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Purpose: This retrospective study investigates the influence of overweight and obesity status on pulmonary function, airway inflammatory markers, and airway responsiveness in elderly asthma patients. Methods: Patients with asthma older than 65 years old who completed a bronchial provocation test (BPT) or bronchial dilation test (BDT) and a fractional exhaled nitric oxide (FeNO) test between December 2015 and June 2020 were identified retrospectively for this study. All of the patients were categorized into overweight/obesity and non-obesity groups based on their BMI. Pulmonary function test (PFT) and FeNO measurements were accomplished according to the 2014 recommendations of the Chinese National Guidelines of Pulmonary Function Test and American Thoracic Society/European Respiratory Society recommendations, respectively. Results: A total of 136 patients with an average age of 71.2 ± 5.40 years were identified. The average BMI was 23.8 ± 3.63, while the value of FeNO was 42.3 ± 38.4 parts per billion (ppb). In contrast to the non-obesity group, which had a value of 48.8 ± 43.1 ppb for FeNO, the overweight/obesity group had a significant lower value of 35.4 ± 31.4 ppb. There was no significant difference in the proportion of individuals with high airway hyperresponsiveness between the overweight/obesity and non-obesity groups (96 patients in total). Multiple linear regression analysis established an inverse correlation between FeNO and Provocation concentration causing a 20% fall in FEV1(PC20) but excluded significant relationships with age and BMI. The model's R is 0.289, and its p value is 0.045. Conclusion: The elderly Chinese Han asthmatics with overweight/obesity had lower FeNO levels than those with non-obese according to our findings. In addition, the FeNO level was inversely correlated between FeNO levels and PC20 in elderly asthmatics.
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Asma , Óxido Nítrico , Obesidad , Sobrepeso , Anciano , Femenino , Humanos , Masculino , Pueblo Asiatico , Asma/fisiopatología , Asma/metabolismo , Asma/diagnóstico , Índice de Masa Corporal , Pruebas Respiratorias , Pruebas de Provocación Bronquial , China/epidemiología , Prueba de Óxido Nítrico Exhalado Fraccionado , Óxido Nítrico/metabolismo , Óxido Nítrico/análisis , Obesidad/fisiopatología , Obesidad/metabolismo , Sobrepeso/fisiopatología , Sobrepeso/metabolismo , Pruebas de Función Respiratoria , Hipersensibilidad Respiratoria/fisiopatología , Hipersensibilidad Respiratoria/metabolismo , Hipersensibilidad Respiratoria/diagnóstico , Estudios RetrospectivosRESUMEN
Airway hyperresponsiveness (AHR) is a key clinical feature of asthma. The presence of AHR in people with asthma provides the substrate for bronchoconstriction in response to numerous diverse stimuli, contributing to airflow limitation and symptoms including breathlessness, wheeze, and chest tightness. Dysfunctional airway smooth muscle significantly contributes to AHR and is displayed as increased sensitivity to direct pharmacologic bronchoconstrictor stimuli, such as inhaled histamine and methacholine (direct AHR), or to endogenous mediators released by activated airway cells such as mast cells (indirect AHR). Research in in vivo human models has shown that the disrupted airway epithelium plays an important role in driving inflammation that mediates indirect AHR in asthma through the release of cytokines such as thymic stromal lymphopoietin and IL-33. These cytokines upregulate type 2 cytokines promoting airway eosinophilia and induce the release of bronchoconstrictor mediators from mast cells such as histamine, prostaglandin D2, and cysteinyl leukotrienes. While bronchoconstriction is largely due to airway smooth muscle contraction, airway structural changes known as remodeling, likely mediated in part by epithelial-derived mediators, also lead to airflow obstruction and may enhance AHR. In this review, we outline the current knowledge of the role of the airway epithelium in AHR in asthma and its implications on the wider disease. Increased understanding of airway epithelial biology may contribute to better treatment options, particularly in precision medicine.
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Asma , Mucosa Respiratoria , Humanos , Asma/inmunología , Asma/fisiopatología , Animales , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Citocinas/metabolismo , Citocinas/inmunología , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/fisiopatología , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/fisiopatología , Mastocitos/inmunología , BroncoconstricciónRESUMEN
OBJECTIVES: This study sought to examine whether ligustrazine was capable of inhibiting phosphodiesterase (PDE) activity and improving lung function in a rat model of asthma. METHODS: Rats were initially sensitized using ovalbumin (OVA) and then were challenged daily with aerosolized OVA beginning 14 days later (30 min/day) to generate a rat model of asthma. Changes in airway function following methacholine (MCh) injection were evaluated by monitoring lung resistance (R L) and dynamic lung compliance (C dyn) values using an AniRes2005 analytic system. In addition, serum IgE was measured via ELISA, while PDE expression was evaluated via qPCR and western blotting. Key Findings. Ligustrazine significantly impaired allergen-induced lung hyperresponsivity and inflammation in this asthma model system. Ligustrazine treatment was also associated with reduced expression of PDEs including PDE4 in the lungs of these rats. CONCLUSIONS: Ligustrazine suppresses airway inflammation and bronchial hyperresponsivity in this rat model system, and these changes are associated with decreased PDE expression at the protein and mRNA levels.
