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In March 2023, the European Forum for Research and Education in Allergy and Airways diseases (EUFOREA) organized its bi-annual Summit in Brussels with expert panel members of EUFOREA, representatives of the EUFOREA patient advisory board, and the EUFOREA board and management teams. Its aim was to define the research, educational and advocacy initiatives to be developed by EUFOREA over the next 2 years until the 10th anniversary in 2025. EUFOREA is an international non-for-profit organization forming an alliance of all stakeholders dedicated to reducing the prevalence and burden of chronic allergic and respiratory diseases via research, education, and advocacy. Based on its medical scientific core competency, EUFOREA offers an evidence-supported platform to introduce innovation and education in healthcare leading to optimal patient care, bridging the gap between latest scientific evidence and daily practice. Aligned with the mission of improving health care, the expert panels of asthma, allergic rhinitis (AR), chronic rhinosinusitis (CRS) & European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS), allergen immunotherapy (AIT) and paediatrics have proposed and elaborated a variety of activities that correspond to major unmet needs in the allergy and respiratory field. The current report provides a concise overview of the achievements, ambitions, and action plan of EUFOREA for the future, allowing all stakeholders in the allergy and respiratory field to be up-dated and inspired to join forces in Europe and beyond.
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Gastro-oesophageal reflux disease (GORD) has long been associated with poor asthma control without an established cause-effect relationship. 610 asthmatics (421 severe/88 mild-moderate) and 101 healthy controls were assessed clinically and a subset of 154 severe asthmatics underwent proteomic analysis of induced sputum using untargeted mass spectrometry, LC-IMS-MSE. Univariate and multiple logistic regression analyses (MLR) were conducted to identify proteins associated with GORD in this cohort. When compared to mild/moderate asthmatics and healthy individuals, respectively, GORD was three- and ten-fold more prevalent in severe asthmatics and was associated with increased asthma symptoms and oral corticosteroid use, poorer quality of life, depression/anxiety, obesity and symptoms of sino-nasal disease. Comparison of sputum proteomes in severe asthmatics with and without active GORD showed five differentially abundant proteins with described roles in anti-microbial defences, systemic inflammation and epithelial integrity. Three of these were associated with active GORD by multiple linear regression analysis: Ig lambda variable 1-47 (pâ¯=â¯0·017) and plasma protease C1 inhibitor (pâ¯=â¯0·043), both in lower concentrations, and lipocalin-1 (pâ¯=â¯0·034) in higher concentrations in active GORD. This study provides evidence which suggests that reflux can cause subtle perturbation of proteins detectable in the airways lining fluid and that severe asthmatics with GORD may represent a distinct phenotype of asthma.
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Asma/complicaciones , Asma/metabolismo , Reflujo Gastroesofágico/complicaciones , Proteómica/métodos , Esputo/metabolismo , Adulto , Asma/epidemiología , Asma/psicología , Endopeptidasas/metabolismo , Unión Europea/organización & administración , Femenino , Reflujo Gastroesofágico/diagnóstico , Reflujo Gastroesofágico/epidemiología , Humanos , Cadenas lambda de Inmunoglobulina/metabolismo , Lipocalina 1/metabolismo , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Prospectivos , Inhibidores de Proteasas/metabolismo , Calidad de Vida , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Eosinophilia is a marker of corticosteroid responsiveness and risk of exacerbation in asthma; although it has been linked to submucosal matrix deposition, its relationship with other features of airway remodelling is less clear. OBJECTIVE: The aim of this study was to investigate the relationship between airway eosinophilia and airway remodelling. METHODS: Bronchial biopsies from subjects (n = 20 in each group) with mild steroid-naïve asthma, with either low (0-0.45 mm(-2)) ) or high submucosal eosinophil (23.43-46.28 mm(-2) ) counts and healthy controls were assessed for in vivo epithelial damage (using epidermal growth factor receptor staining), mucin expression, airway smooth muscle (ASM) hypertrophy and inflammatory cells within ASM. RESULTS: The proportion of in vivo damaged epithelium was significantly greater (P = 0.02) in the high-eosinophil (27.37%) than the low-eosinophil (4.14%) group. Mucin expression and goblet cell numbers were similar in the two eosinophil groups; however, MUC-2 expression was increased (P = 0.002) in the high-eosinophil group compared with controls. The proportion of submucosa occupied by ASM was higher in both asthma groups (P = 0.021 and P = 0.046) compared with controls. In the ASM, eosinophil and T-lymphocyte numbers were higher (P < 0.05) in the high-eosinophil group than both the low-eosinophil group and the controls, whereas the numbers of mast cells were increased in the high-eosinophil group (P = 0.01) compared with controls. CONCLUSION: Submucosal eosinophilia is a marker (and possibly a cause) of epithelial damage and is related to infiltration of ASM with eosinophils and T lymphocytes, but is unrelated to mucus metaplasia or smooth muscle hypertrophy.
