RESUMEN
BACKGROUND: Lianhuaqingwen (LHQW) has been used in the treatment of chronic bronchitis, but the precise mechanism through which LHQW exhibits its anti-inflammatory effects in this context is not yet fully understood. The aim of this study was to investigate the active ingredients and signaling pathways responsible for LHQW's effectiveness in managing chronic bronchitis. METHODS: The research leveraged the TCMSP database to determine the active compounds and drug targets of LHQW. In parallel, the GeneCards, DrugBank, and PharmGkb databases were used to uncover targets pertinent to chronic bronchitis. To discern the potential mechanisms by which LHQW's active ingredients might treat chronic bronchitis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. Network pharmacology facilitated the construction of a drug-active ingredient-disease target network, aiding in forecasting the core targets for chronic bronchitis treatment by LHQW. Subsequently, molecular docking techniques alongside in vitro experiments were applied to confirm the interactions between the active ingredients and the primary targets. RESULTS: A total of 157 active ingredients, 225 potential drug targets, and 594 bronchitis-related targets were derived from various databases. Following this, 76 potential gene targets were pinpointed by integrating drug and related targets. GO and KEGG enrichment analyses were employed to identify key pathways involved in LHQW's mechanism for treating chronic bronchitis. By constructing a protein-protein interaction (PPI) network for the 76 potential gene targets, four core targets (TNF, IL6, IFNG, and STAT3) were identified as primarily involved in responses to lipopolysaccharide, the TNF pathway, and the JAK-STAT pathway. Molecular docking results revealed a favorable affinity between multiple active ingredients of LHQW and the four core targets, suggesting that the therapeutic effects are mediated through the inhibition of inflammatory responses and signaling pathways. Interestingly, quercetin, an active ingredient of LHQW, was observed to bind to all four core targets simultaneously. Furthermore, cell experiment and western blot analysis indicated that both LHQW and quercetin exhibit anti-inflammatory effects by targeting the four core proteins and the JAK-STAT pathways. CONCLUSION: This research emphasizes the diverse active ingredients, targets, channels, and pathways of LHQW in the treatment of chronic bronchitis, providing important perspectives for the creation of novel therapeutic drugs and clinical uses.
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Bronquitis Crónica , Medicamentos Herbarios Chinos , Simulación del Acoplamiento Molecular , Farmacología en Red , Bronquitis Crónica/tratamiento farmacológico , Bronquitis Crónica/metabolismo , Bronquitis Crónica/genética , Farmacología en Red/métodos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/química , Simulación del Acoplamiento Molecular/métodos , Humanos , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Transducción de Señal/efectos de los fármacos , AnimalesRESUMEN
BACKGROUND: Chronic obstructive pulmonary disease (COPD) has the highest increased risk due to household air pollution arising from biomass fuel burning. However, knowledge on COPD patho-mechanisms is mainly limited to tobacco smoke exposure. In this study, a repeated direct wood smoke (WS) exposure was performed using normal- (bro-ALI) and chronic bronchitis-like bronchial (bro-ALI-CB), and alveolar (alv-ALI) lung mucosa models at air-liquid interface (ALI) to assess broad toxicological end points. METHODS: The bro-ALI and bro-ALI-CB models were developed using human primary bronchial epithelial cells and the alv-ALI model was developed using a representative type-II pneumocyte cell line. The lung models were exposed to WS (10 min/exposure; 5-exposures over 3-days; n = 6-7 independent experiments). Sham exposed samples served as control. WS composition was analyzed following passive sampling. Cytotoxicity, total cellular reactive oxygen species (ROS) and stress responsive NFkB were assessed by flow cytometry. WS exposure induced changes in gene expression were evaluated by RNA-seq (p ≤ 0.01) followed by pathway enrichment analysis. Secreted levels of proinflammatory cytokines were assessed in the basal media. Non-parametric statistical analysis was performed. RESULTS: 147 unique compounds were annotated in WS of which 42 compounds have inhalation toxicity (9 very high). WS exposure resulted in significantly increased ROS in bro-ALI (11.2%) and bro-ALI-CB (25.7%) along with correspondingly increased NFkB levels (bro-ALI: 35.6%; bro-ALI-CB: 18.1%). A total of 1262 (817-up and 445-down), 329 (141-up and 188-down), and 102 (33-up and 69-down) genes were differentially regulated in the WS-exposed bro-ALI, bro-ALI-CB, and alv-ALI models respectively. The enriched pathways included the terms acute phase response, mitochondrial dysfunction, inflammation, oxidative stress, NFkB, ROS, xenobiotic metabolism of AHR, and chronic respiratory disorder. The enrichment of the 'cilium' related genes was predominant in the WS-exposed bro-ALI (180-up and 7-down). The pathways primary ciliary dyskinesia, ciliopathy, and ciliary movement were enriched in both WS-exposed bro-ALI and bro-ALI-CB. Interleukin-6 and tumor necrosis factor-α were reduced (p < 0.05) in WS-exposed bro-ALI and bro-ALI-CB. CONCLUSION: Findings of this study indicate differential response to WS-exposure in different lung regions and in chronic bronchitis, a condition commonly associated with COPD. Further, the data suggests ciliopathy as a candidate pathway in relation to WS-exposure.