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Asma/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/farmacología , Pirazinas/farmacología , Resistencia de las Vías Respiratorias/efectos de los fármacos , Alérgenos/administración & dosificación , Alérgenos/inmunología , Animales , Asma/inmunología , Asma/fisiopatología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Biología Computacional , Modelos Animales de Enfermedad , Inmunoglobulina E/sangre , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/fisiopatología , Masculino , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Hidrolasas Diéster Fosfóricas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Hipersensibilidad Respiratoria/tratamiento farmacológico , Hipersensibilidad Respiratoria/fisiopatologíaRESUMEN
BACKGROUND: Deaths attributed to Coronavirus Disease 2019 (COVID-19) are mainly due to severe hypoxemic respiratory failure. Although the inflammatory storm has been considered the main pathogenesis of severe COVID-19, hypersensitivity may be another important mechanism involved in severe cases, which have a perfect response to corticosteroids (CS). METHOD: We detected the serum level of anti-SARS-CoV-2-spike S1 protein-specific IgE (SP-IgE) and anti-SARS-CoV-2 nucleocapsid protein-specific IgE (NP-IgE) in COVID-19. Correlation of levels of specific IgE and clinical severity were analysed. Pulmonary function test and bronchial provocation test were conducted in early convalescence of COVID-19. We also obtained histological samples via endoscopy to detect the evidence of mast cell activation. RESULT: The levels of serum SP-IgE and NP-IgE were significantly higher in severe cases, and were correlated with the total lung severity scores (TLSS) and the PaO2 /FiO2 ratio. Nucleocapsid protein could be detected in both airway and intestinal tissues, which was stained positive together with activated mast cells, binded with IgE. Airway hyperresponsiveness (AHR) exists in the early convalescence of COVID-19. After the application of CS in severe COVID-19, SP-IgE and NP-IgE decreased, but maintained at a high level. CONCLUSION: Hypersensitivity may be involved in severe COVID-19.
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Bronquios/inmunología , COVID-19/inmunología , Proteínas de la Nucleocápside de Coronavirus/inmunología , Duodeno/inmunología , Hipersensibilidad/inmunología , Inmunoglobulina E/inmunología , Mastocitos/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bronquios/metabolismo , Bronquios/patología , COVID-19/metabolismo , COVID-19/patología , COVID-19/fisiopatología , Estudios de Casos y Controles , Proteínas de la Nucleocápside de Coronavirus/metabolismo , Duodeno/metabolismo , Duodeno/patología , Femenino , Humanos , Hipersensibilidad/metabolismo , Hipersensibilidad/patología , Hipersensibilidad/fisiopatología , Pulmón/fisiopatología , Masculino , Mastocitos/metabolismo , Mastocitos/patología , Persona de Mediana Edad , Membrana Mucosa/inmunología , Membrana Mucosa/metabolismo , Membrana Mucosa/patología , Fosfoproteínas/inmunología , Fosfoproteínas/metabolismo , Recuperación de la Función , Hipersensibilidad Respiratoria/fisiopatología , Estudios Retrospectivos , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Glicoproteína de la Espiga del Coronavirus/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Type 2 innate lymphoid cells (ILC2s) are relevant players in type 2 asthma. They initiate eosinophil infiltration and airway hyperreactivity (AHR) through cytokine secretion. Leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is an inhibitory receptor considered to be an immune checkpoint in different inflammatory diseases. OBJECTIVE: Our aim here was to investigate the expression of LAIR-1 and assess its role in human and murine ILC2s. METHODS: Wild-type and LAIR-1 knockout mice were intranasally challenged with IL-33, and pulmonary ILC2s were sorted to perform an ex vivo comparative study based on RNA sequencing and flow cytometry. We next studied the impact of LAIR-1 deficiency on AHR and lung inflammation by using knockout mice and adoptive transfer experiments in Rag2-/-Il2rg-/- mice. Knockdown antisense strategies and humanized mice were used to assess the role of LAIR-1 in human ILC2s. RESULTS: We have demonstrated that LAIR-1 is inducible on activated ILC2s and downregulates cytokine secretion and effector function. LAIR-1 signaling in ILC2s was mediated via inhibitory pathways, including SHP1/PI3K/AKT, and LAIR-1 deficiency led to exacerbated ILC2-dependent AHR in IL-33 and Alternaria alternata models. In adoptive transfer experiments, we confirmed the LAIR-1-mediated regulation of ILC2s in vivo. Interestingly, LAIR-1 was expressed and inducible in human ILC2s, and knockdown approaches of Lair1 resulted in higher cytokine production. Finally, engagement of LAIR-1 by physiologic ligand C1q significantly reduced ILC2-dependent AHR in a humanized ILC2 murine model. CONCLUSION: Our results unravel a novel regulatory axis in ILC2s with the capacity to reduce allergic AHR and lung inflammation.
