPs had a diagnostic and therapeutic approach which was in agreement with the recommendations of the consensus.(ABSTRACT TRUNCATED AT 250 WORDS)

[Treatment of severe asthmatic crisis. Evaluation of international guidelines]. / Traitement de la crise d'asthme sévère. Evaluation de recommandations internationales.

Acute asthma can sometimes be severe and potentially life threatening. International guidelines have defined both characteristics of these severe attacks and the associated therapeutic instructions. The efficacy and feasibility of these recommendations were evaluated in 15 asthmatic patients who were admitted to hospital because a severe asthma attack. These patients fulfilled the criteria of severity defined by a British experts conference in the international guidelines published in 1990 in the British Medical Journal. A first line treatment was given to all the patients and included both systemic corticosteroids and inhaled beta 2-agonists. In case of failure, beta 2-agonists were given intravenously and oxygen was administered as required. Monitoring was carried out between the admission and the 8th hour using the following criteria: peak expiratory flow (DP), respiratory frequency (FR), and heart rate (FC). Both DP and FR significantly improved from 196 +/- 79 to 292 +/- 104 l/min (p < 0.01) and from 27.5 +/- 5.5 to 23.7 +/- 5.6 (p < 0.02), respectively. FR remained unchanged (97 +/- 13 vs 98 +/- 13; ns). There was a favourable outcome in all cases. beta 2-agonists administered intravenously were only necessary in two patients for whom no predictive factor could be determined. It is concluded that international guidelines are applicable to severe acute asthma. Inhaled route for beta 2-agonist is sufficient for the majority of patients presenting with the criteria defining severe acute asthma unless life threatening symptoms are present.

[Moderate asthma in adults: diagnosis and management in general medical practice]. / Asthme modéré de l'adulte: diagnostic et prise en charge en médecine générale.

Moderate asthma is a frequent disorder in general medicine. In 1990, the British Thoracic Society published their first guidelines on the management of asthma. Three years later, we have studied, using a questionnaire, the diagnosis and therapeutic criteria of moderate asthma used by general physicians, and comparing these to the guideline recommendations. Out of 46 physicians questioned in Bordeaux, 40 (87 per cent) agreed to participate in the study. Thirty two physicians (80 per cent) described as moderate an asthma which was mild according to the guidelines; eight physicians (20 per cent) described a moderate asthma according to the guidelines; twenty five (63 per cent) considered as severe a moderate asthma according to the recommendations, although eleven (28 per cent) considered it as moderate and four (10 per cent) did not give an opinion. In total, four (10 per cent) judged asthma severity according to the guidelines (Group R), twenty one (52 per cent) over-estimated the severity of moderate asthma (Group S), and fifteen (37 per cent) gave an inconsistent assessment (Group 1). Twenty six (65 per cent) prescribed an association of beta-2-agonists and inhaled corticosteroids for moderate asthma. Although most of the questioned physicians gave an appropriate treatment for moderate asthma treatment adapted to the severity of the situation, their therapeutic approach did not seem to be based upon the same criteria than that recommended in the guidelines.

[Evolution of the management of lung diseases in general medicine in Bordeaux (1992-1995)]. / Evolution de la prise en charge des pneumopathies en médicine générale à Bordeaux (1992-1995).

Lower respiratory tract infections (LRTI) are very often managed by General Practitioners (GPs). In France, the 1991 Lille Consensus Conference set out guidelines for the management of respiratory tract infections; in 1994, the Ministry of Health published Official Medical Recommendations (OMR) to be applied to seasonal respiratory infections. The aim of the study is to evaluate the impact of these OMR in 1995 on GPs' attitude when confronted with a community-acquired pneumonia in a previously healthy 40-year-old adult, with no sign of complications. Sixty seven GPs took, part in the same study by questionnaire in 1992 and 1995; we observed an increase in the prescription of aminopenicillin without a beta-lactamase inhibitor (41% in 1992 vs 66% in 1995; p = 0.009), and a reduction in both the use of aminopenicillin with a beta-lactamase inhibitor (35% in 1992 vs 11% in 1995; p = 0.002) and the concomitant prescription of cortico-steroids (43% in 1992 vs 14% vs 14% in 1995; p = 0.0009). Between 1992 and 1995, general practitioners in the Bordeaux region have changed their therapeutic choices in community-acquired pneumonia. In 1995, antibiotic prescriptions followed consensus guidelines more closely.