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Bronquitis Crónica , Ciliopatías , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Bronquitis Crónica/inducido químicamente , Bronquitis Crónica/metabolismo , Humo/efectos adversos , Madera/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Pulmón/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Membrana Mucosa , Productos de TabacoRESUMEN
The aim of this review is to update and synthesize the molecular mechanisms that lead to the heterogeneous effect on tissue remodeling observed in the two most important clinical phenotypes of chronic obstructive pulmonary disease (COPD), pulmonary emphysema (PE) and chronic bronchitis (CB). Clinical and experimental evidence suggests that this heterogeneous response to promote PE, CB, or both, is related to differentiated genetic, epigenetic, and molecular conditions. Specifically, a tendency toward PE could be related to a variant in the DSP gene, SIRT1 downregulation, macrophage polarization to M1, as well as the involvement of the noncanonical Wnt5A signaling pathway, among other alterations. Additionally, in advanced stages of COPD, PE development is potentiated by dysregulations in autophagy, which promotes senescence and subsequently cell apoptosis, through exacerbated inflammasome activation and release of caspases. On the other hand, CB or the pro-fibrotic phenotype could be potentiated by the downregulated activity of HDAC2, the activation of the TGF-ß/Smad or Wnt/ß-catenin signaling pathways, macrophage polarization to M2, upregulation of TIMP-1, and/or the presence of the epithelial-mesenchymal transition (EMT) mechanism. Interestingly, the upregulated activity of MMPs, especially MMP-9, is widely involved in the development of both phenotypes. Furthermore, MMP-9 and MMP-12 enhance the severity, perpetuation, and exacerbation of COPD, as well as the development of autoimmunity in this disease.
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Bronquitis Crónica , Enfermedad Pulmonar Obstructiva Crónica , Enfisema Pulmonar , Humanos , Enfisema Pulmonar/patología , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/genética , Enfermedad Pulmonar Obstructiva Crónica/patología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/genética , Bronquitis Crónica/metabolismo , Bronquitis Crónica/patología , Bronquitis Crónica/genética , Animales , Transducción de SeñalRESUMEN
Patients living with chronic bronchitis (CB) suffer from physical limitations and poor quality of life. In general, treatment options that directly address the mucus hypersecretion component of CB are quite limited. Chronic airway inflammation and the associated hypersecretion and cough that are pathognomonic for CB generally result from long-term exposure to airway irritants such as tobacco use and other environmental insults. This, in turn, results in an increase in the quantity and change in composition of the airway mucosa as a consequence of altered goblet cells, club cells, and submucosal glands. Pulsed electric fields (PEFs) provide a method for eradicating the cellular constituents of tissue with limited impact on the stromal proteins. Preclinical evidence in porcine airways demonstrated that particular PEF waveforms allowed for salutary remodeling of the epithelial and submucosal airway tissue layers and appeared to foster rapid regeneration and recovery of the tissue. Therefore, a therapeutic opportunity might exist whereby the application of a specific form of PEF may result in a reduction of the cellular secretory constituents of the airway while also reducing airway mucosal inflammation. This review discusses the use of such PEF to address the underlying disease processes in CB including challenges around device design, dosing, and appropriate delivery methods. Further, we outline considerations for the transition to human airways along with a brief examination of the initial work treating CB patients, suggesting that the therapy is well tolerated with limited adverse events.
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Bronquitis Crónica , Humanos , Animales , Porcinos , Bronquitis Crónica/terapia , Bronquitis Crónica/metabolismo , Calidad de Vida , Moco/metabolismo , Células Caliciformes/metabolismo , Inflamación/metabolismo , Membrana Mucosa/metabolismoRESUMEN
Theophylline is an important drug for treatment of canine chronic bronchitis and bradyarrhythmias, but new products require validation since pharmacokinetics in dogs can vary by formulation. A new, 503B outsourcing facility-produced theophylline product (OFT) is available for veterinary use. Outsourcing facilities have many advantages over traditional compounding sources including current good manufacturing practice compliance. The purpose of this study was to establish the pharmacokinetics of OFT in dogs. Eight healthy dogs received 11 mg/kg intravenous aminophylline and 10 mg/kg oral OFT followed by serial blood sampling in a two-way, randomized, crossover design with 7-day washout. Plasma theophylline concentrations were quantified by liquid chromatography-mass spectrometry. Bioavailability, maximum concentration, time to maximum concentration, half-life and area under the curve were: 97 ± 10%, 7.13 ± 0.71 µg/mL, 10.50 ± 2.07 h, 9.20 ± 2.87 h, and 141 ± 37.6 µg*h/mL, respectively. Steady-state predictions supported twice daily dosing of the OFT, but specific dosage recommendations are hindered by lack of a canine-specific therapeutic range for plasma theophylline concentration. These findings suggest that the OFT is well absorbed and can likely be dosed twice daily in dogs, but future pharmacodynamic and clinical studies are needed to establish a definitive therapeutic range for theophylline in this species.