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Alternariosis/inmunología , Linfocitos/inmunología , Neumonía/inmunología , Receptores Inmunológicos/inmunología , Hipersensibilidad Respiratoria/inmunología , Traslado Adoptivo , Alternaria , Alternariosis/fisiopatología , Animales , Citocinas/inmunología , Femenino , Humanos , Inmunidad Innata , Interleucina-33/farmacología , Pulmón/inmunología , Pulmón/fisiopatología , Transfusión de Linfocitos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Neumonía/fisiopatología , Receptores Inmunológicos/genética , Hipersensibilidad Respiratoria/fisiopatologíaRESUMEN
LABA/ICS and LABA/LAMA/ICS combinations elicit beneficial effects in asthma. Specific evidence concerning the impact of combining indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF) on human airway hyperresponsiveness (AHR) and airway inflammation is still missing. The aim of this study was to characterize the synergy of IND/MF and IND/GLY/MF combinations, both once-daily treatments for asthma, in hyperresponsive airways. Passively sensitized human medium and small airways were stimulated by histamine and treated with IND/MF (molar ratio: 100/45, 100/90) and IND/GLY/MF (molar ratio: 100/37/45, 100/37/90). The effect on contractility and airway inflammation was tested. Drug interaction was assessed by Bliss Independence equation and Unified Theory. IND/MF 100/90 elicited middle-to-very strong synergistic relaxation in medium and small airways (+≈20-30% vs. additive effect, P < 0.05), for IND/MF 100/45 the synergy was middle-to-very strong in small airways (+≈20% vs. additive effect, P < 0.05), and additive in medium bronchi (P > 0.05 vs. additive effect). IND/GLY/MF 100/37/45 and 100/37/90 induced very strong synergistic relaxation in medium and small airways (+≈30-50% vs. additive effect, P < 0.05). Synergy was related with significant (P < 0.05) reduction in IL-4, IL-5, IL-6, IL-9, IL-13, TNF-α, TSLP, NKA, SP, and non-neuronal ACh, and enhancement in cAMP. IND/MF and IND/GLY/MF combinations synergistically interact in hyperresponsive medium and small airways and modulate the levels of cytokines, neurokinins, ACh, and intracellular cAMP. The concentrations of MF in the combinations modulate the effects in the target tissue.
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Antiinflamatorios/farmacología , Bronquios/efectos de los fármacos , Broncodilatadores/farmacología , Glicopirrolato/farmacología , Indanos/farmacología , Furoato de Mometasona/farmacología , Quinolonas/farmacología , Hipersensibilidad Respiratoria/tratamiento farmacológico , Acetilcolina/metabolismo , Bronquios/metabolismo , Bronquios/fisiología , AMP Cíclico/metabolismo , Citocinas/metabolismo , Interacciones Farmacológicas , Quimioterapia Combinada , Humanos , Contracción Isométrica/efectos de los fármacos , Hipersensibilidad Respiratoria/metabolismo , Hipersensibilidad Respiratoria/fisiopatologíaRESUMEN
Epidemiological research has identified that exposure to fine particulate matter (PM2.5) can increase airway hyperresponsiveness (AHR) which is considered a typical characteristic of asthma. Although the effect of PM2.5 on AHR has been elucidated to a certain degree, its exact mechanism remains unclear. Bromodomain-containing protein 4 (BRD4) is recognized as a member of the bromodomain and extraterminal (BET) family, with the ability to maintain higher-order chromatin configuration and regulate gene expression programs. The primary objective of our study was to examine the role of BRD4 in AHR triggered by PM2.5, and to elucidate its possible molecular mechanism. A mouse model with AHR was established using a nose-only PM2.5 exposure system. We observed that PM2.5 enhanced AHR in the experimental group compared to the control group, and this alteration was accompanied by increased lung inflammation and BRD4 expression in bronchi-lung tissue. However, the BRD4 inhibitor (ZL0420) could alleviate the aforementioned alterations in the mouse model with PM2.5 exposure. To explore the exact molecular mechanism, we further examined the role of BRD4 in human airway smooth muscle cells (hASMCs) after exposure to PM2.5 DMSO extracts. We found that PM2.5 DMSO extracts, which promoted the contraction and migration of hASMCs, was accompanied by an increase in the levels of BRD4, kallikrein 14 (KLK14), bradykinin 2 receptor (B2R), matrix metalloproteinases2(MMP-2), matrix metalloproteinases9(MMP-9), vimentin and bradykinin (BK) secretion, while ZL0420 and BRD4 gene silencing could reverse this response. In summary, these results demonstrate that BRD4 is an important player in AHR triggered by PM2.5, and BRD4 inhibition can ameliorate AHR induced by PM2.5. In addition, PM2.5 DMSO extracts can promote the contraction and migration of hASMCs by increasing BRD4 expression.
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Proteínas de Ciclo Celular/metabolismo , Material Particulado/toxicidad , Hipersensibilidad Respiratoria/inducido químicamente , Factores de Transcripción/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Pulmón/efectos de los fármacos , Ratones , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/patología , Neumonía/inducido químicamente , Hipersensibilidad Respiratoria/fisiopatologíaRESUMEN
BACKGROUND: CD56-expressing natural killer (NK) cells as well as invariant NK T (iNKT) cells have been shown to either promote or inhibit allergic immune responses. OBJECTIVE: The aim of the present study was to investigate the impact of these cells in a recently developed humanized mouse model of allergen-induced IgE-dependent gut and lung inflammation. METHODS: Nonobese diabetic-severe combined immunodeficiency γ-chain knockout mice were injected intraperitoneally with human PBMCs or CD56-depleted (CD56neg) PBMCs from highly sensitized donors with birch or grass pollen allergy together with the respective allergen or with NaCl as a control. Three weeks later, the mice were challenged with the allergen rectally and gut inflammation was monitored by video miniendoscopy and by histology. Furthermore, airway inflammation was measured after an additional intranasal allergen challenge. RESULTS: Allergen-specific human IgE in mouse sera, detectable only after coinjection of the respective allergen, was reduced in mice being injected with CD56neg PBMCs compared with in mice receiving nondepleted PBMCs. Consequently, allergen-induced IgE-dependent colitis, airway hyperreactivity, and mucus-producing goblet cells were significantly inhibited in these mice. Interestingly, reconstitution of CD56neg PBMCs with nondepleted CD56+ cells and with CD56+CD3+ iNKT cells restored gut as well as lung inflammation, whereas addition of CD3-depleted CD56+ cells did not. CONCLUSION: These results demonstrate that allergen-specific gut and lung inflammation in PBMC-engrafted humanized mice is promoted by CD56+CD3+ iNKT cells, which opens new possibilities of therapeutic intervention in allergic diseases.