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Remodelación de las Vías Aéreas (Respiratorias) , Asma/inmunología , Asma/patología , Eosinofilia/patología , Adulto , Asma/metabolismo , Estudios de Casos y Controles , Femenino , Células Caliciformes/patología , Humanos , Hiperplasia , Masculino , Persona de Mediana Edad , Mucinas/metabolismo , Músculo Liso/metabolismo , Músculo Liso/patología , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Adulto JovenRESUMEN
Toxic injury can induce squamous metaplasia of respiratory epithelium, which normally is pseudostratified. Terminally differentiated squamous epithelial cells have a flattened, elongated appearance. During differentiation, they have an intermediate phenotype that is difficult to identify and distinguish from tangentially cut columnar cells in tissue sections from endobronchial biopsies, whose small size makes orientation difficult. The aim of our study was to develop a panel of antibodies that could be employed to distinguish normal epithelium from metaplastic epithelium and would be suitable for use on endobronchial biopsies. Nasal polyp tissue and tonsil tissue, which have pseudostratified and squamous epithelia, respectively, were collected from surgical cases and embedded in glycol methacrylate resin. Cut sections were stained immunohistochemically with a panel of antibodies to cytokeratins (CK), whose expression varies with epithelial type and stage of differentiation, and involucrin, a marker of terminal squamous differentiation. Squamous epithelium stained positively for CK5/6, CK13 and involucrin. In the pseudostratified epithelium, basal cells exhibited weak staining for CK13 and strong staining for CK5/6, and columnar cells exhibited strong immunoreactivity for CK7, CK8 and CK18. Application of this panel to endobronchial biopsies from smokers enabled areas of squamous metaplasia to be distinguished from tangentially sectioned epithelium.
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Anticuerpos/metabolismo , Bronquios/metabolismo , Bronquios/patología , Queratinas/metabolismo , Fumar/efectos adversos , Biopsia , Células Epiteliales/metabolismo , Células Epiteliales/patología , Epitelio/metabolismo , Humanos , Inmunohistoquímica , Metaplasia/etiología , Metaplasia/metabolismoAsunto(s)
Agonistas Adrenérgicos beta/efectos adversos , Albuterol/análogos & derivados , Asma/tratamiento farmacológico , Asma/mortalidad , Etanolaminas/efectos adversos , Agonistas Adrenérgicos beta/administración & dosificación , Albuterol/administración & dosificación , Albuterol/efectos adversos , Etanolaminas/administración & dosificación , Fumarato de Formoterol , Glucocorticoides/uso terapéutico , Humanos , Xinafoato de SalmeterolRESUMEN
The bronchial epithelium is an important physical barrier that regulates physiological processes including leukocyte trafficking. The aim of the present study was to elucidate the mechanisms whereby the bronchial epithelium, stimulated by epidermal growth factor (EGF) as part of a response to acute or chronic injury, could activate and chemoattract human neutrophils. Subconfluent human bronchial epithelial (16HBE) cells were stimulated with EGF to mimic the in vivo events after injury. The effect of the resulting EGF-conditioned media (CM) was compared with that of basal-CM with respect to neutrophil activation and chemotaxis. Such findings were then confirmed using primary bronchial epithelial cells (PBECs) from healthy volunteers. EGF-CM from 16HBE cells caused increased expression of CD11b/CD66b and CD62L loss on neutrophils when compared with basal-CM. EGF-CM contained significant neutrophil chemotactic activity involving granulocyte-macrophage colony-stimulating factor and interleukin-8 that was potentiated by leukotriene B(4). This was dependent on neutrophil phosphatidylinositol-3-kinase activation and Akt phosphorylation, with partial regulation by phospholipase D, but not mammalian target of rapamycin. Consistent with these observations, EGF-CM derived from PBECs displayed increased chemotactic activity. The present results suggest that the enhanced chemotactic activity of the epidermal growth factor-conditioned epithelium can enhance neutrophil-mediated immunity during acute injury, while during continued injury and repair, as in chronic asthma, this could contribute to persistent neutrophilic inflammation.
