RESUMEN
Introduction: Reports have shown that the onset of diabetes mellitus (DM) in patients previously diagnosed with asthma decreases asthmatic symptoms, whereas insulin aggravates asthma. The present study evaluated the modulatory effect of insulin on the development of allergic airway inflammation in diabetic mice. Materials and Methods: To evaluate the effects of relative insulin deficiency, an experimental model of diabetes was induced by a single dose of alloxan (50 mg/kg, i.v.). After 10 days, the mice were sensitized with ovalbumin [OVA, 20 µg and 2 mg of Al(OH)3, i.p.]. A booster immunization was performed 6 days after the first sensitization [20 µg of OVA and 2 mg of Al(OH)3, i.p.]. The OVA challenge (1 mg/mL) was performed by daily nebulization for 7 days. Diabetic animals were treated with multiple doses of neutral protamine Hagedorn (NPH) before each challenge with OVA. The following parameters were measured 24 h after the last challenge: (a) the levels of p38 MAP kinase, ERK 1/2 MAP kinases, JNK, STAT 3, and STAT 6 in lung homogenates; (b) the serum profiles of immunoglobulins IgE and IgG1; (c) the concentrations of cytokines (IL-4, IL-5, IL-10, IL-13, TNF-α, VEGF, TGF-ß, and IFN-γ) in lung homogenates; (d) cells recovered from the bronchoalveolar lavage fluid (BALF); (e) the profiles of immune cells in the bone marrow, lung, thymus, and spleen; and (f) pulmonary mechanics using invasive (FlexiVent) and non-invasive (BUXCO) methods. Results: Compared to non-diabetic OVA-challenged mice, OVA-challenged diabetic animals showed decreases in ERK 1 (2-fold), ERK 2 (7-fold), JNK (phosphor-54) (3-fold), JNK/SAPK (9-fold), STAT3 (4-fold), the levels of immunoglobulins, including IgE (1-fold) and IgG1 (3-fold), cytokines, including Th2 profile cytokines such as IL-4 (2-fold), IL-5 (2-fold), IL-13 (4-fold), TNF-α (2-fold), VEGF (2-fold), and TGF-ß (2-fold), inflammatory infiltrates (14-fold), T cells, NK cells, B cells and eosinophils in the bone marrow, lung, thymus and spleen, and airway hyperreactivity. STAT6 was absent, and no eosinophilia was observed in BALF. Insulin treatment restored all parameters. Conclusion: The data suggested that insulin modulates immune cell phenotypes and bronchial hyperresponsiveness in the development of allergic airway inflammation in diabetic mice.
Asunto(s)
Asma/inmunología , Hiperreactividad Bronquial/inmunología , Diabetes Mellitus Experimental/tratamiento farmacológico , Eosinófilos/efectos de los fármacos , Hipoglucemiantes/administración & dosificación , Insulina Isófana/administración & dosificación , Linfocitos/efectos de los fármacos , Fenotipo , Aloxano/efectos adversos , Animales , Asma/inducido químicamente , Hiperreactividad Bronquial/inducido químicamente , Líquido del Lavado Bronquioalveolar/inmunología , Citocinas/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/inmunología , Modelos Animales de Enfermedad , Eosinófilos/inmunología , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Pulmón/inmunología , Pulmón/metabolismo , Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/efectos adversos , Organismos Libres de Patógenos EspecíficosRESUMEN
OBJECTIVE: To examine the effect of metanol extract of Petiveria alliacea (PM) on airway inflflammation in a murine model of chronic asthma. METHODS: Two-month-old male BALB/c mice (n=6-8/group) were sensitized on days 0 and 14 by intraperitoneal injection of 20 µg ovalbumin (OVA). On day 25, the mice received an airway challenge with OVA (3%, w/v, in phosphate buffered saline). PM was administered orally by oral gavage to mice at doses of 100, 200 and 400 mg/kg body weight once daily from days 18 to 23. Control mice were orally administered phosphate buffered saline (PBS) to induce a model of asthma. At the end of the test, respiratory reactivity was assayed, the total cell number, interleukin-4 (IL-4), IL-5, IL-13, tumor necrosis factor-alpha (TNF-α) and reactive oxygen species (ROS) in the bronchoalveolar lavage fluid (BALF) were determined and the levels of serum IgE, intercellular cell adhesion molecule 1 (ICAM-1) and eotoxin were measured. In addition, lung tissue was used to qualify the IL-4, IL-5, IL-13, TNF-α and transforming growth factor beta 1 (TGF-ß1). Histologic examination was performed to observe inflammatory cellular infiltration. RESULTS: The administration of PM in comparison with the OVA-only treated group signifificantly attenuated the infifiltration of eosinophils and other inflflammatory cells (P<0.01). Airway resistance (RI) in the OVA-only induced group was significantly higher than that of the PBS control group (P<0.01) when methacholine was added. TNF-α, IgE, TGF-ß1 and cytokine levels IL-4, IL-5, IL-13 in the BALF decreased compared to control mice (P<0.01 or P<0.05). PM treatment also inhibited the production of chemokines, eotaxin and ICAM-1 in BALF (P<0.01), which improved lung function. Histopathological examination revealed that the sensitized treated PM groups had significant lower in inflammatory scores similar to dexamethasone treatments and the untreated group. CONCLUSION: Administration of PM could inhibit airway inflammation, regulate cytokines, chemokines and enhance pulmonary conditions in allergic murine model of asthma.