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Colitis/inmunología , Células T Asesinas Naturales/inmunología , Hipersensibilidad Respiratoria/inmunología , Rinitis Alérgica Estacional/inmunología , Alérgenos/inmunología , Animales , Betula/inmunología , Complejo CD3/inmunología , Antígeno CD56/inmunología , Colitis/patología , Colitis/fisiopatología , Colon/inmunología , Colon/patología , Femenino , Humanos , Inmunoglobulina E/sangre , Pulmón/inmunología , Pulmón/patología , Pulmón/fisiopatología , Masculino , Ratones Transgénicos , Poaceae/inmunología , Polen/inmunología , Hipersensibilidad Respiratoria/patología , Hipersensibilidad Respiratoria/fisiopatología , Rinitis Alérgica Estacional/patología , Rinitis Alérgica Estacional/fisiopatologíaRESUMEN
BACKGROUND: Specific allergy sensitization pattern, using "component-resolved diagnosis" (CRD), is a central component of allergy and asthma in childhood. Besides this, allergic asthma has been characterized by a Th2-shifted endotype with elevation of classical Th2 cytokines. Recently, other endotypes with distinct mechanisms focusing on cytokine regulation evolved, yet those pathways are still not well understood. OBJECTIVE: (a) To define reproducible immunological endotypes using cytokine expression in an asthma cohort and (b) to characterize their sensitization profile and clinical phenotype. METHODS: Supernatants from PBMCs of 234 children (median age 10 years) of an asthma cohort were analysed for cytokine expressions. The children were split into a training (n = 49) and validation (n = 185) group. The training group was used to identify immunological endotypes by clustering cytokine expressions, which were then assessed regarding clinical characteristics and specific IgE of recombinant allergen components. Next, our findings were validated in the validation group. RESULTS: We identified novel endotypes based on primarily unstimulated cytokine expression. One endotype showed an IFN-γ/Interleukin (IL)-17/IL-5 predominance, a different sensitization pattern (high in birch/apple; p < .01), and inferior lung function (p < .01). A second endotype grouped young children with food allergy and reduced lung function. Our findings were reproducible in the validation group. CONCLUSION AND CLINICAL RELEVANCE: We identified two novel clinical asthma endotypes via cytokine expression pattern with distinct sensitization patterns. These novel findings are critical for clinical guidance and open avenues for identifying underlying mechanisms and more patient-specific therapies.
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Asma/inmunología , Citocinas/inmunología , Hipersensibilidad a los Alimentos/inmunología , Pulmón/fisiopatología , Animales , Antígenos Dermatofagoides/inmunología , Asma/clasificación , Asma/fisiopatología , Betula/inmunología , Gatos , Niño , Alérgenos Animales/inmunología , Perros , Femenino , Volumen Espiratorio Forzado , Humanos , Inmunoglobulina E/inmunología , Interferón gamma/inmunología , Interleucina-17/inmunología , Interleucina-5/inmunología , Masculino , Malus/inmunología , Fenotipo , Phleum/inmunología , Reproducibilidad de los Resultados , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/fisiopatología , Células Th2/inmunología , Capacidad VitalRESUMEN
BACKGROUND Chronic cough is the main reason why parents seek medical treatment for their children. This study aimed to evaluate changes in airway function and inflammation levels and associated values in diagnosing and treating chronic cough. MATERIAL AND METHODS This study involved 118 children with chronic cough, including 45 cough-variant asthma (CVA) patients, 53 upper-airway cough syndrome (UACS) patients, and 20 post-infection cough (PIC) patients. Chronic cough was diagnosed as described by guidelines of the American College of Chest Physicians for evaluating chronic cough. Pulmonary ventilation function and airway hyperresponsiveness (AHR) were evaluated. Fractional exhaled nitric oxide (FeNO) levels and eosinophilic airway inflammation were measured. Eosinophil (EOS) count in sputum was also examined. CVA patients were treated with inhaled glucocorticoids, which have anti-inflammatory effects. RESULTS FeNO and sputum EOS levels were higher in CVA patients compared with UACS and PIC patients (P<0.05). CVA patients demonstrated significantly higher small airway indexes, including 25% forced expiratory flow (FEF), 50% FEF, and 75% FEF, compared with UACS and PIC patients (P<0.05). FeNO level was positively correlated with EOS in sputum (r=0.468, P=0.0001) and cough symptom scores (r=0.402, P<0.05). FeNO, EOS, and cough symptoms were significantly improved in CVA patients after glucocorticoid treatment. AHR was improved in all chronic cough patients after treatment. Cough-relief CVA patients demonstrated significantly higher FeNO levels compared with those without cough relief (P<0.05). CONCLUSIONS FeNO integrating pulmonary function and AHR examination can improve etiologic diagnosis and treatment for chronic cough in children.