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Teofilina/farmacocinética , Aminofilina/farmacocinética , Aminofilina/farmacología , Animales , Disponibilidad Biológica , Bradicardia/tratamiento farmacológico , Bradicardia/metabolismo , Bradicardia/veterinaria , Bronquitis Crónica/tratamiento farmacológico , Bronquitis Crónica/metabolismo , Bronquitis Crónica/veterinaria , Estudios Cruzados , Perros , Femenino , Semivida , Inyecciones Intravenosas/métodos , Masculino , Servicios Externos/métodos , Teofilina/farmacologíaRESUMEN
BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) frequently suffer from chronic bronchitis (CB) and display steroid-resistant inflammation with increased sputum neutrophils and macrophages. Recently, a causal link between mucus hyper-concentration and disease progression of CB has been suggested. METHODS: In this study, we have evaluated the steroid sensitivity of purified, patient-derived sputum and alveolar macrophages and used a novel mechanistic cross-talk assay to examine how macrophages and bronchial epithelial cells cross-talk to regulate MUC5B production. RESULTS: We demonstrate that sputum plug macrophages isolated from COPD patients with chronic bronchitis (COPD/CB) are chronically activated and only partially respond to ex vivo corticosteroid treatment compared to alveolar macrophages isolated from lung resections. Further, we show that pseudo-stratified bronchial epithelial cells grown in air-liquid-interface are inert to direct bacterial lipopolysaccharide stimulation and that macrophages are able to relay this signal and activate the CREB/AP-1 transcription factor complex and subsequent MUC5B expression in epithelial cells through a soluble mediator. Using recombinant protein and neutralizing antibodies, we identified a key role for TNFα in this cross-talk. CONCLUSIONS: For the first time, we describe ex vivo pharmacology in purified human sputum macrophages isolated from chronic bronchitis COPD patients and identify a possible basis for the steroid resistance frequently seen in this population. Our data pinpoint a critical role for chronically activated sputum macrophages in perpetuating TNFα-dependent signals driving mucus hyper-production. Targeting the chronically activated mucus plug macrophage phenotype and interfering with aberrant macrophage-epithelial cross-talk may provide a novel strategy to resolve chronic inflammatory lung disease.
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Bronquitis Crónica/metabolismo , Resistencia a Medicamentos , Glucocorticoides/farmacología , Pulmón/patología , Macrófagos Alveolares/metabolismo , Mucina 5B/biosíntesis , Moco/metabolismo , Anciano , Biomarcadores/metabolismo , Bronquitis Crónica/tratamiento farmacológico , Bronquitis Crónica/patología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Inflamación/metabolismo , Recuento de Leucocitos , Macrófagos Alveolares/patología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Metabolic syndrome and insulin resistance are associated with worsened outcomes of chronic lung disease. The triglyceride-glucose index (TyG), a measure of metabolic dysfunction, is associated with metabolic syndrome and insulin resistance, but its relationship to lung health is unknown. RESEARCH QUESTION: What is the relationship of TyG to respiratory symptoms, chronic lung disease, and lung function? STUDY DESIGN AND METHODS: This study analyzed data from the National Health and Nutrition Examination Survey from 1999 to 2012. Participants included fasting adults age ≥ 40 years (N = 6,893) with lung function measurements in a subset (n = 3,383). Associations of TyG with respiratory symptoms (cough, phlegm production, wheeze, and exertional dyspnea), chronic lung disease (diagnosed asthma, chronic bronchitis, and emphysema), and lung function (FEV1, FVC, and obstructive or restrictive spirometry pattern) were evaluated, adjusting for sociodemographic variables, comorbidities, and smoking. TyG was compared vs insulin resistance, represented by the homeostatic model assessment of insulin resistance (HOMA-IR), and vs the metabolic syndrome. RESULTS: TyG was moderately correlated with HOMA-IR (Spearman ρ = 0.51) and had good discrimination for metabolic syndrome (area under the receiver-operating characteristic curve, 0.80). A one-unit increase in TyG was associated with higher odds of cough (adjusted OR [aOR], 1.28; 95% CI, 1.06-1.54), phlegm production (aOR, 1.20; 95% CI, 1.01-1.43), wheeze (aOR, 1.18; 95% CI, 1.03-1.35), exertional dyspnea (aOR, 1.21; 95% CI, 1.07-1.38), and a diagnosis of chronic bronchitis (aOR, 1.21; 95% CI, 1.02-1.43). TyG was associated with higher relative risk of a restrictive spirometry pattern (adjusted relative risk ratio, 1.45; 95% CI, 1.11-1.90). Many associations were maintained with additional adjustment for HOMA-IR or metabolic syndrome. INTERPRETATION: TyG was associated with respiratory symptoms, chronic bronchitis, and a restrictive spirometry pattern. Associations were not fully explained by insulin resistance or metabolic syndrome. TyG is a satisfactory measure of metabolic dysfunction with relevance to pulmonary outcomes. Prospective study to define TyG as a biomarker for impaired lung health is warranted.
