RESUMO
Allergic asthma is one of the inflammatory diseases, which has become a major public health problem. Qu zhi qiao (QZQ), a dry and immature fruit of Citrus paradisi cv. Changshanhuyou, has various flavonoids with pharmacological properties. However, there is a knowledge gap on the pharmacological properties of QZQ on allergic asthma. Therefore, here, we explored the efficacy and mechanism of total flavonoids from QZQ (TFCH) on allergic asthma. We extracted and purified TFCH and conducted animal experiments using an Ovalbumin (OVA)-induced mice model. Bronchoalveolar lavage fluid and Swiss-Giemsa staining were used to count different inflammatory cells in allergic asthma mice. We conducted histopathology and immunohistochemistry to evaluate the changes in the lungs of allergic asthma mice. Moreover, we used ELISA assays to analyze chemokines and inflammatory cytokines. Furthermore, western blot analyses were conducted to elucidate the mechanism of TFCH on allergic asthma. We established that TFCH has anti-inflammatory effects and inhibits airway remodeling, providing a potential therapeutic strategy for allergic asthma.
Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Asma/prevenção & controle , Citrus paradisi , Flavonoides/uso terapêutico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Proteína Smad2/antagonistas & inibidores , Proteína Smad3/antagonistas & inibidores , Remodelação das Vias Aéreas/fisiologia , Animais , Asma/induzido quimicamente , Asma/metabolismo , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Frutas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Ovalbumina/toxicidade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Proteína Smad2/metabolismo , Proteína Smad3/metabolismoRESUMO
Airway remodeling is one important feature of childhood asthma, which is one of the most common chronic childhood diseases. Phenotype switching of airway smooth muscle cells (ASMCs), defined as a reversible switching between contractile and proliferative phenotypes, plays an important role in the process of airway remodeling. Esculetin has shown antiinflammatory action in animal models of asthma; however, the effects of esculetin on ASMC phenotype switching have not been investigated. In the present study, platelet-derived growth factor (PDGF) was used to induce the phenotype modulation of ASMCs. The results demonstrated that esculetin pretreatment mitigated the PDGF-caused inhibitory effects on expressions of contractile phenotype protein markers, including calponin and SM22α. Esculetin also inhibited PDGF-induced migration and proliferation of ASMCs. Besides, the PDGF-induced expressions of extracellular matrix components, collagen I and fibronectin, were attenuated by esculetin pretreatment. Furthermore, PDGF-caused activation of PI3K/Akt pathway in ASMCs was inhibited by esculetin. These findings suggest that esculetin might exert its inhibitory effect on PDGF-induced ASMC phenotype switching through inhibition of PI3K/Akt pathway.
Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Umbeliferonas/farmacologia , Remodelação das Vias Aéreas/fisiologia , Asma/metabolismo , Asma/fisiopatologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Criança , Colágeno Tipo I/metabolismo , Humanos , Contração Muscular/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/fisiologiaRESUMO
Bu-Shen-Yi-Qi formula (BSYQF) could suppress chronic airway inflammation according to previous studies. However, there is relatively little direct experimental evidence to evaluate the effects of BSYQF treatment on airway remodeling in chronic asthma. Recent evidence suggests that oxidative stress is involved in airway inflammation and airway remodeling in chronic asthma. BSYQF which includes various of chemical components having antioxidant effects, could be beneficial in attenuating airway remodeling in chronic asthma. The purpose of this study was to elucidate the effect of BSYQF treatment on airway remodeling and investigate its potential mechanisms in chronic asthma. To develop the murine models of chronic asthma, BALB/c mice were sensitized and challenged to ovalbumin for 8 weeks. BSYQF (5, 10, 20 g raw herbs/kg body weight) or tiotropium bromide (0.1 mM) were administered orally and intranasal instillation, respectively. The effect of BSYQF on pulmonary inflammation and remodeling was evaluated. The parameters of oxidative stress in the lung were analyzed. BSYQF treatment reduced airway hyperresponsiveness (AHR), Th2 response including IL-4, IL-13, and OVA-specific IgE and IgG1, transforming growth factor-ß (TGF-ß), vascular endothelium growth factor (VEGF), airway inflammation and airway remodeling including smooth muscle thickening and peribronchial collagen deposition. As for oxidative stress, BSYQF treatment reduced reactive oxygen species (ROS), Malondialdehyde (MDA), NO, and the expression of inducible nitric oxide synthase (iNOS), but increased significantly glutathione (GSH) /Oxidized glutathione(GSSH) ratios in the lung, restored mitochondrial ultrastructural changes of bronchial epithelia and ATP levels in the lung. In summary, this study suggested that BSYQF treatment ameliorated airway remodeling and alleviated asthmatic features in chronic asthma models. Anti-inflammatory and antioxidant effect of BSYQF may explain why BSYQF has effects on preventing airway remodeling.
Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Antiasmáticos/uso terapêutico , Asma/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Pneumonia/metabolismo , Remodelação das Vias Aéreas/fisiologia , Animais , Antiasmáticos/química , Antiasmáticos/farmacologia , Asma/induzido quimicamente , Asma/tratamento farmacológico , Composição de Medicamentos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo/fisiologia , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Distribuição AleatóriaRESUMO
BACKGROUND: Asthma is a chronic disease involving an immune response, which is characterized by non-specific inflammation and airway remodeling. Glucocorticoids are clinically beneficial in controlling asthma, but further options are needed. In our study, fastigial nucleus electrostimulation (FNS) was applied in a rat asthma model for the first time to investigate the effects of pre-intervention. OBJECTIVE: To observe the effects of FNS on airway inflammation and remodeling in asthmatic rats. METHODS: Forty rats were assigned randomly to the normal control (CON), model (MDL), FNS, or budesonide (BUD) groups. Asthma was induced with chicken egg (OVA). The animals in the CON and MDL groups were treated with normal saline. The animals in the other two groups received FNS or budesonide, respectively. RESULTS: The results indicated that IgE in the serum and airway fiber areas were higher in the MDL group than in other groups. After treatment for 3 weeks, collagen fibers in the bronchial wall in the FNS group were significantly lower compared with the MDL group. CONCLUSION: FNS significantly reduced IL-4, IL-13, TNF-α, OVA-IgE and TGF-ß1 in serum and BALF, and increased IFN-γ. Our results suggest that FNS may ameliorate asthma symptoms and induce changes of cytokines in the serum and lung milieu.
Assuntos
Remodelação das Vias Aéreas/fisiologia , Asma/imunologia , Asma/patologia , Núcleos Cerebelares/fisiologia , Terapia por Estimulação Elétrica/métodos , Animais , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Inflammatory cell infiltration, cytokine release, epithelial damage, airway/lung remodelling and fibrosis are central features of inflammatory lung disorders, which include asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome and idiopathic pulmonary fibrosis. Although the lung has some ability to repair itself from acute injury, in the presence of ongoing pathological stimuli and/or insults that lead to chronic disease, it no longer retains the capacity to heal, resulting in fibrosis, the final common pathway that causes an irreversible loss of lung function. Despite inflammation, genetic predisposition/factors, epithelial-mesenchymal transition and mechanotransduction being able to independently contribute to airway remodelling and fibrosis, current therapies for inflammatory lung diseases are limited by their ability to only target the inflammatory component of the disease without having any marked effects on remodelling (epithelial damage and fibrosis) that can cause lung dysfunction independently of inflammation. Furthermore, as subsets of patients suffering from these diseases are resistant to currently available therapies (such as corticosteroids), novel therapeutic approaches are required to combat all aspects of disease pathology. This review discusses emerging therapeutic approaches, such as trefoil factors, relaxin, histone deacetylase inhibitors and stem cells, amongst others that have been able to target airway inflammation and airway remodelling while improving related lung dysfunction. A better understanding of the mode of action of these therapies and their possible combined effects may lead to the identification of their clinical potential in the setting of lung disease, either as adjunct or alternative therapies to currently available treatments.