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Tos/etiología , Óxido Nítrico/análisis , Hipersensibilidad Respiratoria/fisiopatología , Asma/fisiopatología , Pruebas Respiratorias/métodos , Niño , Enfermedad Crónica , Tos/diagnóstico , Tos/fisiopatología , Pruebas Diagnósticas de Rutina/efectos adversos , Eosinófilos , Espiración , Femenino , Humanos , Pulmón/fisiopatología , Masculino , Curva ROC , Esputo/inmunologíaRESUMEN
BACKGROUND: Previous reports have shown that pathogen-associated patterns (PAMPs) induce the production of interleukin (IL)-1ß in macrophages. Moreover, studies using mouse models also suggest that chitin, which acts as a PAMP, induces adjuvant effects and eosinophilic infiltration in the lung. Thus, we investigated the effects of inhaled chitin in mouse models. METHODS: We developed mouse models of inhaled chitin particle-induced airway inflammation and steroid-resistant ovalbumin (OVA)-induced airway inflammation. Some experimental groups of mice were treated additionally with dexamethasone (DEX). Murine alveolar macrophages (AMs), which were purified from bronchoalveolar lavage (BAL) fluids, were incubated with chitin, and treated with or without DEX. RESULTS: The numbers of total cells, AMs, lymphocytes, eosinophils, and neutrophils among BAL-derived cells, as well as the IL-1ß levels in BAL fluids and the numbers of IL-1ß-positive cells in lung, were significantly increased by chitin stimulation. Airway hyperresponsiveness (AHR) was aggravated in mice of the chitin inflammation model compared to control animals. The production of IL-1ß was significantly increased in murine AMs by chitin treatment, but DEX administration did not inhibit this chitin-induced IL-1ß production. Furthermore, in mouse models, DEX treatment inhibited the OVA-induced airway inflammation and AHR but not the airway inflammation and AHR induced by chitin or the combination of OVA and chitin. CONCLUSIONS: These results suggest that inhaled chitin induces airway inflammation, AHR, and the production of IL-1ß. Furthermore, our findings demonstrate for the first time that inhaled chitin induces steroid-resistant airway inflammation and AHR. Inhaled chitin may contribute to features of steroid-resistant asthma.
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Quitina/inmunología , Glucocorticoides/farmacología , Inflamación/inmunología , Pulmón/efectos de los fármacos , Macrófagos Alveolares/efectos de los fármacos , Hipersensibilidad Respiratoria/inmunología , Administración por Inhalación , Animales , Asma/inducido químicamente , Asma/inmunología , Asma/fisiopatología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Quitina/farmacología , Dexametasona/farmacología , Modelos Animales de Enfermedad , Resistencia a Medicamentos , Inflamación/inducido químicamente , Inflamación/fisiopatología , Interleucina-1beta/efectos de los fármacos , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Pulmón/inmunología , Pulmón/fisiopatología , Macrófagos Alveolares/inmunología , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Ovalbúmina/inmunología , Ovalbúmina/farmacología , Moléculas de Patrón Molecular Asociado a Patógenos , Hipersensibilidad Respiratoria/inducido químicamente , Hipersensibilidad Respiratoria/fisiopatologíaRESUMEN
In this study, we investigated whether humidifier disinfectants (HDs) induce asthmatic airway inflammation in an animal model and compared the features of HD-induced inflammatory symptoms with ovalbumin (OVA)-induced allergic asthma. Mice were intratracheally instilled three times with either the control or 0.1, 0.3, or 0.5 mg/kg of polyhexamethylene guanidine phosphate (PHMG-P). To characterize asthmatic features, the following parameters were analyzed: (i) differential cell counts and cytokine expression in the bronchoalveolar lavage fluid (BALF); (ii) presence of mucus-producing goblet cells and pulmonary eosinophilic infiltration in the lungs; (iii) serum immunoglobulin levels; and (iv) airway hyperresponsiveness (AHR). RNA-Seq and bioinformatics tools were used to investigate whether PHMG-P altered asthma-related gene expression in lung tissues. The PHMG-P exposure groups showed higher peribronchial/perivascular inflammation, elevated goblet cell hyperplasia, and inhaled methacholine-induced airway resistance. Additionally, IL-13 and IL-17 in BALF were significantly increased in the PHMG-P exposure groups. However, there were no significant differences in total serum IgE and BALF IL-4 and IL-5 levels in the PHMG-P exposure groups compared to the control group. PHMG-P exposure modulated the expression of genes related to Th17 signaling pathways including the IL-17A, IL-23, and STAT3 signaling pathways, but not the Th2 signaling pathway. Altogether, our results suggest that repeated exposure to low does PHMG-P induces asthma-like symptoms and is thus a possible risk factor for developing asthma. The PHMG-P-induced asthmatic airway inflammation showed a different pattern from that found in typical allergic asthma and may be related to irritant-induced airway inflammation and hyperresponsiveness characterized by Th2-low, Th17-related, IgE-independent, and mixed granulocytic features.