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Alérgenos/inmunología , Asma/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Pulmón/patología , Ovalbúmina/inmunología , Phytolaccaceae/química , Extractos Vegetales/uso terapéutico , Células Th2/inmunología , Animales , Asma/sangre , Asma/inmunología , Asma/fisiopatología , Hiperreactividad Bronquial/complicaciones , Hiperreactividad Bronquial/tratamiento farmacológico , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/fisiopatología , Líquido del Lavado Bronquioalveolar , Quimiocinas/metabolismo , Modelos Animales de Enfermedad , Inmunoglobulina E/sangre , Inflamación/sangre , Inflamación/complicaciones , Inflamación/inmunología , Pulmón/inmunología , Pulmón/fisiopatología , Masculino , Metanol , Ratones Endogámicos BALB C , Moco/metabolismo , Fitoterapia , Extractos Vegetales/farmacología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Uncaria tomentosa (Willd. Ex Schult) DC is used by indigenous tribes in the Amazonian region of Central and South America to treat inflammation, allergies and asthma. The therapeutic properties of U. tomentosa have been attributed to the presence of tetracyclic and pentacyclic oxindole alkaloids and to phenolic acids. AIMS OF THE STUDY: To characterize aqueous bark extracts (ABE) and aqueous leaf extracts (ALE) of U. tomentosa and to compare their anti-inflammatory effects. MATERIALS AND METHODS: Constituents of the extracts were identified by ultra performance liquid chromatography-mass spectrometry. Anti-inflammatory activities were assessed in vitro by exposing lipopolysaccharide-stimulated macrophage cells (RAW264.7-Luc) to ABE, ALE and standard mitraphylline. In vivo assays were performed using a murine model of ovalbumin (OVA)-induced asthma. OVA-sensitized animals were treated with ABE or ALE while controls received dexamethasone or saline solution. Bronchial hyperresponsiveness, production of Th1 and Th2 cytokines, total and differential counts of inflammatory cells in the bronchoalveolar lavage (BAL) and lung tissue were determined. RESULTS: Mitraphylline, isomitraphylline, chlorogenic acid and quinic acid were detected in both extracts, while isorhyncophylline and rutin were detected only in ALE. ABE, ALE and mitraphylline inhibited the transcription of nuclear factor kappa-B in cell cultures, ALE and mitraphylline reduced the production of interleukin (IL)-6, and mitraphylline reduced production of tumor necrosis factor-alpha. Treatment with ABE and ALE at 50 and 200â¯mgâ¯kg-1, respectively, reduced respiratory elastance and tissue damping and elastance. ABE and ALE reduced the number of eosinophils in BAL, while ALE at 200â¯mgâ¯kg-1 reduced the levels of IL-4 and IL-5 in the lung homogenate. Peribronchial inflammation was significantly reduced by treatment with ABE and ALE at 50 and 100â¯mgâ¯kg-1 respectively. CONCLUSION: The results clarify for the first time the anti-inflammatory activity of U. tomentosa in a murine model of asthma. Although ABE and ALE exhibited distinct chemical compositions, both extracts inhibited the production of pro-inflammatory cytokines in vitro. In vivo assays revealed that ABE was more effective in treating asthmatic inflammation while ALE was more successful in controlling respiratory mechanics. Both extracts may have promising applications in the phytotherapy of allergic asthma.
Asunto(s)
Antiasmáticos/uso terapéutico , Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Hiperreactividad Bronquial/tratamiento farmacológico , Uña de Gato , Extractos Vegetales/uso terapéutico , Ácidos Carbocíclicos/análisis , Ácidos Carbocíclicos/farmacología , Ácidos Carbocíclicos/uso terapéutico , Alérgenos/inmunología , Animales , Antiasmáticos/análisis , Antiasmáticos/farmacología , Antiinflamatorios/análisis , Antiinflamatorios/farmacología , Asma/inmunología , Hiperreactividad Bronquial/inmunología , Líquido del Lavado Bronquioalveolar , Supervivencia Celular/efectos de los fármacos , Citocinas/inmunología , Modelos Animales de Enfermedad , Alcaloides Indólicos/análisis , Alcaloides Indólicos/farmacología , Alcaloides Indólicos/uso terapéutico , Pulmón/efectos de los fármacos , Pulmón/inmunología , Ratones , Ovalbúmina/inmunología , Fitoterapia , Corteza de la Planta , Extractos Vegetales/análisis , Extractos Vegetales/farmacología , Hojas de la Planta , Células RAW 264.7RESUMEN
The upper and lower airways behave as a physiological and pathophysiological unit. Subclinical lower airways abnormalities have been described in patients with rhinitis without asthma. These are expressed as bronchial hyperreactivity, abnormalities in lung function and bronchial inflammation, likely as a result of the same phenomenon with systemic inflammatory impact that reaches both the nose and the lungs, which for unknown reasons does not always have a full clinical expression. Patients with rhinitis are at increased risk of developing asthma; therefore, most authors suggest a careful clinical evaluation and monitoring of these patients, especially if symptoms related to inflammation in the lower airways are observed. Although current treatments, such as H1-antihistamines, intranasal steroids and allergen immunotherapy, are quite effective for the management of rhinitis, it is difficult to prove their capacity to prevent asthma among subjects with rhinitis. Evidence showing that the treatment of rhinitis has a favourable impact on indicators of bronchial hyperreactivity and inflammation among subjects that have no symptoms of asthma is more frequently described. In this review, we address the frequency and characteristics of lower airway abnormalities in subjects with rhinitis, both in paediatric and adult populations, their likely predictive value for the development of asthma and the possibilities for therapeutic intervention that could modify the risk of subjects with rhinitis towards presenting asthma.
Asunto(s)
Alérgenos/uso terapéutico , Hiperreactividad Bronquial/prevención & control , Desensibilización Inmunológica/métodos , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Pulmón/inmunología , Rinitis Alérgica/terapia , Animales , Hiperreactividad Bronquial/etiología , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/patología , Humanos , Pulmón/patología , Rinitis Alérgica/complicaciones , Rinitis Alérgica/inmunología , Rinitis Alérgica/patologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Mandevilla longiflora, popularly known as "velame" in central Brazil, is a subshrub widely distributed in South America. Its xylopodium is used in the form of a decoction or infusion to treat inflammation and other ailments. AIM OF THE STUDY: This study aimed to evaluate the anti-inflammatory potential of M. longiflora in an in vivo model of ovalbumin-induced immediate hypersensitivity, identifying its effects on leukocyte infiltration, IgE and LTB4 levels, and Th2 cytokine production. In addition, HPLC fingerprint of the extract was performed. MATERIAL AND METHODS: The hydroethanolic extract 70% of M. longiflora (HEMI) was obtained by maceration of the plant xylopodium. Swiss mice were sensitized by i.p. injection OVA-aluminium hydroxide on days 1 and 10. Nine days after the last sensitisation animals were challenged for 6 consecutive days with OVA solution for 20min daily in a closed chamber under continuous flow of aerosol. The animals were treated with HEMl (20, 50 and 200mg/kg p.o.), 2 times per day, and euthanized 24h later. Animals treated with vehicle (2% Tween-20) or dexamethasone were used as negative and positive controls, respectively. The recruitment of inflammatory cells into the pulmonary cavity was evaluated by counting cells present in broncho-alveolar lavage fluid (BALF). Lung tissue was also collected for histopathology and infiltration analysis. Quantification of IL-4, IL-5 and IL-13 from the BALF, and IgE, and LTB4 from plasma, were conducted by immunoassay. RESULTS AND CONCLUSIONS: The HEMl attenuated leukocyte migration into the airways, which was evidenced by a decrease in eosinophils, neutrophils and mononuclear cells, both in BALF quantification and by histopathological analysis, as well as decreasing the concentrations of IL-4, IL-5, IL-13, IgE and LTB4. All of these events are typical of air-mucosa inflammatory disease. These findings scientifically evidence for the first time the ethnopharmacological use of M. longiflora to treat chronic inflammatory events, such as asthma, and suggest a potential therapeutic use or complementary therapy for this plant extract.