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Asma , Bronquitis Crónica , Glucosa/análisis , Síndrome Metabólico , Enfisema Pulmonar , Triglicéridos/análisis , Adulto , Asma/diagnóstico , Asma/metabolismo , Asma/fisiopatología , Biomarcadores/análisis , Bronquitis Crónica/diagnóstico , Bronquitis Crónica/metabolismo , Bronquitis Crónica/fisiopatología , Correlación de Datos , Femenino , Humanos , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/fisiopatología , Encuestas Nutricionales/estadística & datos numéricos , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/fisiopatología , Pruebas de Función Respiratoria/métodos , Evaluación de Síntomas/métodos , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: This study was performed to evaluate the anti-inflammatory effect of atorvastatin in patients with chronic bronchitis, exposed to sulfur mustard gas. METHODS: In this randomized double-blinded clinical trial we recruited patients with chronic bronchitis after exposure to sulfur mustard gas. Ninety men 45-75 years old diagnosed with chronic bronchitis after exposure to mustard gas during the Iran-Iraq war, were randomly assigned to receive either atorvastatin (40 mg) or placebo once a day for 3 months. The interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), procalcitonin, highly sensitive CRP and COPD assessment test (CAT) score was compared at baseline and after 12 weeks. RESULTS: After consuming atorvastatin for 12 weeks, IL-6 level (mean difference [95%CI]; 0.2 [- 0.05, 0.5]), TNF-α (mean difference [95%CI]; - 0.07 [- 0.2, 0.07]), high sensitive CRP (mean difference [95%CI] - 0.1 [- 1.2, 0.9]), and procalcitonin (mean difference [95%CI]; 0.003 [- 0.02, 0.03]) did not change significantly. However, in the placebo group, only IL-6 (mean difference [95%CI]; 0.6 [0.2, 1.05]) decreased significantly after 12 weeks, but levels of high sensitive CRP (mean difference [95%CI]; - 0.3 [- 1.4, 0.8]) TNF-α (mean difference [95%CI]; - 0.2 [- 0.34, - 0.06]) and procalcitonin (mean difference [95%CI]; 0.02 [- 0.001, 0.04]) did not change significantly. After 12 weeks, the mean differences in TNF- α, IL-6 level, high sensitive CRP, procalcitonin, and CAT score did not significantly differ between the two groups. CONCLUSIONS: The administration of 40 mg atorvastatin for 3 months did not significantly change the inflammatory markers or the quality of life of patients exposed to mustard gas with chronic bronchitis. TRIAL REGISTRATION: IRCT, IRCT138904144312N1. Registered 16 August 2014, https://en.irct.ir/trial/4577 .
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Atorvastatina/uso terapéutico , Bronquitis Crónica/tratamiento farmacológico , Mediadores de Inflamación/sangre , Gas Mostaza/toxicidad , Calidad de Vida , Anciano , Conflictos Armados , Bronquitis Crónica/metabolismo , Proteína C-Reactiva/metabolismo , Método Doble Ciego , Humanos , Interleucina-6/sangre , Irán , Masculino , Persona de Mediana Edad , Polipéptido alfa Relacionado con Calcitonina/sangre , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/sangreRESUMEN
BACKGROUND: Although phosphodiesterase-4 (PDE4) inhibitors have been shown to reduce COPD exacerbation rate, their biological mechanism of action is not completely elucidated at the molecular level. We aimed to characterise the whole genome gene expression profile of the inhaled PDE4-inhibitor CHF6001 on top of triple therapy in sputum cells and whole blood of patients with COPD and chronic bronchitis. METHODS: Whole genome gene expression analysis was carried out by microarray in 54 patients before and after 32 days treatment with CHF6001 800 and 1600 µg and placebo twice daily (BID) in a randomised crossover study. RESULTS: CHF6001 had a strong effect in sputum, with 1471 and 2598 significantly differentially-expressed probe-sets relative to placebo (p-adjusted for False Discovery Rate < 0.05) with 800 and 1600 µg BID, respectively. Functional enrichment analysis showed significant modulation of key inflammatory pathways involved in cytokine activity, pathogen-associated-pattern-recognition activity, oxidative stress and vitamin D with associated inhibition of downstream inflammatory effectors. A large number of pro-inflammatory genes coding for cytokines and matrix-metalloproteinases were significantly differentially expressed for both doses; the majority (> 87%) were downregulated, including macrophage inflammatory protein-1-alpha and 1-beta, interleukin-27-beta, interleukin-12-beta, interleukin-32, tumour necrosis factor-alpha-induced-protein-8, ligand-superfamily-member-15, and matrix-metalloproteinases-7,12 and 14. The effect in blood was not significant. CONCLUSIONS: Inhaled PDE4 inhibition by CHF6001 on top of triple therapy in patients with COPD and chronic bronchitis significantly modulated key inflammatory targets and pathways in the lung but not in blood. Mechanistically these findings support a targeted effect in the lung while minimising unwanted systemic class-effects. TRIAL REGISTRATION: ClinicalTrial.gov, EudraCT, 2015-005550-35. Registered 15 July 2016.