Assuntos
Remodelação das Vias Aéreas/fisiologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/terapia , Remodelação das Vias Aéreas/efeitos dos fármacos , Animais , Humanos , Mediadores da Inflamação/metabolismo , Pneumopatias/diagnóstico , Pneumopatias/metabolismo , Pneumopatias/patologia , Fibrose Pulmonar/diagnóstico , Relaxina/farmacologia , Transplante de Células-Tronco/tendências , Fator Trefoil-2RESUMO
Low-level laser therapy (LLLT) controls bronchial hyperresponsiveness (BHR) associated with increased RhoA expression as well as pro-inflammatory mediators associated with NF-kB in acute lung inflammation. Herein, we explore if LLLT can reduce both BHR and Th2 cytokines in allergic asthma. Mice were studied for bronchial reactivity and lung inflammation after antigen challenge. BHR was measured through dose-response curves to acetylcholine. Some animals were pretreated with a RhoA inhibitor before the antigen. LLLT (660 nm, 30 mW and 5.4 J) was applied on the skin over the right upper bronchus and two irradiation protocols were used. Reduction of BHR post LLLT coincided with lower RhoA expression in bronchial muscle as well as reduction in eosinophils and eotaxin. LLLT also diminished ICAM expression and Th2 cytokines as well as signal transducer and activator of transduction 6 (STAT6) levels in lungs from challenged mice. Our results demonstrated that LLLT reduced BHR via RhoA and lessened allergic lung inflammation via STAT6.
Assuntos
Remodelação das Vias Aéreas/efeitos da radiação , Asma/radioterapia , Broncoconstrição/efeitos da radiação , Citocinas/metabolismo , Hipersensibilidade/radioterapia , Terapia com Luz de Baixa Intensidade , Remodelação das Vias Aéreas/efeitos dos fármacos , Remodelação das Vias Aéreas/fisiologia , Amidas/farmacologia , Animais , Asma/tratamento farmacológico , Asma/fisiopatologia , Brônquios/efeitos dos fármacos , Brônquios/fisiopatologia , Brônquios/efeitos da radiação , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/fisiopatologia , Hiper-Reatividade Brônquica/radioterapia , Broncoconstrição/efeitos dos fármacos , Broncoconstrição/fisiologia , Inibidores Enzimáticos/farmacologia , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/fisiopatologia , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Pulmão/efeitos da radiação , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiopatologia , Músculo Liso/efeitos da radiação , Ovalbumina/efeitos adversos , Pneumonia/tratamento farmacológico , Pneumonia/fisiopatologia , Pneumonia/radioterapia , Piridinas/farmacologia , Fator de Transcrição STAT6/metabolismo , Proteínas rho de Ligação ao GTP/antagonistas & inibidores , Proteínas rho de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTPRESUMO
In addition to parenchymal fibrosis, fibrotic remodeling of the distal airways has been reported in interstitial lung diseases. Mechanisms of airway wall remodeling, which occurs in a variety of chronic lung diseases, are not well defined and current animal models are limited. The authors quantified airway remodeling in lung sections from subjects with idiopathic pulmonary fibrosis (IPF) and controls. To investigate intratracheal bleomycin as a potential animal model for fibrotic airway remodeling, the authors evaluated lungs from C57BL/6 mice after bleomycin treatment by histologic scoring for fibrosis and peribronchial inflammation, morphometric evaluation of subepithelial connective tissue volume density, TUNEL (terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling) assay, and immunohistochemistry for transforming growth factor ß1 (TGFß1), TGFß2, and the fibroblast marker S100A4. Lung mechanics were determined at 3 weeks post bleomycin. IPF lungs had small airway remodeling with increased bronchial wall thickness compared to controls. Similarly, bleomycin-treated mice developed dose-dependent airway wall inflammation and fibrosis and greater airflow resistance after high-dose bleomycin. Increased TUNEL(+) bronchial epithelial cells and peribronchial inflammation were noted by 1 week, and expression of TGFß1 and TGFß2 and accumulation of S100A4(+) fibroblasts correlated with airway remodeling in a bleomycin dose-dependent fashion. IPF is characterized by small airway remodeling in addition to parenchymal fibrosis, a pattern also seen with intratracheal bleomycin. Bronchial remodeling from intratracheal bleomycin follows a cascade of events including epithelial cell injury, airway inflammation, profibrotic cytokine expression, fibroblast accumulation, and peribronchial fibrosis. Thus, this model can be utilized to investigate mechanisms of airway remodeling.