Asunto(s)
Antiinflamatorios/uso terapéutico , Apocynaceae , Asma/tratamiento farmacológico , Hiperreactividad Bronquial/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Animales , Antiinflamatorios/aislamiento & purificación , Asma/inmunología , Asma/patología , Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/toxicidad , Extractos Vegetales/aislamiento & purificaciónRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Eclipta prostrata (L.) L. (Asteraceae) has been used in Brazilian traditional medicine to treat asthma and other respiratory illnesses. AIMS OF THE STUDY: To investigate the effects of different doses of a standardized extract of E. prostrata using a murine model of allergen induced asthma. MATERIALS AND METHODS: Balb/c mice were sensitized twice with ovalbumin (OVA) administered intraperitoneally and challenged over four alternate days with nasal instillations of OVA solution. The standardized methanol extract of E. prostrata was administered in doses of 100, 250 and 500mgkg-1 concomitantly with nasal instillation over seven consecutive days. Control animals were treated with dexamethasone or saline solution. Bronchial hyperresponsiveness, production of Th1 and Th2 cytokines, allergen sensitization, airway and lung inflammation, mucous secretion and airway remodeling were assessed. RESULTS: The concentrations of chemical markers in the standardized methanol extract were 0.02% oroboside, 1.69% demethylwedelolactone and 1.71% wedelolactone. Treatment with 250mgkg-1 of extract, which provided 0.745, 4.22 and 4.30mgkg-1day-1 of oroboside, demethylwedelolactone and wedelolactone, respectively, significantly reduced (P<0.05) respiratory resistance and elastance. Such effects were comparable with those produced by dexamethasone. The total number of inflammatory cells and eosinophils in the bronchoalveolar lavage and the concentrations of interleukin (IL)-4, IL-5 and IL-13 in lung homogenate were significantly reduced (P<0.05) by the methanol extract of E. prostrata. CONCLUSION: The results presented herein demonstrate for the first time the anti-inflammatory activity of E. prostrata in a murine model of asthma, thereby supporting the ethnopharmacological uses of the plant.
Asunto(s)
Asma/tratamiento farmacológico , Hiperreactividad Bronquial/tratamiento farmacológico , Eclipta/química , Extractos Vegetales/farmacología , Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Alérgenos/inmunología , Animales , Antiasmáticos/administración & dosificación , Antiasmáticos/aislamiento & purificación , Antiasmáticos/farmacología , Antiinflamatorios/administración & dosificación , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/farmacología , Asma/inmunología , Asma/patología , Brasil , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/patología , Líquido del Lavado Bronquioalveolar/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Eosinófilos/metabolismo , Masculino , Medicina Tradicional/métodos , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/inmunología , Extractos Vegetales/administración & dosificación , Células Th2/inmunologíaRESUMEN
Agricultural workers represent a population that is highly vulnerable to the toxic effects of pesticide exposure. This cross sectional study aimed to describe the health conditions of terrestrial pesticide applicators in Córdoba Province, Argentina, their work practices and socio-demographic characteristics, by means of a standardized self-administered questionnaire (n = 880). A descriptive analysis reported a high prevalence of occasional or frequent symptoms: 47.4% had symptoms of irritation, 35.5% fatigue, 40.4% headache and 27.6% nervousness or depression. Using logistic regression models, risk and protective factors were found for symptoms of irritation, medical consultation and hospitalization. Among the occupational exposure variables, marital status, length of time in the job, low level of protection with regard to the use of personal protective equipment, combined use of different pesticides and the application of the insecticide endosulfan, were associated with a higher frequency of reported symptoms and higher consultation rates and hospitalization.
Los trabajadores agrícolas son una población altamente vulnerable a los efectos tóxicos de la exposición a plaguicidas. Con el objetivo de describir las condiciones de salud de agroaplicadores terrestres de plaguicidas de la Provincia de Córdoba, Argentina, sus prácticas laborales y características sociodemográficas, se realizó un estudio transversal, mediante cuestionario (n = 880). Un análisis descriptivo reportó alta prevalencia de sintomatología ocasional o frecuente: 47,4% síntomas irritativos, 35,5% cansancio, 40,4% cefalea y 27,6% ansiedad o depresión. Mediante modelos logísticos se detectaron factores protectores y de riesgo que explican la presencia de síntomas irritativos, la consulta médica y la hospitalización. El estado civil, la antigüedad en la tarea, el nivel de protección considerando uso de equipo de protección personal, la exposición múltiple a plaguicidas y la aplicación del insecticida endosulfán, se asociaron a mayor frecuencia de reporte de síntomas, consultas médicas y hospitalizaciones por causas relacionadas con la exposición a plaguicidas.