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Bronquios/inmunología , Quimiotaxis de Leucocito/inmunología , Factor de Crecimiento Epidérmico/inmunología , Inflamación/inmunología , Neutrófilos/inmunología , Bronquios/citología , Línea Celular , Medios de Cultivo Condicionados , Factor de Crecimiento Epidérmico/fisiología , Células Epiteliales/inmunología , Humanos , Síndrome de Dificultad Respiratoria/inmunología , Transducción de SeñalRESUMEN
Neutrophilic airway inflammation is a prominent feature of chronic obstructive pulmonary disease (COPD) and correlates with disease severity. The mechanisms that determine the extent of neutrophilia could involve increased influx or prolonged survival of neutrophils. The aim of the study was to assess whether neutrophil pro-survival mechanisms are increased in the airways of subjects with COPD owing to the presence of anti-apoptotic factors in the bronchial lining fluid. Induced sputum samples were collected from 20 subjects with stable COPD, 14 healthy smokers and 14 healthy controls. Quantification of apoptotic neutrophils was based on typical morphological cell changes. Anti-apoptotic, pro-survival activity in the sputum was studied by culturing peripheral blood neutrophils with the fluid phase of induced sputum. Apoptosis was assessed both by morphology and flow cytometry using Annexin V/7-aminoactinomycin D staining. COPD patients and healthy smokers had significantly higher percentages of sputum neutrophils than healthy controls. However, there were no significant differences between the three subject groups in either the proportion of apoptotic neutrophils in sputum or the in vitro anti-apoptotic activity detected in the sputum fluid phase. In conclusion, prolonged survival of neutrophils in sputum is not a feature of chronic obstructive pulmonary disease and cannot explain the increased numbers of airway neutrophils in this disease.
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Apoptosis/fisiología , Neutrófilos/patología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Sistema Respiratorio/patología , Adulto , Anciano , Anexina A5/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Femenino , Citometría de Flujo , Estudios de Seguimiento , Volumen Espiratorio Forzado/fisiología , Humanos , Masculino , Persona de Mediana Edad , Activación Neutrófila/fisiología , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Sistema Respiratorio/metabolismo , Fumar/fisiopatología , Esputo/metabolismoRESUMEN
Airway inflammation is central to the pathogenesis of both airway remodelling and parenchymal destruction in chronic obstructive pulmonary disease (COPD). Neutrophils, macrophages, and CD8+ T lymphocytes have been implicated in a number of studies, but a detailed profile of disease-phenotype specific inflammation has yet to emerge. The heterogeneity of the disease has hindered data interpretation while extrapolation of the results of relatively non-invasive studies to the actual pathology found in the distal lung is difficult. Moreover, prominent studies have had frequently conflicting results. Further investigations are needed to marry the different clinical phenotypes of COPD to their respective inflammatory profiles in the airways and thus improve our understanding of the pathogenesis of the disease as a whole.