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Asma/fisiopatología , Desinfectantes/inmunología , Inflamación/fisiopatología , Hipersensibilidad Respiratoria/fisiopatología , Animales , Asma/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Citocinas/inmunología , Modelos Animales de Enfermedad , Femenino , Humidificadores , Inmunoglobulina E/inmunología , Inflamación/inmunología , Pulmón/inmunología , Pulmón/fisiopatología , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/inmunología , Hipersensibilidad Respiratoria/inmunología , Células Th17/inmunologíaRESUMEN
Allergic airway disease models use laboratory mice housed in highly controlled and hygienic environments, which provide a barrier between the mice and a predetermined list of specific pathogens excluded from the facility. In this study, we hypothesized that differences in facility barrier level and, consequently, the hygienic quality of the environment that mice inhabit impact the severity of pulmonary inflammation and lung function. Allergen-naive animals housed in the cleaner, high barrier (HB) specific pathogen-free facility had increased levels of inflammatory cytokines and higher infiltration of immune cells in the lung tissue but not in the bronchoalveolar lavage compared with mice housed in the less hygienic, low barrier specific pathogen-free facility. In both genders, house dust mite-induced airway disease was more severe in the HB than the low barrier facility. Within each barrier facility, female mice developed the most severe inflammation. However, allergen-naive male mice had worse lung function, regardless of the housing environment, and in the HB, the lung function in female mice was higher in the house dust mite model. Severe disease in the HB was associated with reduced lung microbiome diversity. The lung microbiome was altered across housing barriers, gender, and allergen-exposed groups. Thus, the housing barrier level impacts microbial-driven disease and gender phenotypes in allergic asthma. The housing of laboratory mice in more clean HB facilities aggravates lung immunity and causes a more severe allergic lung disease.
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Polvo/inmunología , Vivienda , Pyroglyphidae/inmunología , Hipersensibilidad Respiratoria/fisiopatología , Animales , Asma/etiología , Citocinas/biosíntesis , Femenino , Inmunoglobulina E/sangre , Pulmón/inmunología , Pulmón/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Hipersensibilidad Respiratoria/etiología , Factores SexualesRESUMEN
BACKGROUND: Asthma is an airway inflammatory disease and a major health problem worldwide. Anti-inflammatory steroids and bronchodilators are the gold-standard therapy for asthma. However, they do not prevent the development of the disease, and critically, a subset of asthmatics are resistant to steroid therapy. OBJECTIVE: To elucidate the therapeutic potential of human ß-defensins (hBD), such as hBD2 mild to moderate and severe asthma. METHODS: We investigated the role of hBD2 in a steroid-sensitive, house dust mite-induced allergic airways disease (AAD) model and a steroid-insensitive model combining ovalbumin-induced AAD with C muridarum (Cmu) respiratory infection. RESULTS: In both models, we demonstrated that therapeutic intranasal application of hBD2 significantly reduced the influx of inflammatory cells into the bronchoalveolar lavage fluid. Furthermore, key type 2 asthma-related cytokines IL-9 and IL-13, as well as additional immunomodulating cytokines, were significantly decreased after administration of hBD2 in the steroid-sensitive model. The suppression of inflammation was associated with improvements in airway physiology and treatment also suppressed airway hyper-responsiveness (AHR) in terms of airway resistance and compliance to methacholine challenge. CONCLUSIONS AND CLINICAL RELEVANCE: These data indicate that hBD2 reduces the hallmark features and has potential as a new therapeutic agent in allergic and especially steroid-resistant asthma.
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Resistencia de las Vías Respiratorias/efectos de los fármacos , Asma/metabolismo , Interleucina-13/metabolismo , Interleucina-9/metabolismo , Rendimiento Pulmonar/efectos de los fármacos , Pulmón/efectos de los fármacos , beta-Defensinas/farmacología , Animales , Asma/fisiopatología , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Infecciones por Chlamydia/metabolismo , Infecciones por Chlamydia/fisiopatología , Chlamydia muridarum , Modelos Animales de Enfermedad , Inflamación/metabolismo , Inflamación/fisiopatología , Pulmón/metabolismo , Pulmón/fisiopatología , Ratones , Ovalbúmina , Pyroglyphidae , Hipersensibilidad Respiratoria/metabolismo , Hipersensibilidad Respiratoria/fisiopatología , Infecciones del Sistema Respiratorio/metabolismo , Infecciones del Sistema Respiratorio/fisiopatologíaRESUMEN
BACKGROUND: Epidemiological data show that traffic-related air pollution contributes to the increasing prevalence and severity of asthma. DNA methylation (DNAm) changes may elucidate adverse health effects of environmental exposures. OBJECTIVES: We sought to assess the effects of allergen and diesel exhaust (DE) exposures on global DNAm and its regulation enzymes in human airway epithelium. METHODS: A total of 11 participants, including 7 with and 4 without airway hyperresponsiveness, were recruited for a randomized, double-blind crossover study. Each participant had 3 exposures: filtered air + saline, filtered air + allergen, and DE + allergen. Forty-eight hours postexposure, endobronchial biopsies and bronchoalveolar lavages were collected. Levels of DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes, 5-methylcytosine, and 5-hydroxymethylcytosine were determined by immunohistochemistry. Cytokines and chemokines in bronchoalveolar lavages were measured by electrochemiluminescence multiplex assays. RESULTS: Predominant DNMT (the most abundant among DNMT1, DNMT3A, and DNMT3B) and predominant TET (the most abundant among TET1, TET2, and TET3) were participant-dependent. 5-Methylcytosine and its regulation enzymes differed between participants with and without airway hyperresponsiveness at baseline (filtered air + saline) and in response to allergen challenge (regardless of DE exposure). Predominant DNMT and predominant TET correlated with lung function. Allergen challenge effect on IL-8 in bronchoalveolar lavages was modified by TET2 baseline levels in the epithelium. CONCLUSIONS: Response to allergen challenge is associated with key DNAm regulation enzymes. This relationship is generally unaltered by DE coexposure but is rather dependent on airway hyperresponsiveness status. These enzymes therefore warranted further inquiry regarding their potential in diagnosis, prognosis, and treatment of asthma.