Os trabalhadores agrícolas são uma população altamente vulnerável aos efeitos tóxicos da exposição a pesticidas. Este estudo transversal teve o objetivo de descrever as condições de saúde de aplicadores terrestres de pesticidas da Província de Córdoba, Argentina, suas práticas de trabalho e características sociodemográficas, por meio de um questionário padronizado autoadministrado (n = 880). A análise descritiva relatou alta prevalência de sintomas ocasionais ou frequentes: 47,4% sintomas irritativos, 35,5% fadiga, 40,4% dor de cabeça e 27,6% ansiedade ou depressão. Mediante modelos logísticos foram detectados os fatores protetores e do risco que explicam a presença de sintomas irritativos, consulta médica e hospitalização. O estado civil, anos de trabalho, o nível de proteção considerando o uso de equipamentos de proteção individual, a exposição a vários pesticidas e aplicação do inseticida endosulfan, foram associados com maior frequência de sintomas, consultas médicas e hospitalização por causas relacionadas à exposição ao agrotóxico.
Asunto(s)
Animales , Gatos , Humanos , Ratones , Asma , Epítopos/inmunología , Tolerancia Inmunológica/inmunología , /inmunología , Péptidos , Alérgenos/inmunología , Asma/inmunología , Asma/terapia , Hiperreactividad Bronquial/inmunología , Desensibilización Inmunológica , Modelos Animales de Enfermedad , Método Doble Ciego , Factores de Transcripción Forkhead/inmunología , Genes MHC Clase II , Glicoproteínas/genética , Glicoproteínas/inmunología , Antígeno HLA-DR1/inmunología , Pulmón/citología , Pulmón/inmunología , Pulmón/patología , Ratones Transgénicos , Placebos , Péptidos/inmunología , Péptidos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , /inmunología , /inmunología , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
BACKGROUND: Information about the biological properties of Blomia tropicalis allergens is scarce. It is predicted that Blo t 12, an allergen with two described isoforms, contains a chitin-binding domain, similar to that found in peritrophins. Th2 adjuvant properties have been described for chitin. Therefore, it is feasible that binding to this carbohydrate influences its allergenicity. We aimed to evaluate the chitin-binding activity of Blo t 12 isoallergens and its effect on airway inflammation and antibody responses in a murine model of allergen sensitization. METHODS: Chitin-binding assays were conducted with the recombinant isoallergens Blo t 12.0101 and Blo t 12.0102. BALB/c mice were sensitized via i.p. with any of the two isoforms (alone, with chitin or alum) and then challenged intranasally. Methacholine-induced bronchial hyperreactivity was tested by whole-body plethysmography and lung sections were stained with hematoxylin and eosin and periodic-acid Schiff. Total IgE and allergen-specific IgE, IgG1 and IgG2 levels were measured by ELISA. RESULTS: The two isoforms bound chitin, but Blo t 12.0101 showed a stronger binding capacity. Both isoforms induced total and allergen-specific IgE, airway hyperreactivity, bronchial inflammation and mucus secretion without any adjuvant; however, when administered with chitin, Blo t 12.0101 induced higher total IgE levels. The IgG1/IgG2a ratio was significantly higher in mice immunized with Blo t 12.0101 than those immunized with Blo t 12.0102. As peritrophins, Blo t 12 was detected in mite feces. CONCLUSIONS: Blo t 12 isoforms are chitin-binding proteins that induce airway inflammation and bronchial hyperreactivity. However, for Blo t 12.0101, chitin reinforces its effects on total IgE production.
Asunto(s)
Antígenos Dermatofagoides/inmunología , Quitina/inmunología , Hipersensibilidad/inmunología , Hipersensibilidad Respiratoria/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/metabolismo , Secuencia de Aminoácidos , Animales , Antígenos Dermatofagoides/química , Hiperreactividad Bronquial/inmunología , Extractos Celulares , Microambiente Celular , Quitina/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunidad Humoral , Inmunoglobulina E/inmunología , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Fragmentos de Péptidos/química , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/metabolismo , Unión Proteica/inmunología , Isoformas de Proteínas/química , Isoformas de Proteínas/inmunología , Isoformas de Proteínas/metabolismo , Pyroglyphidae/inmunología , Células Th2/inmunologíaRESUMEN
Bronchial hyperresponsiveness is a hallmark of asthma and many factors modulate bronchoconstriction episodes. A potential correlation of formaldehyde (FA) inhalation and asthma has been observed; however, the exact role of FA remains controversial. We investigated the effects of FA inhalation on Ovalbumin (OVA) sensitisation using a parameter of respiratory mechanics. The involvement of nitric oxide (NO) and cyclooxygenase-derived products were also evaluated. The rats were submitted, or not, to FA inhalation (1%, 90 min/day, 3 days) and were OVA-sensitised and challenged 14 days later. Our data showed that previous FA exposure in allergic rats reduced bronchial responsiveness, respiratory resistance (Rrs) and elastance (Ers) to methacholine. FA exposure in allergic rats also increased the iNOS gene expression and reduced COX-1. L-NAME treatment exacerbated the bronchial hyporesponsiveness and did not modify the Ers and Rrs, while Indomethacin partially reversed all of the parameters studied. The L-NAME and Indomethacin treatments reduced leukotriene B4 levels while they increased thromboxane B2 and prostaglandin E2. In conclusion, FA exposure prior to OVA sensitisation reduces the respiratory mechanics and the interaction of NO and PGE2 may be representing a compensatory mechanism in order to protect the lung from bronchoconstriction effects.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Hiperreactividad Bronquial/tratamiento farmacológico , Modelos Animales de Enfermedad , Eicosanoides/metabolismo , Óxido Nítrico/metabolismo , Insuficiencia Respiratoria/prevención & control , Mucosa Respiratoria/efectos de los fármacos , Administración por Inhalación , Resistencia de las Vías Respiratorias/efectos de los fármacos , Animales , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/metabolismo , Hiperreactividad Bronquial/fisiopatología , Broncoconstrictores/farmacología , Ciclooxigenasa 1/genética , Ciclooxigenasa 1/metabolismo , Dinoprostona/agonistas , Dinoprostona/metabolismo , Formaldehído/administración & dosificación , Formaldehído/toxicidad , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Leucotrieno B4/antagonistas & inhibidores , Leucotrieno B4/metabolismo , Masculino , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas , Ratas Wistar , Insuficiencia Respiratoria/etiología , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/fisiopatología , Tromboxano B2/agonistas , Tromboxano B2/metabolismoRESUMEN
BALB/c mice received saline (SAL groups) or ovalbumin (OVA groups) intraperitoneally (days 1, 3, 5, 7, 9, 11 and 13). After 27 days, a burst of intratracheal OVA or SAL (days 40, 43 and 46) was performed. Animals were then divided into four groups (N=8, each) and intranasally instilled with saline (SAL-SAL and OVA-SAL) or residual oil fly ash (SAL-ROFA and OVA-ROFA). 24h later, total, initial and difference resistances (Rtot, Rinit, Rdiff) and static elastance (Est) were measured. Lung responsiveness to methacholine was assessed as slope and sensitivity of Est, Rtot, Rinit, and Rdiff. Lung morphometry (collapsed and normal areas and bronchoconstriction index) and cellularity (polymorphonuclear, mononuclear and mast cells) were determined. OVA or ROFA similarly impaired lung mechanics and increased the amount of polymorphonuclear cells and collapsed areas. OVA-ROFA showed even higher hyperresponsiveness, bronchoconstriction and mast cell infiltration. Thus, we concluded that ROFA exposure may add an extra burden to hyperresponsive lungs.