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Bronquitis/patología , Enfermedad Pulmonar Obstructiva Crónica/patología , Eosinófilos/patología , Humanos , Linfocitos/patología , Macrófagos/patología , Mastocitos/patología , Neutrófilos/patologíaAsunto(s)
Asma/inmunología , Neutrófilos/inmunología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Asma/tratamiento farmacológico , Humanos , Interleucina-5/inmunología , Pulmón/inmunología , Moco/inmunología , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
BACKGROUND: Control of eosinophil migration to sites of inflammatory responses is a potentially therapeutic intervention in diseases such as bronchial asthma. Chemoattractants, their receptors and the associated signalling pathways may, therefore, be important targets for novel therapeutics. While several potentially important chemoattractants have been identified, the signalling pathways mediating their actions are incompletely understood. AIMS OF THE STUDY: The role of phosphoinositide 3-kinase (PI3K) in responses of human eosinophils to two important eosinophil chemoattractants -- platelet-activating factor (PAF) and eotaxin (CCL11) -- was studied to determine whether this enzyme activity might be crucial for eosinophil migration. METHODS: Eosinophils were isolated from atopic donor blood by immunomagnetic selection. Chemotaxis was assayed in a 96-well blind-chamber cell fluorescence assay. Respiratory burst and leukotriene C(4) secretion were also assayed. RESULTS: Two PI3K inhibitors, wortmannin and LY294002, caused concentration-dependent inhibition of PAF-induced eosinophil chemotaxis (IC(50) = 0.54 nM and 0.15 microM, respectively) but exhibited at least 100-fold lower potency against eotaxin-induced responses (IC(50) = 48 nM and >100 microM, respectively), indicating that these responses were not dependent upon PI3K. Wortmannin and LY294002 also inhibited PAF induced respiratory burst but not PAF-induced LTC(4) secretion. CONCLUSIONS: We conclude that PI3K-dependence varies with stimulus and response, and that eotaxin-induced eosinophil migration is not controlled by PI3K. This may indicate a limit to the potential of PI3K inhibitors to suppress tissue eosinophilia in diseases such as asthma.
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Factores Quimiotácticos Eosinófilos/farmacología , Quimiotaxis de Leucocito/inmunología , Eosinófilos/inmunología , Fosfatidilinositol 3-Quinasas/inmunología , Inhibidores de Proteínas Quinasas/farmacología , Androstadienos/farmacología , Células Cultivadas , Quimiocina CCL11 , Quimiocinas CC/farmacología , Quimiotaxis de Leucocito/efectos de los fármacos , Cromonas/farmacología , Eosinófilos/efectos de los fármacos , Humanos , Morfolinas/farmacología , Factor de Activación Plaquetaria/farmacología , Transducción de Señal , WortmaninaRESUMEN
Omalizumab is a humanized monoclonal anti-IgE antibody developed for the treatment of allergic disease, with established efficacy in patients with moderate-to-severe allergic asthma and in patients with intermittent (seasonal) and persistent (perennial) allergic rhinitis (AR). Omalizumab is known to result in a marked reduction in serum levels of free IgE and down-regulation of IgE receptors on circulating basophils. Recent work has shed further light on its mechanism of action, showing significant and profound reductions in tissue (nasal and bronchial) eosinophils and in bronchial IgE+ cells (mast cells), as well as T cells and B cells. Omalizumab treatment was also shown to be associated with down-regulation of IgE receptors on circulating (precursor) dendritic cells, suggesting that blocking IgE may inhibit more chronic aspects of allergic inflammation involving T cell activation. Further work with omalizumab demonstrated it to have important benefits in patients with poorly controlled asthma despite high-dose inhaled corticosteroid therapy, and analysis of clinical data suggests that the patients who are the best 'responders' to anti-IgE treatment are those with asthma at the more severe end of the spectrum. Notably, systemic anti-IgE therapy with omalizumab has been shown to improve symptoms, quality of life and disease control (asthma exacerbations) in patients with concomitant asthma and persistent AR. These impressive clinical data and the studies elucidating the anti-inflammatory profile of omalizumab also serve to emphasize the fundamental importance of IgE in the pathogenesis of allergic diseases.