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Bronquitis Crónica/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Esputo/citología , Administración por Inhalación , Anciano , Antiinflamatorios/administración & dosificación , Biomarcadores/sangre , Biomarcadores/metabolismo , Bronquitis Crónica/metabolismo , Estudios Cruzados , Femenino , Humanos , Mediadores de Inflamación , Masculino , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Esputo/metabolismo , Sulfonamidas , Transcriptoma , para-AminobenzoatosRESUMEN
With increasing air pollution, chronic bronchitis (CB) has become a major public health problem worldwide. Previous studies have shown beneficial effects of Bergenin (Ber) on chronic bronchitis. To facilitate understanding of the pathogenesis underlying CB as well as to elucidate the Ber therapeutic mechanism, it is crucial to confirm the rational biomarkers of CB and its treatment. This study aimed to investigate the preventive chronic bronchitis mechanism of Ber by applying a serum metabolomics strategy. In this study, 18 Sprague-Dawley rats were randomly divided into three groups,with six rats in each group. Rats from the CB and Ber groups were exposed to tobacco smoke for 1 hd-1 (1 h per day) for 28 days. Ber was administered orally to Ber rats 3 h after exposure every day, and the others were administered water. According to the morphometric analysis of the airway epithelium and the count of white blood cells in the bronchoalveolar lavage fluid, Ber suppressed the infiltration of inflammatory cells, inhibited the secretion of mucus, and reduced white blood cells in bronchoalveolar lavage fluid. The metabolic profiles of sera were analyzed by multivariate statistical analyses, including PCA, PLS-DA and OPLS-DA models, and revealed that the levels of thirteen metabolites were significantly changed and identified as potential biomarkers in the CB group and Ber group. The results suggested that the therapeutic mechanism of Ber may be related to the regulation of dysfunctions in glycerophospholipid, tryptophan, arginine and proline metabolism induced by CB, and changes in arachidonic acid metabolism.
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Benzopiranos/uso terapéutico , Bronquitis Crónica/tratamiento farmacológico , Bronquitis Crónica/metabolismo , Metabolómica/métodos , Espectrometría de Masas en Tándem/métodos , Animales , Cromatografía Liquida/métodos , Ratas , Ratas Sprague-Dawley , Resultado del TratamientoRESUMEN
The aim of this study was to analyze whether FeNO levels in acute exacerbation of COPD (AECOPD) with hospital admission have better diagnostic value than eosinophilia in blood, and to evaluate its usefulness in predicting a better clinical response. An observational prospective study of patients with AECOPD was carried out. FeNO determinations were made on arrival at the emergency room (ER), at discharge and during stability 3-6 months after discharge. Co-morbidities, bronchodilators, inhaled (IGC) and systemic (SGC) glucocorticoids, eosinophils, systemic inflammation markers (procalcitonin, C-reactive protein), eosinophil cationic protein, and total IgE were collected. Fifty consecutive patients (92% men, mean age 75 ± 6 years) were included in this study. Phenotypes were 26% Asthma-COPD Overlap Syndrome (ACOS), 42% chronic bronchitis (CB) and 32% emphysema. ACOS patients showed significantly higher levels of FeNO (73 ppb) and eosinophils (508 cells/mm3) than the rest (CB: 23 ppb, 184 cells/mm3, emphysema: 27 ppb, 159 cells/mm3; p < 0.05). A significant correlation between FeNO levels measured in ER and eosinophils was observed (r = 0.7; p < 0.001), but not at discharge or in stable phase. No significant association was found with parameters of systemic inflammation and mean stay. In conclusion, the determination of FeNO in AECOPD does not offer advantages over the evaluation of eosinophilia. These parameters rise at arrival in ER, descend at discharge, and remain unchanged in the stable phase. Both present similar diagnostic utility and are able to better identify the ACOS phenotype, which helps select a population that could benefit from a glucocorticoids therapy.