Asunto(s)
Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/inmunología , Ceniza del Carbón/toxicidad , Hipersensibilidad/inmunología , Contaminantes Atmosféricos/inmunología , Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/efectos adversos , Animales , Hiperreactividad Bronquial/fisiopatología , Ceniza del Carbón/inmunología , Hipersensibilidad/fisiopatología , Masculino , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/inmunología , Ovalbúmina/toxicidad , Pruebas de Función RespiratoriaRESUMEN
Female sex hormones (FSHs) exert profound regulatory effects on the course of lung inflammation due to allergic and non-allergic immune responses. As pollution is one of the pivotal factors to induce lung dysfunction, in this study we investigated the modulatory role of FSHs on lung inflammation after a formaldehyde (FA) exposure. For this purpose, lung and systemic inflammatory responses were evaluated in terms of leukocytes countings in bronchoalveolar lavage (BAL), peripheral blood and bone marrow lavage from 7-day ovariectomized (OVx) and Sham-OVx rats subjected to FA inhalation for 3 consecutive days. The hypothesized link between effects of FSHs on expression of adhesion molecules and mast cells degranulation was also studied. Once exposed to FA, Sham-OVx rats increased the number of total cells recovered in BAL and of leukocytes in peripheral blood, and decreased the counts in bone marrow. By contrast, in OVx rats upon FA exposure there was a reduction of the total cells counts in BAL and of blood leukocytes; lung expressions of ICAM-1 and Mac-1 were depressed, but the number of bone marrow cells did not vary. Estradiol treatment of OVx rats increased the total cells in BAL and decreased the number of blood leukocytes, whereas the number of bone marrow cell remained unaltered. Progesterone treatment, in turn increased the total cells in BAL and blood leukocytes, but decreased the number of bone marrow cells. OVx rats exposed to FA developed tracheal hyperresponsiveness to methacholine (MCh). A similarly altered response was found between the tracheal segments of Sham-OVx rats after FA exposure and that found in tracheae of naïve rats. Estradiol treatment prevented FA-induced tracheal hyperresponsiveness to MCh whereas progesterone was ineffective in this regard. In addition, OVx rats upon FA exposure significantly increased both, the ability of mast cell degranulation and serum corticosterone levels. In conclusion, it was found that FSHs act by distinct control mechanisms on FA-induced lung inflammation and tracheal hyperresponsiveness, since at low circulating levels of FSHs (such as those after OVx) there is some resistance to the development of a lung inflammatory response, but the cholinergic tracheal responsiveness is exacerbated. Our data also help to understand the involvement of FSHs on mast cells activity after pollutants exposure and add information regarding the role of FSHs on the mechanisms related to endothelium-leukocyte interactions.
Asunto(s)
Hiperreactividad Bronquial/inducido químicamente , Estradiol/metabolismo , Formaldehído/toxicidad , Pulmón/efectos de los fármacos , Progesterona/metabolismo , Tráquea/efectos de los fármacos , Contaminantes Atmosféricos/toxicidad , Animales , Médula Ósea/efectos de los fármacos , Médula Ósea/inmunología , Médula Ósea/metabolismo , Médula Ósea/patología , Hiperreactividad Bronquial/sangre , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/metabolismo , Líquido del Lavado Bronquioalveolar/citología , Moléculas de Adhesión Celular/metabolismo , Degranulación de la Célula/efectos de los fármacos , Corticosterona/sangre , Femenino , Técnicas In Vitro , Leucocitos/efectos de los fármacos , Leucocitos/inmunología , Leucocitos/metabolismo , Leucocitos/patología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Activación de Linfocitos/efectos de los fármacos , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Mastocitos/metabolismo , Mastocitos/fisiología , Especificidad de Órganos , Ovariectomía , Neumonía/inducido químicamente , Neumonía/inmunología , Neumonía/metabolismo , Neumonía/patología , Ratas , Ratas Wistar , Tráquea/inmunología , Tráquea/metabolismoRESUMEN
BACKGROUND: Inhalation of the local anaesthetic lidocaine has been suggested to be beneficial for asthmatics, but airway anaesthesia is unpleasant and may exacerbate bronchoconstriction. Our previous study showed that inhalation of the lidocaine analogue JMF2-1 can elicit the anti-inflammatory properties of lidocaine without anaesthesia. This prompted further research on the mechanism of action and putative therapeutic application of JMF2-1. OBJECTIVE: We tested the hypothesis that JMF2-1 would prevent allergen-induced lung inflammation and airway hyperresponsiveness (AHR) by modulating T cell function in vivo and in vitro. Methods Local and systemic changes in leucocyte levels, cytokine production and lung mechanics were examined in a murine model of lung inflammation. JMF2-1 (0.05-2%) or saline was aerosolized twice a day during the ovalbumin (OVA)-provocation period (19-21 days post-sensitization). Analyses were performed 24 h after the final challenge. Primary cultured lymph node cells were used to assess the effects of JMF2-1 (100-600 µm) at the cellular level. RESULTS: OVA challenge resulted in lung recruitment of CD4(+) T cells and eosinophils, increased generation of inflammatory cytokines and AHR to inhaled methacholine within 24 h. These changes were prevented by JMF2-1 nebulization, and occurred in parallel with an increase in the number of apoptotic cells in the lung. JMF2-1 treatment did not alter levels of CD4(+) or CD8(+) T cells in the thymus or lymph nodes of naïve mice, although it inhibited OVA-induced IL-13 production and the lymphocyte proliferative response in vitro. It also induced apoptosis of OVA-activated lymphocytes in a mechanism sensitive to z-VAD, indicating that JMF2-1 mediates caspase-dependent apoptosis. CONCLUSION: Inhalation of JMF2-1 prevents the cardinal features of asthma by reducing T(H) 2 cytokine generation and lung eosinophilic inflammatory infiltrates via local inhibition of T cell function and survival. JMF2-1 may represent a novel therapeutic alternative for asthma control with distinct advantages over local anaesthetics.