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Contaminación del Aire , Alérgenos/administración & dosificación , Metilasas de Modificación del ADN/metabolismo , Exposición por Inhalación , Oxigenasas de Función Mixta/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Hipersensibilidad Respiratoria/metabolismo , Mucosa Respiratoria/metabolismo , Emisiones de Vehículos , Adulto , Bronquios , Líquido del Lavado Bronquioalveolar/química , Línea Celular , Estudios Cruzados , Citocinas/metabolismo , Metilasas de Modificación del ADN/genética , Método Doble Ciego , Femenino , Humanos , Pulmón/metabolismo , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Oxigenasas de Función Mixta/genética , Proteínas Proto-Oncogénicas/genética , Hipersensibilidad Respiratoria/fisiopatología , Adulto JovenRESUMEN
BACKGROUND: During the COVID-19 pandemic, a metered-dose inhaler (MDI) with a valved holding chamber (VHC) is a preferred route of bronchodilator delivery. We have developed a new homemade VHC, made of a paper coffee cup, and a drinking water bottle. This study was conducted to compare the bronchodilator response in children with airway hyperresponsiveness after the use of our homemade VHC and that of a standard commercial one. METHODS: In a randomized, two-period, two-sequence crossover trial, we recruited 20 children, aged 6-15 years, who had a greater than 12% increase in FEV1 after inhaled salbutamol. They were randomized into Group A and B. Group A used our VHC on the first day and Aerochamber® on the second day. Group B used the same VHCs but in alternate sequence. Spirometries were performed before and after 400 µg of salbutamol, MDI was administered via those VHCs. RESULTS: Baseline demographic data and spirometric values did not have statistically significant differences between group A and B and between the first and second day (p > .05). After giving salbutamol MDI, both VHCs produced significant increases in FVC, FEV1 , and FEF25-75% (p < .005). The improvement in FEV1 did not significantly differ between our homemade VHC and Aerochamber® (p > .05). CONCLUSION: Our homemade VHC is effective for an MDI bronchodilator delivery. Since it is very cheap and easy to make, it may be used as a disposable device to minimize airborne transmission especially when commercial VHC is not available.
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Albuterol/administración & dosificación , Broncodilatadores/administración & dosificación , Diseño de Equipo , Inhaladores de Dosis Medida , Hipersensibilidad Respiratoria/tratamiento farmacológico , Administración por Inhalación , Adolescente , COVID-19 , Niño , Estudios Cruzados , Femenino , Volumen Espiratorio Forzado , Humanos , Espaciadores de Inhalación , Masculino , Pandemias , Hipersensibilidad Respiratoria/fisiopatologíaRESUMEN
Airway examination procedures can potentially transmit infectious diseases to patients and to the health care professionals who perform them via various mechanisms. The COVID-19 pandemic has halted most of the activity of the clinics and laboratories involved in assessment of lung and nasal function, and clear recommendations in this regard have been made. Today, we still do not know for sure what its consequences will be in the short or long term, since important gaps remain in our knowledge of aspects as fundamental as virus transmission mechanisms, pathophysiology, immune response, and diagnosis. In this review, we study the examination techniques used to assess patients with respiratory allergy, asthma, and associated diseases during this period and highlight their possible advantages and disadvantages. Therefore, we focus on exploring the entire upper and lower airways, from the perspective of the safety of both health professionals and patients and their specific characteristics. We also analyze the intrinsic value of these interventions in terms of diagnosis and patient management. The changing situation of COVID-19 may mean that some of the assertions presented in this review will have to be modified in the future. While we seek to ensure a consistently broad approach, some differences in operational details may apply owing to local regulations.
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COVID-19 , Salud Laboral , Seguridad del Paciente , Hipersensibilidad Respiratoria/fisiopatología , Sistema Respiratorio/fisiopatología , SARS-CoV-2 , COVID-19/diagnóstico , COVID-19/transmisión , Personal de Salud , Humanos , Tamizaje Masivo , Pruebas de Función Respiratoria , VentilaciónRESUMEN
Flavonol kaempferol possesses a broad spectrum of potent pharmacological activities that seem to be effective in the modulation of allergic respiratory diseases. In our study, an experimental animal model of ovalbumin (OVA)-induced allergic airway inflammation in guinea pigs was used to determine the anti-asthmatic potential of kaempferol. The parameters of specific airway resistance (sRaw) and cough reflex response were evaluated in vivo. In vitro, an assessment of tracheal smooth muscle (TSM) contractility and analyses of inflammatory cytokines (IL-4, IL-5, IL-13, GM-CSF, IFN-γ), transforming growth factor (TGF-ß1), immune cells count and ciliary beating frequency (CBF) were performed. Both single (6, 20 mg/kg b. w. p. o.) and long-term administered doses of kaempferol (20 mg/kg b. w. p. o., 21 days) suppressed sRaw provoked by histamine in conscious animals. The administration of kaempferol for 21 days attenuated histamine-induced TSM contractility in vitro and ameliorated the progression of chronic airway inflammation by decreasing the levels of IL-5, IL-13, GM-CSF, eosinophil count in bronchoalveolar lavage (BAL) fluid and TGF-ß1 protein level in lung tissue. Kaempferol also eliminated the alterations in cough reflex sensitivity invoked by OVA-sensitization, but it did not affect CBF. The results demonstrate that flavonol kaempferol can modulate allergic airway inflammation and associated asthma features (AHR, aberrant stimulation of cough reflex).