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Anticuerpos Antiidiotipos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Inmunoglobulina E/inmunología , Hipersensibilidad Respiratoria/tratamiento farmacológico , Anticuerpos Antiidiotipos/efectos adversos , Anticuerpos Antiidiotipos/inmunología , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales Humanizados , Asma/tratamiento farmacológico , Asma/inmunología , Linfocitos B/inmunología , Eosinófilos/inmunología , Humanos , Mastocitos/inmunología , Omalizumab , Hipersensibilidad Respiratoria/inmunología , Rinitis Alérgica Perenne/tratamiento farmacológico , Rinitis Alérgica Perenne/inmunología , Rinitis Alérgica Estacional/tratamiento farmacológico , Rinitis Alérgica Estacional/inmunología , Linfocitos T/inmunología , Resultado del TratamientoRESUMEN
BACKGROUND: Airway epithelial goblet cell hyperplasia is known to occur in chronic smokers. Although the epidermal growth factor receptor has been implicated in this process, neither ErbB receptor expression nor the mucosecretory phenotype of the epithelium have been characterised in current smokers. METHODS: Bronchial biopsies obtained from non-smokers (n = 10) and current smokers, with or without chronic obstructive pulmonary disease (n = 51), were examined immunohistochemically to measure the expression of epidermal growth factor receptor, ErbB2, ErbB3, ErbB4 and mucin subtypes (MUC2, MUC5AC and MUC5B) in the bronchial epithelium. The results were correlated with neutrophil counts measured in the airway wall and induced sputum. RESULTS: Epidermal growth factor receptor, ErbB3 and MUC5AC expression, in addition to PAS staining, were significantly increased in all smokers compared with non-smokers, irrespective of the presence of chronic obstructive pulmonary disease. MUC5AC expression was significantly associated with both PAS staining and ErbB3 expression; no correlation was observed between either mucin or ErbB receptor expression and neutrophil counts. CONCLUSIONS: The results suggest that long term current smoking induces enhanced epidermal growth factor receptor, ErbB3, and MUC5AC expression in vivo; these increases are not associated with the presence of neutrophilic inflammation. ErbB receptors may contribute to epithelial responses to cigarette smoke.
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Bronquios/metabolismo , Mucinas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Fumar/metabolismo , Broncoscopía , Receptores ErbB/metabolismo , Femenino , Humanos , Inmunohistoquímica/métodos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Neutrófilos , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Receptor ErbB-4 , Mucosa Respiratoria/metabolismo , Esputo/citologíaRESUMEN
BACKGROUND: Considerable research has been conducted into the nature of airway inflammation in chronic obstructive pulmonary disease (COPD) but the relationship between proximal airways inflammation and both dynamic collapse of the peripheral airways and HRCT determined emphysema severity remains unknown. A number of research tools have been combined to study smokers with a range of COPD severities classified according to the GOLD criteria. METHODS: Sixty five subjects (11 healthy smokers, 44 smokers with stage 0-IV COPD, and 10 healthy non-smokers) were assessed using lung function testing and HRCT scanning to quantify emphysema and peripheral airway dysfunction and sputum induction to measure airway inflammation. RESULTS: Expiratory HRCT measurements and the expiratory/inspiratory mean lung density ratio (both indicators of peripheral airway dysfunction) correlated more closely in smokers with the severity of airflow obstruction (r = -0.64, p<0.001) than did inspiratory HRCT measurements (which reflect emphysema severity; r = -0.45, p<0.01). Raised sputum neutrophil counts also correlated strongly in smokers with HRCT indicators of peripheral airway dysfunction (r = 0.55, p<0.001) but did not correlate with HRCT indicators of the severity of emphysema. CONCLUSIONS: This study suggests that peripheral airway dysfunction, assessed by expiratory HRCT measurements, is a determinant of COPD severity. Airway neutrophilia, a central feature of COPD, is closely associated with the severity of peripheral airway dysfunction in COPD but is not related to the overall severity of emphysema as measured by HRCT.