Asunto(s)
Antiinflamatorios/farmacología , Hiperreactividad Bronquial/tratamiento farmacológico , Hiperreactividad Bronquial/inmunología , Lidocaína/análogos & derivados , Ovalbúmina/antagonistas & inhibidores , Ovalbúmina/inmunología , Linfocitos T/efectos de los fármacos , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Hiperreactividad Bronquial/patología , Citocinas/biosíntesis , Citocinas/inmunología , Dexametasona/farmacología , Inflamación/inmunología , Inflamación/prevención & control , Lidocaína/síntesis química , Lidocaína/química , Lidocaína/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: Atopy and bronchial hyperreactivity are factors related to severe and unremitting asthma of childhood; however, the prevalence of these factors could be different according to age of the child. OBJECTIVE: To determine if methacholine bronchial hyperreactivity (BHR) differs between atopic and nonatopic preschoolers and schoolchildren with mild-moderate asthma. METHODS: Data obtained from 340 children with diagnosis of asthma or recurrent wheezing, matched by atopic conditions (positive or negative skin prick test) and age, and who underwent a methacholine bronchial challenge test (by spirometry in schoolchildren and by transcutaneous oxygen pressure [TcP(O2)] in preschoolers) were reviewed. RESULTS: Among 136 schoolchildren (9.07 ± 2.5 years), the prevalence of positive BHR was significantly higher among atopics than nonatopics (75% versus 48.5%, p = .001, respectively), even after controlling for gender and nutritional status (adjusted odds ratio [aOR] = 3.2129, 95% confidence interval [CI]: 1.5-6.8; p = .002). In addition, atopic schoolchildren had lower PC(20) and required a lower threshold dose of methacholine to induce a reaction (0.53 versus 0.82 mg/ml, p = .055 and .5 versus 1 mg/ml, p = .02, respectively) than nonatopics. Nevertheless, basal and predicted forced expiratory volume in one second (FEV1) were similar between groups. In contrast, among 204 preschoolers (4.74 ± 1.1 years), there were no differences in the prevalence of positive BHR between atopics and nonatopics (74.5% versus 72.5%, p = .75, respectively). Furthermore, basal TcP(O2), a higher fall of TcP(O2) and lower threshold doses of methacholine required for induction as measured by TcP(O2) were similar between the atopic and nonatopic preschoolers. CONCLUSIONS: Atopic asthmatic schoolchildren have greater hyperresponsiveness to methacholine than nonatopics (only among those with normal nutritional status). However, atopic and nonatopic asthmatic preschoolers have similar hyperresponsiveness to methacholine. Therefore, factors different from atopy may be responsible for wheeze in younger children.
Asunto(s)
Asma/fisiopatología , Hiperreactividad Bronquial/fisiopatología , Hipersensibilidad Inmediata/fisiopatología , Asma/diagnóstico , Asma/inmunología , Hiperreactividad Bronquial/diagnóstico , Hiperreactividad Bronquial/inmunología , Pruebas de Provocación Bronquial/métodos , Distribución de Chi-Cuadrado , Niño , Preescolar , Femenino , Volumen Espiratorio Forzado , Humanos , Hipersensibilidad Inmediata/diagnóstico , Masculino , Cloruro de Metacolina , Estudios Retrospectivos , Pruebas CutáneasRESUMEN
There is evidence that sex and sex hormones influence the severity of asthma. Airway and lung parenchyma remodeling and the relationship of ultrastructural changes to airway responsiveness and inflammation in male, female, and oophorectomized mice (OVX) were analyzed in experimental chronic allergic asthma. Seventy-two BALB/c mice were randomly divided into three groups (n=24/each): male, female, and OVX mice, whose ovaries were removed 7 days before the start of sensitization. Each group was further randomized to be sensitized and challenged with ovalbumin (OVA) or saline. Twenty-four hours after the last challenge, collagen fiber content in airways and lung parenchyma, the volume proportion of smooth muscle-specific actin in alveolar ducts and terminal bronchiole, the amount of matrix metalloproteinase (MMP)-2 and MMP-9, and the number of eosinophils and interleukin (IL)-4, IL-5, and transforming growth factor (TGF)-ß levels in bronchoalveolar lavage fluid were higher in female than male OVA mice. The response of OVX mice was similar to that of males, except that IL-5 remained higher. Nevertheless, after OVA provocation, airway responsiveness to methacholine was higher in males compared with females and OVX mice. In conclusion, sex influenced the remodeling process, but the mechanisms responsible for airway hyperresponsiveness seemed to differ from those related to remodeling.