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Antiasmáticos/farmacología , Broncoconstricción/efectos de los fármacos , Quempferoles/farmacología , Pulmón/efectos de los fármacos , Neumonía/prevención & control , Hipersensibilidad Respiratoria/prevención & control , Tráquea/efectos de los fármacos , Resistencia de las Vías Respiratorias/efectos de los fármacos , Animales , Líquido del Lavado Bronquioalveolar/química , Tos/inducido químicamente , Tos/metabolismo , Tos/fisiopatología , Tos/prevención & control , Citocinas/metabolismo , Modelos Animales de Enfermedad , Cobayas , Mediadores de Inflamación/metabolismo , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Pulmón/metabolismo , Pulmón/fisiopatología , Masculino , Ovalbúmina , Neumonía/inducido químicamente , Neumonía/metabolismo , Neumonía/fisiopatología , Hipersensibilidad Respiratoria/inducido químicamente , Hipersensibilidad Respiratoria/metabolismo , Hipersensibilidad Respiratoria/fisiopatología , Tráquea/metabolismo , Tráquea/fisiopatología , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Acrylamide is a toxic chemical substance produced when starch-rich foods are fried at high temperatures. Asthma is a chronic and complicated respiratory disease, of which genetic and environmental factors are the main triggers. Orally-received components may have an effect on asthma pathophysiology. The aim of this study was to investigate the role of AA as a stimulus in asthma. BALB/c mice were allocated into four groups as follows: two OVA-sensitized asthmatic groups, including one treated with AA by gavage feeding and one non-treated (asthma group), and two healthy (non-asthmatic) groups, one treated with AA by gavage feeding and one non-treated (negative control group). Airway hyperresponsiveness, cell count, cytokine levels in BAL fluid, lung histopathology, IgE levels, and oxidative stress indices including plasma level of MDA, pulmonary antioxidant enzymes (SOD and CAT) levels, HP content, and collagen fiber accumulation in lung tissue were measured. We found that the group of mice treated with both OVA and AA (asthmatic and AA-treated mice) experienced higher levels of asthma-associated biomarkers, including higher enhanced pause (Penh value), eosinophilic inflammation, mucus hyper secretion, goblet cell hyperplasia, total and OVA-specific IgE levels, IL-4, IL-5, and IL-13 levels than the group sensitized only with OVA (asthmatic mice). The OVA-AA-treated mice also experienced worsened levels of oxidative stress indicators. Healthy (non-asthmatic) mice that only received AA were in similar conditions to healthy untreated mice (negative control group). The OVA-AA-treated group showed more severe allergic asthma symptoms in comparison to the group only sensitized with OVA. Therefore, food/water contaminated with AA can act as a stimulant of allergic asthma and exacerbate the bronchial inflammatory responses.
Asunto(s)
Acrilamida/toxicidad , Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Asma/inducido químicamente , Broncoconstricción/efectos de los fármacos , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Pulmón/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Hipersensibilidad Respiratoria/inducido químicamente , Acrilamida/administración & dosificación , Administración Oral , Animales , Asma/inmunología , Asma/metabolismo , Asma/fisiopatología , Líquido del Lavado Bronquioalveolar/inmunología , Femenino , Fibrosis , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/fisiopatología , Ratones Endogámicos BALB C , Ovalbúmina , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/metabolismo , Hipersensibilidad Respiratoria/fisiopatologíaRESUMEN
In the present work, the anti-inflammatory and antiasthmatic potential of biseugenol, isolated as the main component from n-hexane extract from leaves of Nectandra leucantha and chemically prepared using oxidative coupling from eugenol, was evaluated in an experimental model of mixed-granulocytic asthma. Initially, in silico studies of biseugenol showed good predictions for drug-likeness, with adherence to Lipinski's rules of five (RO5), good Absorption, Distribution, Metabolism and Excretion (ADME) properties and no alerts for Pan-Assay Interference Compounds (PAINS), indicating adequate adherence to perform in vivo assays. Biseugenol (20 mg·kg-1) was thus administered intraperitoneally (four days of treatment) and resulted in a significant reduction in both eosinophils and neutrophils of bronchoalveolar lavage fluid in ovalbumin-sensitized mice with no statistical difference from dexamethasone (5 mg·kg-1). As for lung function parameters, biseugenol (20 mg·kg-1) significantly reduced airway and tissue damping in comparison to ovalbumin group, with similar efficacy to positive control dexamethasone. Airway hyperresponsiveness to intravenous methacholine was reduced with biseugenol but was inferior to dexamethasone in higher doses. In conclusion, biseugenol displayed antiasthmatic effects, as observed through the reduction of inflammation and airway hyperresponsiveness, with similar effects to dexamethasone, on mixed-granulocytic ovalbumin-sensitized mice.