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Bronquitis/patología , Enfermedad Pulmonar Obstructiva Crónica/patología , Obstrucción de las Vías Aéreas/patología , Obstrucción de las Vías Aéreas/fisiopatología , Bronquitis/fisiopatología , Volumen Espiratorio Forzado/fisiología , Humanos , Recuento de Leucocitos , Persona de Mediana Edad , Neutrófilos/patología , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Tomografía Computarizada por Rayos X/métodos , Capacidad Vital/fisiologíaRESUMEN
BACKGROUND: Inhalation of hypertonic or even isotonic saline during sputum induction may cause bronchospasm in susceptible patients with asthma, despite premedication with 400 microg inhaled salbutamol delivered by pressurised metered dose inhaler (pMDI). The bronchoprotection afforded by additional inhaled salbutamol administered through the ultrasonic nebuliser during sputum induction was investigated. METHODS: Twenty patients with moderate to severe asthma underwent sputum induction by inhaling saline 4.5% (or 0.9% if post-bronchodilation forced expiratory volume in 1 second (FEV1) <65% predicted) for 10 minutes according to two protocols given 1 week apart in random order. At visit A the patients received 400 microg salbutamol administered through a pMDI+spacer 20 minutes before induction while at visit B the premedication was supplemented by 1500 microg nebulised salbutamol inhaled throughout the induction procedure. Both the investigator and the patients were blind to the nebulised solution used. FEV1 was recorded during sputum induction at 1, 3, 5, and 10 minutes. Sputum cell counts and histamine, tryptase and albumin levels in the supernatants were determined. RESULTS: The mean (SE) maximal reduction in FEV1 over the 10 minute period of sputum induction was 11.7 (2.8)% at visit A, which was significantly greater than at visit B (2.6 (1.2)%; mean difference 9% (95% CI 2.7 to 15.4), p<0.01). Total and differential sputum cell counts as well as albumin, tryptase, and histamine levels did not differ between the two visits. CONCLUSION: The addition of inhaled salbutamol through an ultrasonic nebuliser markedly improves bronchoprotection against saline induced bronchoconstriction in patients with moderate to severe asthma undergoing sputum induction without affecting cell counts and inflammatory markers.
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Albuterol/administración & dosificación , Asma/tratamiento farmacológico , Broncodilatadores/administración & dosificación , Administración por Inhalación , Adulto , Anciano , Anciano de 80 o más Años , Asma/fisiopatología , Estudios Cruzados , Femenino , Volumen Espiratorio Forzado/fisiología , Humanos , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Solución Salina Hipertónica , EsputoRESUMEN
INTRODUCTION: The technique of induced expectoration generates sputum by the inhalation of hypertonic saline. On account of its non-invasive character, its simplicity, its relative harmlessness, its cost effectiveness and its reproducibility this technique, that appeared in the early 1990's, has rapidly established itself as the technique of choice in the investigation of bronchial inflammation in asthma. STATE OF THE ART: We present the results of our studies that have contributed to the validation of the technique at the methodological level and to the exploitation of the cellular contents as much as the fluid phase of the expectorations in characterising bronchial inflammation in asthmatics. Our results confirm an infiltration of the airways of asthmatics with eosinophils that appears to be proportional to the severity of the illness. We evaluate the effect of inhaled steroids and of theophylline on sputum eosinophilia and bronchial reactivity and discuss the role of eosinophils on bronchial hyperreactivity. Finally we discuss the use of induced expectoration in clinical practice in asthma. PERSPECTIVES: The analysis of induced sputum could well become a valuable tool in the clinical evaluation and monitoring of asthma in the same way as symptoms and abnormalities of lung function. CONCLUSIONS: Induced expectoration has certainly contributed to the understanding of the cellular and molecular mechanisms of asthma as well as the role of bronchial inflammation in the clinical manifestations of the disease.