Asunto(s)
Asma/metabolismo , Hiperreactividad Bronquial/metabolismo , Matriz Extracelular/metabolismo , Mediadores de Inflamación/metabolismo , Pulmón/metabolismo , Neumonía/metabolismo , Animales , Asma/inmunología , Asma/patología , Asma/fisiopatología , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/patología , Hiperreactividad Bronquial/fisiopatología , Pruebas de Provocación Bronquial , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Broncodilatadores/administración & dosificación , Enfermedad Crónica , Colágeno/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Pulmón/inmunología , Pulmón/fisiopatología , Pulmón/ultraestructura , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Cloruro de Metacolina/administración & dosificación , Ratones , Ratones Endogámicos BALB C , Ovalbúmina , Ovariectomía , Neumonía/inmunología , Neumonía/patología , Neumonía/fisiopatología , Factores Sexuales , Factores de Tiempo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: The dust mite Blomia tropicalis is an important source of aeroallergens in tropical areas. Although a mouse model for B. tropicalis extract (BtE)-induced asthma has been described, no study comparing different mouse strains in this asthma model has been reported. The relevance and reproducibility of experimental animal models of allergy depends on the genetic background of the animal, the molecular composition of the allergen and the experimental protocol. OBJECTIVES: This work had two objectives. The first was to study the anti-B. tropicalis allergic responses in different mouse strains using a short-term model of respiratory allergy to BtE. This study included the comparison of the allergic responses elicited by BtE with those elicited by ovalbumin in mice of the strain that responded better to BtE sensitization. The second objective was to investigate whether the best responder mouse strain could be used in an experimental model of allergy employing relatively low BtE doses. METHODS: Groups of mice of four different syngeneic strains were sensitized subcutaneously with 100 microg of BtE on days 0 and 7 and challenged four times intranasally, at days 8, 10, 12, and 14, with 10 microg of BtE. A/J mice, that were the best responders to BtE sensitization, were used to compare the B. tropicalis-specific asthma experimental model with the conventional experimental model of ovalbumin (OVA)-specific asthma. A/J mice were also sensitized with a lower dose of BtE. RESULTS: Mice of all strains had lung inflammatory-cell infiltration and increased levels of anti-BtE IgE antibodies, but these responses were significantly more intense in A/J mice than in CBA/J, BALB/c or C57BL/6J mice. Immunization of A/J mice with BtE induced a more intense airway eosinophil influx, higher levels of total IgE, similar airway hyperreactivity to methacholine but less intense mucous production, and lower levels of specific IgE, IgG1 and IgG2 antibodies than sensitization with OVA. Finally, immunization with a relatively low BtE dose (10 microg per subcutaneous injection per mouse) was able to sensitize A/J mice, which were the best responders to high-dose BtE immunization, for the development of allergy-associated immune and lung inflammatory responses. CONCLUSIONS: The described short-term model of BtE-induced allergic lung disease is reproducible in different syngeneic mouse strains, and mice of the A/J strain was the most responsive to it. In addition, it was shown that OVA and BtE induce quantitatively different immune responses in A/J mice and that the experimental model can be set up with low amounts of BtE.
Asunto(s)
Alérgenos/administración & dosificación , Asma/inmunología , Pyroglyphidae/inmunología , Administración Intranasal , Animales , Antígenos de Plantas , Asma/genética , Asma/fisiopatología , Hiperreactividad Bronquial/inmunología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta Inmunológica , Inmunoglobulina E/sangre , Inyecciones Subcutáneas , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ovalbúmina , Eosinofilia Pulmonar/inmunología , Ratas , Ratas Wistar , Especificidad de la Especie , Factores de TiempoRESUMEN
In the present study the effects of bradykinin receptor antagonists were investigated in a murine model of asthma using BALB/c mice immunized with ovalbumin/alum and challenged twice with aerosolized ovalbumin. Twenty four hours later eosinophil proliferation in the bone marrow, activation (lipid bodies formation), migration to lung parenchyma and airways and the contents of the pro-angiogenic and pro-fibrotic cytokines TGF-beta and VEGF were determined. The antagonists of the constitutive B(2) (HOE 140) and inducible B(1) (R954) receptors were administered intraperitoneally 30min before each challenge. In sensitized mice, the antigen challenge induced eosinophil proliferation in the bone marrow, their migration into the lungs and increased the number of lipid bodies in these cells. These events were reduced by treatment of the mice with the B(1) receptor antagonist. The B(2) antagonist increased the number of eosinophils and lipid bodies in the airways without affecting eosinophil counts in the other compartments. After challenge the airway levels of VEGF and TGF-beta significantly increased and the B(1) receptor antagonist caused a further increase. By immunohistochemistry techniques TGF-beta was found to be expressed in the muscular layer of small blood vessels and VEGF in bronchial epithelial cells. The B(1) receptors were expressed in the endothelial cells. These results showed that in a murine model of asthma the B(1) receptor antagonist has an inhibitory effect on eosinophils in selected compartments and increases the production of cytokines involved in tissue repair. It remains to be determined whether this effects of the B(1) antagonist would modify the progression of the allergic inflammation towards resolution or rather towards fibrosis.
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Asma/inmunología , Antagonistas del Receptor de Bradiquinina B1 , Líquido del Lavado Bronquioalveolar/química , Eosinófilos/efectos de los fármacos , Pulmón/inmunología , Factor de Crecimiento Transformador beta/inmunología , Factor A de Crecimiento Endotelial Vascular/inmunología , Análisis de Varianza , Animales , Asma/inducido químicamente , Asma/tratamiento farmacológico , Antagonistas del Receptor de Bradiquinina B2 , Hiperreactividad Bronquial/inmunología , Recuento de Células , Movimiento Celular/efectos de los fármacos , Movimiento Celular/inmunología , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Eosinófilos/inmunología , Inmunohistoquímica , Ratones , Receptor de Bradiquinina B1/inmunología , Receptor de Bradiquinina B2/inmunología , Factor de Crecimiento Transformador beta/análisis , Factor A de Crecimiento Endotelial Vascular/análisisRESUMEN
Allergic asthma is a chronic inflammatory disease of the lung whose incidence and morbidity continues to rise in developed nations. Despite being a hallmark of asthma, the molecular mechanisms that determine airway hyperresponsiveness (AHR) are not completely established. Transcription factors of the NFAT family are involved in the regulation of several asthma-related genes. It has been shown that the absence of NFAT1 leads to an increased pleural eosinophilic allergic response accompanied by an increased production of Th2 cytokines, suggesting a role for NFAT1 in the regulation of allergic diseases. Herein, we analyze NFAT1-/- mice to address the role of NFAT1 in a model of allergic airway inflammation and its influence in AHR. NFAT1-/- mice submitted to airway inflammation display a significant exacerbation of several features of the allergic disease, including lung inflammation, eosinophilia, and serum IgE levels, which were concomitant with elevated Th2 cytokine production. However, in spite of the increased allergic phenotype, NFAT1-/- mice failed to express AHR after methacholine aerosol. Refractoriness of NFAT1-/- mice to methacholine was confirmed in naïve mice, suggesting that this refractoriness occurs in an intrinsic way, independent of the lung inflammation. In addition, NFAT1-/- mice exhibit increased AHR in response to serotonin inhalation, suggesting a specific role for NFAT1 in the methacholine pathway of bronchoconstriction. Taken together, these data add support to the interpretation that NFAT1 acts as a counterregulatory mechanism to suppress allergic inflammation. Moreover, our findings suggest a novel role for NFAT1 protein in airway responsiveness mediated by the cholinergic pathway.