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Asma/inmunología , Eosinofilia/inmunología , Óxido Nítrico/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Anciano , Anciano de 80 o más Años , Asma/complicaciones , Asma/metabolismo , Asma/fisiopatología , Pruebas Respiratorias , Bronquitis Crónica/complicaciones , Bronquitis Crónica/inmunología , Bronquitis Crónica/metabolismo , Bronquitis Crónica/fisiopatología , Proteína C-Reactiva/inmunología , Progresión de la Enfermedad , Proteína Catiónica del Eosinófilo/inmunología , Eosinofilia/complicaciones , Eosinofilia/metabolismo , Eosinófilos , Femenino , Hospitalización , Humanos , Inmunoglobulina E/inmunología , Recuento de Leucocitos , Masculino , Óxido Nítrico/análisis , Polipéptido alfa Relacionado con Calcitonina/inmunología , Estudios Prospectivos , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfisema Pulmonar/complicaciones , Enfisema Pulmonar/inmunología , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/fisiopatologíaRESUMEN
Mucus hydration is important in mucus clearance and lung health. This study sought to test the relative utility of spontaneous sputum (SS) versus the reasonably noninvasive induced sputum (IS) samples for measurement of mucus hydration. SS and IS samples were collected over a 2-day study interval. Sputum was induced with escalating inhaled nebulized 3-5% hypertonic saline. Viscous portions of the samples ("plugs") were utilized for percent solids and total mucin analyses. Cytokines, nucleotides/nucleosides and cell differentials were measured in plugs diluted into 0.1% Sputolysin. Overall, 61.5% of chronic bronchitis (CB) subjects produced a SS sample and 95.2% an IS sample. Total expectorate sample weights were less for the SS (0.94 ± 0.98 g) than the IS (2.67 ± 2.33 g) samples. Percent solids for the SS samples (3.56% ± 1.95; n = 162) were significantly greater than the IS samples (3.08% ± 1.81; n = 121), p = 0.133. Total mucin concentrations also exhibited a dilution of the IS samples: SS = 4.15 ± 3.23 mg/ml (n = 62) versus IS= 3.34 ± 2.55 mg/ml (n = 71) (p = 0.371). Total mucins (combined SS and IS) but not percent solids, were inversely associated with FEV1 percent predicted (p = 0.052) and FEV1,/FVC % (p = 0.035). There were no significant differences between sample types in cytokine or differential cell counts. The probability of sample collections was less for SS than IS samples. Measurements of hydration revealed modest dilution of the IS samples compared to SS. Thus for measurements of mucus hydration, both SS and IS samples appear to be largely interchangeable.
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Bronquitis Crónica/metabolismo , Mucinas/metabolismo , Moco/metabolismo , Esputo/metabolismo , Anciano , Bronquitis Crónica/fisiopatología , Recuento de Células , Citocinas/metabolismo , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana Edad , Nucleósidos/metabolismo , Nucleótidos/metabolismo , Solución Salina Hipertónica , Esputo/citología , Capacidad Vital , Agua/metabolismoAsunto(s)
Asma/metabolismo , Bronquitis Crónica/metabolismo , Fibrosis Quística/metabolismo , Células Caliciformes/metabolismo , Ácidos Hidroxieicosatetraenoicos/metabolismo , Fibrosis Pulmonar Idiopática/metabolismo , Mucinas/biosíntesis , Animales , Asma/patología , Bronquitis Crónica/patología , Fibrosis Quística/patología , Células Caliciformes/patología , Humanos , Fibrosis Pulmonar Idiopática/patologíaRESUMEN
For decades in China, the Yin-Huang-Qing-Fei capsule (YHQFC) has been widely used in the treatment of chronic bronchitis, with good curative effects. Owing to the complexity of traditional Chinese herbal formulas, the pharmacological mechanism of YHQFC remains unclear. To address this problem, a network pharmacology-based strategy was proposed in this study. At first, the putative target profile of YHQFC was predicted using MedChem Studio, based on structural and functional similarities of all available YHQFC components to the known drugs obtained from the DrugBank database. Then, an interaction network was constructed using links between putative YHQFC targets and known therapeutic targets of chronic bronchitis. Following the calculation of four topological features (degree, betweenness, closeness, and coreness) of each node in the network, 475 major putative targets of YHQFC and their topological importance were identified. In addition, a pathway enrichment analysis based on the Kyoto Encyclopedia of Genes and Genomes pathway database indicated that the major putative targets of YHQFC are significantly associated with various pathways involved in anti-inflammation processes, immune responses, and pathological changes caused by asthma. More interestingly, eight major putative targets of YHQFC (interleukin [IL]-3, IL-4, IL-5, IL-10, IL-13, FCER1G, CCL11, and EPX) were demonstrated to be associated with the inflammatory process that occurs during the progression of asthma. Finally, a molecular docking simulation was performed and the results exhibited that 17 pairs of chemical components and candidate YHQFC targets involved in asthma pathway had strong binding efficiencies. In conclusion, this network pharmacology-based investigation revealed that YHQFC may attenuate the inflammatory reaction of chronic bronchitis by regulating its candidate targets, which may be implicated in the major pathological processes of the asthma pathway.