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Asma/diagnóstico , Solución Salina Hipertónica , Manejo de Especímenes/métodos , Esputo/citología , Asma/clasificación , Asma/tratamiento farmacológico , Asma/inmunología , Biomarcadores/análisis , Análisis Costo-Beneficio , Eosinófilos/inmunología , Humanos , Inflamación , Recuento de Leucocitos , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Manejo de Especímenes/economía , Manejo de Especímenes/normas , Esputo/química , Esputo/inmunologíaRESUMEN
T-helper (Th)2 cytokines play a central role in asthma. Therefore, a double-blind randomised study was conducted to investigate whether heat-killed Mycobacterium vaccae (SRL172), a potent downregulator of Th2 cytokines, can reduce allergen-induced airway responses in patients with atopic asthma. A total 24 male asthmatics participated in this study. A bronchial allergen challenge was performed along with early (EAR) and late asthmatic responses (LAR) 2 weeks before and 3 weeks after a single intradermal injection of SRL172 or placebo. Before and after treatment, serum immunoglobulin (Ig)E levels and in vitro production of interleukin (IL)-5 by peripheral blood lymphocytes were studied. Neither treatment affected the EAR. SRL172 caused a mean 34% reduction of the area under the curve of the forced expiratory volume in one second (FEV1) changes during the LAR, which failed to reach conventional statistical significance when compared with placebo. SRL172 also caused a mean 25% decrease in the maximum fall in FEV1 during LAR, but this was not significantly different from placebo. SRL172 caused a reduction in serum IgE and IL-5 synthesis in vitro 3 weeks post-treatment (p = 0.07). This study shows a trend toward significance for the effects of heat-killed Mycobacterium vaccae (SRL172) on allergen-induced airway responses. Further clinical trials, involving multiple dosing, are needed.
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Alérgenos/inmunología , Asma/tratamiento farmacológico , Asma/inmunología , Vacunas Bacterianas/uso terapéutico , Bronquios/fisiopatología , Hipersensibilidad/inmunología , Adulto , Asma/fisiopatología , Células Cultivadas , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Inmunoglobulina E/efectos de los fármacos , Inmunoglobulina E/metabolismo , Interleucina-5/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: The extent of epithelial injury in asthma is reflected by expression of the epidermal growth factor receptor (EGFR), which is increased in proportion to disease severity and is corticosteroid refractory. Although the EGFR is involved in epithelial growth and differentiation, it is unknown whether it also contributes to the inflammatory response in asthma. OBJECTIVES: Because severe asthma is characterized by neutrophilic inflammation, we investigated the relationship between EGFR activation and production of IL-8 and macrophage inhibitory protein-1 alpha (MIP-1alpha) using in vitro culture models and examined the association between epithelial expression of IL-8 and EGFR in bronchial biopsies from asthmatic subjects. METHODS: H292 or primary bronchial epithelial cells were exposed to EGF or H2O2 to achieve ligand-dependent and ligand-independent EGFR activation; IL-8 mRNA was measured by real-time PCR and IL-8 and MIP-1alpha protein measured by enzyme-linked immunosorbent assay (ELISA). Epithelial IL-8 and EGFR expression in bronchial biopsies from asthmatic subjects was examined by immunohistochemistry and quantified by image analysis. RESULTS: Using H292 cells, EGF and H2O2 increased IL-8 gene expression and release and this was completely suppressed by the EGFR-selective tyrosine kinase inhibitor, AG1478, but only partially by dexamethasone. MIP-1alpha release was not stimulated by EGF, whereas H2O2 caused a 1.8-fold increase and this was insensitive to AG1478. EGF also significantly stimulated IL-8 release from asthmatic or normal primary epithelial cell cultures established from bronchial brushings. In bronchial biopsies, epithelial IL-8, MIP-1alpha, EGFR and submucosal neutrophils were all significantly increased in severe compared to mild disease and there was a strong correlation between EGFR and IL-8 expression (r = 0.70, P < 0.001). CONCLUSIONS: These results suggest that in severe asthma, epithelial damage has the potential to contribute to neutrophilic inflammation through enhanced production of IL-8 via EGFR- dependent mechanisms.