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Asma/inmunología , Hiperreactividad Bronquial/inmunología , Factores de Transcripción NFATC/inmunología , Neumonía/inmunología , Animales , Líquido del Lavado Bronquioalveolar/inmunología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Contracción Muscular/fisiología , Músculo Liso/fisiología , Factores de Transcripción NFATC/genética , Receptores Muscarínicos/metabolismo , Hipersensibilidad Respiratoria/inmunologíaRESUMEN
Helminths and their products have a profound immunomodulatory effect upon the inductive and effector phases of inflammatory responses, including allergy. We have demonstrated that PAS-1, a protein isolated from Ascaris suum worms, has an inhibitory effect on lung allergic inflammation due to its ability to down-regulate eosinophilic inflammation, Th2 cytokine release and IgE antibody production. Here, we investigated the role of IL-12, IFN-gamma and IL-10 in the PAS-1-induced inhibitory mechanism using a murine model of asthma. Wild type C57BL/6, IL-12(-/-), IFN-gamma(-/-) and IL-10(-/-) mice were immunized with PAS-1 and/or OVA and challenged with the same antigens intranasally. The suppressive effect of PAS-1 was demonstrated on the cellular influx into airways, with reduction of eosinophil number and eosinophil peroxidase activity in OVA+PAS-1-immunized wild type mice. This effect well correlated with a significant reduction in the levels of IL-4, IL-5, IL-13 and eotaxin in BAL fluid. Levels of IgE and IgG1 antibodies were also impaired in serum from these mice. The inhibitory activity of PAS-1 was also observed in IL-12(-/-) mice, but not in IFN-gamma(-/-) and IL-10(-/-) animals. These data show that IFN-gamma and IL-10, but not IL-12, play an important role in the PAS-1 modulatory effect.
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Ascaris suum/inmunología , Hiperreactividad Bronquial/inmunología , Proteínas del Helminto/metabolismo , Interferón gamma/inmunología , Interleucina-10/inmunología , Animales , Formación de Anticuerpos/inmunología , Hiperreactividad Bronquial/genética , Hiperreactividad Bronquial/metabolismo , Movimiento Celular/inmunología , Inmunoglobulina G/inmunología , Interferón gamma/deficiencia , Interferón gamma/genética , Interferón gamma/metabolismo , Interleucina-10/deficiencia , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-12/deficiencia , Interleucina-12/genética , Interleucina-12/inmunología , Interleucina-12/metabolismo , Leucocitos/citología , Leucocitos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Levels of endothelins are particularly high in the lung, and there is evidence that these peptides are involved in asthma. Asthma is a chronic inflammatory disease associated with lymphocyte infiltration. In the present study, we used a murine model of asthma to investigate the role of endothelins in lymphocyte and eosinophil infiltration into the airway hyperreactivity and mucus secretion. Sensitized C57Bl/6 mice were treated with endothelin ETA receptor antagonist (BQ123) or endothelin ETB receptor antagonist (BQ788) 30 min before an antigen aerosol challenge. After 24 h, dose response curves to methacholine were performed in isolated lungs, FACS analysis of lymphocytes and eosinophil counts were performed in bronchoalveolar lavage fluid and mucus index was determined by histopathology. In sensitized and antigen-challenged mice there is a marked increase in the T CD4+, T CD8+, B220+, Tgammadelta+ and NK1.1+ lymphocyte subsets. Treatment with BQ123 further increased these cell populations. The number of eosinophils, airway hyperreactivity and mucus were all reduced by BQ123 treatment. The BQ 788 had no significant effect on the parameters analyzed. Treatment with BQ123 reduced the endothelin concentration in lung homogenates, suggesting that endothelins exert a positive feedback on their synthesis. We show here that in murine asthma the ETA receptor antagonist up-regulates lymphocyte infiltration and reduces eosinophils, hyperreactivity and mucus.
Asunto(s)
Asma/inmunología , Antagonistas de los Receptores de la Endotelina A , Eosinófilos/efectos de los fármacos , Subgrupos Linfocitarios/efectos de los fármacos , Péptidos Cíclicos/farmacología , Animales , Asma/metabolismo , Hiperreactividad Bronquial/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Modelos Animales de Enfermedad , Eosinófilos/inmunología , Eosinófilos/metabolismo , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/metabolismo , Subgrupos Linfocitarios/inmunología , Masculino , Cloruro de Metacolina/análisis , Ratones , Ratones Endogámicos C57BL , Moco/efectos de los fármacos , Moco/metabolismo , Ovalbúmina/inmunologíaRESUMEN
Non-atopic asthma is the predominant phenotype in non-affluent parts of Latin America. We recently reported that infestation with Ascaris lumbricoides increased the risk of non-atopic asthma in less affluent areas of Brazil but the mechanism is unclear. The present study was conducted to determine whether helminth infestation is associated with heightened bronchial responsiveness (BHR), a common finding in asthma. A random sample of 50 asthmatic and 50 non-asthmatic controls (mean age 10.1 years) were selected from a larger cohort (n = 1,011) without knowledge of their helminth infestation status. Three stool samples were collected from each child on different days and each sample was analyzed by the Kato-Katz method for quantitative determination of helminth eggs. Bronchial provocation tests were performed with inhaled 4.5% hypertonic saline using the ISAAC Phase II standardized protocol. There was no difference between the prevalence of positive BHR in the asthmatics (20.4%) compared with the controls (14.6%) (P = 1.0). Helminth infestation was detected in 24.0% of children, with A. lumbricoides being the most common. Children with high load infestation (>or=100 eggs/g) were five times more likely to have BHR than children with low load or no infestation. Despite the small sample size the results of the present study suggest that the link between high load helminth infestation and non-atopic asthma may be mediated via heightened bronchial responsiveness, possibly due to an inflammatory response to the pulmonary phase of the helminth life cycle.