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Antiasmáticos/farmacología , Antiinflamatorios/farmacología , Asma/tratamiento farmacológico , Bronquitis Crónica/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Mediadores de Inflamación/antagonistas & inhibidores , Pulmón/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Biología de Sistemas/métodos , Administración Oral , Antiasmáticos/administración & dosificación , Antiasmáticos/química , Antiasmáticos/metabolismo , Antiinflamatorios/administración & dosificación , Antiinflamatorios/química , Antiinflamatorios/metabolismo , Asma/diagnóstico , Asma/metabolismo , Asma/fisiopatología , Bronquitis Crónica/diagnóstico , Bronquitis Crónica/metabolismo , Cápsulas , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Pulmón/metabolismo , Pulmón/fisiopatología , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Mapeo de Interacción de Proteínas , Mapas de Interacción de Proteínas , Relación Estructura-ActividadRESUMEN
The club cell secretory protein (CCSP) is a regulator of lung inflammation following acute respiratory infection or lung injury. Recently, the relationship between CCSP and COPD has been reported. Since COPD results from an abnormal inflammatory response, we hypothesized that CCSP could have a protective role against chronic inflammation-induced lung damage. To address this issue, the pathophysiology of chronic lung inflammation induced by Pseudomonas aeruginosa in CCSP-deficient mice was determined. A tube of 5 mm in length was soaked in a fluid containing P. aeruginosa (PAO01 strain) for 1 week and inserted into the trachea of CCSP-deficient mice. One week later, P. aeruginosa was administered into the trachea. Five weeks after insertion of tube, the mice were sacrificed. Bronchoalveolar lavage fluids were collected to determine the bacterial growth, and the lung histology and physiology were also examined. P. aeruginosa was continuously detected in bronchoalveolar lavage fluids during the study. Neutrophils were increased in the bronchoalveolar lavage fluids from the CCSP-deficient mice in comparison to wild-type mice. A histological study demonstrated chronic inflammation around bronchus, serious bronchial stenosis, and alveolar enlargement in the CCSP-deficient mice. The lung physiology study demonstrated an increase in the lung compliance of the CCSP-deficient mice. Chronic P. aeruginosa inflammation resulted in chronic bronchitis and emphysematous changes in the CCSP-deficient mice. CCSP could play an important role in protecting the host from the chronic inflammation-induced lung damage.
Asunto(s)
Bronquitis Crónica/microbiología , Pulmón/microbiología , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/crecimiento & desarrollo , Enfisema Pulmonar/microbiología , Infecciones del Sistema Respiratorio/microbiología , Uteroglobina/deficiencia , Animales , Bronquitis Crónica/genética , Bronquitis Crónica/metabolismo , Bronquitis Crónica/fisiopatología , Líquido del Lavado Bronquioalveolar/microbiología , Citocinas/metabolismo , Predisposición Genética a la Enfermedad , Mediadores de Inflamación/metabolismo , Pulmón/metabolismo , Pulmón/fisiopatología , Linfocitos/metabolismo , Linfocitos/microbiología , Macrófagos/metabolismo , Macrófagos/microbiología , Ratones de la Cepa 129 , Ratones Noqueados , Infiltración Neutrófila , Neutrófilos/metabolismo , Neutrófilos/microbiología , Fenotipo , Infecciones por Pseudomonas/genética , Infecciones por Pseudomonas/metabolismo , Infecciones por Pseudomonas/fisiopatología , Pseudomonas aeruginosa/aislamiento & purificación , Enfisema Pulmonar/genética , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/fisiopatología , Infecciones del Sistema Respiratorio/genética , Infecciones del Sistema Respiratorio/metabolismo , Infecciones del Sistema Respiratorio/fisiopatología , Uteroglobina/genéticaRESUMEN
Abnormalities in mucus production and qualitative properties such as mucus hydration are central to the pathophysiology of airway disease including cystic fibrosis, asthma, and chronic bronchitis. In vitro air-liquid interface epithelial cell cultures demonstrate direct relationships between mucociliary transport, periciliary liquid (PCL) height, and mucus concentration (expressed as percent solids or partial osmotic pressure). In health, the osmotic modulus/pressure of the PCL exceeds that of the mucus layer, resulting in efficient, low-friction movement of mucus. In disease, through multiple mechanisms, the osmotic pressure of the mucus begins to exceed basal PCL values, resulting in compression of the cilia and slowing of mucus transport. The in vivo data in both cystic fibrosis and chronic bronchitis parallel in vitro data demonstrating that when mucus osmotic pressure is increased, mucociliary clearance is decreased. In chronic bronchitis, there is a direct correlation between FEV1 and percent solids of mucus, demonstrating a strong relationship between disease progression and mucus abnormalities. Animal models, based mechanistically on raised sodium absorption (and therefore water absorption) from airway surfaces, mimic the pathophysiology of chronic obstructive pulmonary disease. Collectively, these data suggest the importance of mucus concentration in the pathogenesis of airway disease. It is important to understand the precise mechanisms that result in mucus hyperconcentration, for example, mucin overproduction versus abnormal regulation of ion/water transport, which may be unique to and characteristic of each disease phenotype. The measurement of mucus concentration may be a simple method to diagnose chronic bronchitis, monitor its progression, and serve as a biomarker for development of new therapies.
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Bronquitis Crónica/metabolismo , Depuración Mucociliar , Moco/metabolismo , Cilios , Fibrosis Quística/metabolismo , Células Epiteliales/metabolismo , Humanos , Presión Osmótica , Fenotipo , Sodio/metabolismoRESUMEN
Chronic obstructive pulmonary disease is a common cause of morbidity and a rising cause of mortality worldwide. Its rising impact indicates the ongoing unmet need for novel and effective therapies. Previous work has established a pathophysiological link between the chronic bronchitis phenotype of chronic obstructive pulmonary disease and cystic fibrosis as well as phenotypic similarities between these two airways diseases. An extensive body of evidence has established that cigarette smoke and its constituents contribute to acquired dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in the airways, pointing to a mechanistic link with smoking-related and chronic bronchitis. Recent interest surrounding new drugs that target both mutant and wild-type CFTR channels has paved the way for a new treatment opportunity addressing the mucus defect in chronic bronchitis. We review the clinical and pathologic evidence for modulating CFTR to address acquired CFTR dysfunction and pragmatic issues surrounding clinical trials as well as a discussion of other ion channels that may represent alternative therapeutic targets.
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Corticoesteroides/uso terapéutico , Antibacterianos/uso terapéutico , Bronquitis Crónica/terapia , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Expectorantes/uso terapéutico , Modalidades de Fisioterapia , Bronquitis Crónica/metabolismo , Fibrosis Quística/metabolismo , Fibrosis Quística/terapia , Humanos , Fumar/metabolismoRESUMEN
Patients with the chronic bronchitis form of chronic obstructive pulmonary disease and cystic fibrosis share similar clinical features, including mucus obstruction of airways and the development of chronic/recurrent airways infections that often manifest as disease exacerbations. There is growing evidence that these diseases may have parallels in disease pathogenesis as well, including cystic fibrosis transmembrane conductance regulator dysfunction, mucus dehydration, and defective mucociliary clearance. As progress is made in the development of therapies that target the basic defects that lead to cystic fibrosis lung disease, it is possible that similar approaches could also benefit patients with chronic bronchitis. A deeper understanding of how tobacco smoke and other triggers of chronic bronchitis actually lead to disease, and exploration of the concept that therapies that restore cystic fibrosis transmembrane conductance regulator function, mucus hydration, and/or mucociliary clearance may benefit patients with chronic bronchitis, hold the prospect of significant progress in treating this prevalent disease.
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Bronquitis Crónica/terapia , Bloqueadores del Canal de Sodio Epitelial/uso terapéutico , Depuración Mucociliar , Solución Salina Hipertónica/uso terapéutico , Administración por Inhalación , Bronquitis Crónica/metabolismo , Fibrosis Quística/metabolismo , Fibrosis Quística/terapia , Diuréticos Osmóticos/uso terapéutico , Humanos , Manitol/uso terapéutico , Moco/metabolismoRESUMEN
In order to compare the effect of dexamethasone and bergenin on chronic bronchitis and to reveal their anti-inflammatory mechanisms, (1)H NMR-based metabolomics was performed to explore the potential biomarkers of the disease and study the therapeutic mechanisms of the drugs. In this study, 40 Sprague-Dawley male rats were randomly divided into 4 groups, namely control, model, dexamethasone and bergenin groups, with 10 rats in each group. Except for the control group, rats from the other three groups were exposed to tobacco smoke for 1 h d(-1) for 28 days. During the modeling, dexamethasone (0.2 mg kg(-1)) and bergenin (87 mg kg(-1)) were administered orally to dexamethasone or bergenin rats 3 h after exposure every day. On the other hand, control and model rats were intragastrically administered water. According to the results of morphometric analysis of the airway epithelium and the count of white blood cells in the bronchoalveolar lavage fluid (BALF), dexamethasone and bergenin could suppress the infiltration of inflammatory cells, inhibit the secretion of mucus, and reduce white blood cells in BALF. Serum samples from the rats' orbits were collected every week. The metabolic profiles of sera were analyzed by multivariate statistical analyses, including PCA, PLS-DA and OPLS-DA models, and 18 metabolites were identified. The dynamic fluctuations of these biomarkers in sera from different groups were detected. The results suggested that the anti-inflammatory mechanism of dexamethasone may be associated with BCAA metabolism and glycolysis while bergenin could change BCAA metabolism, glycine, serine and threonine metabolism, and glycolysis to treat chronic bronchitis.
Asunto(s)
Antiinflamatorios/farmacología , Benzopiranos/farmacología , Bronquitis Crónica/metabolismo , Dexametasona/farmacología , Metabolómica , Resonancia Magnética Nuclear Biomolecular , Animales , Antiinflamatorios/uso terapéutico , Benzopiranos/uso terapéutico , Biomarcadores , Peso Corporal , Bronquitis Crónica/tratamiento farmacológico , Bronquitis Crónica/patología , Líquido del Lavado Bronquioalveolar , Análisis por Conglomerados , Dexametasona/uso terapéutico , Modelos Animales de Enfermedad , Masculino , Metaboloma , Metabolómica/métodos , Curva ROC , Ratas , Resultado del TratamientoRESUMEN
Chronic obstructive pulmonary disease (COPD) is a major public health problem. No therapies alter the natural history of the disease. Chronic bronchitis is perhaps the most clinically troublesome phenotype. Emerging data strongly suggest that cigarette smoke and its components can lead to acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. Findings in vitro, in animal models, and in smokers with and without COPD also show acquired CFTR dysfunction, which is associated with chronic bronchitis. This abnormality is also present in extrapulmonary organs, suggesting that CFTR dysfunction may contribute to smoking-related systemic diseases.