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1.
BMC Pulm Med ; 22(1): 180, 2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35524325

RESUMO

Allergic asthma is an allergic inflammatory disease of the airways, in which numerous cell types and cytokines have been shown to contribute to pathogenesis of the disease. Although increased expression of IL-9 has been shown to influence the activity of structural as well as eosinophils and mast cells in asthma, the influence of IL-9 on function of ILC2 and Th2 cells remains unclear. This study therefore aimed to elucidate the role of IL-9 on ILC2 and Th2 cells using a murine model of asthma. A murine model of asthma was established using wild type (WT) and IL-9-deficient (Il9-/-) transgenic mice sensitized to house dust mite (HDM). Bronchoalveolar lavage fluid (BALF) and lung tissues were collected, and analysed for inflammatory cells (eosinophils, mast cells, Th2 cells and ILC2 cells), histopathological changes, and several cytokines. HDM challenge significantly increased accumulation of ILC2 cells, Th2 cells and mast cells, as well as goblet cell hyperplasia, and the expression of cytokines IL-4, IL-5 and IL-13, but not IFN-γ, in WT mice compared to saline-challenged control group. In contrast, all pathological changes, including infiltration of ILC2 cells, Th2 cells and mast cells, were significantly attenuated in HDM-challenged Il9-/- mice. Furthermore, the number of Ki67+ILC2 cells, Ki67+Th2 cells and Ki67+mast cells were significantly reduced in the absence of IL-9 signalling. These data suggest that IL-9 promotes the proliferation and type 2 cytokine production of type 2 cells in the murine models of asthma, and therefore might be a potential therapeutic target for asthma treatment.


Assuntos
Asma , Hipersensibilidade , Interleucina-9 , Animais , Asma/patologia , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Modelos Animais de Doenças , Imunidade Inata , Inflamação/metabolismo , Interleucina-9/metabolismo , Antígeno Ki-67/metabolismo , Pulmão/patologia , Linfócitos/metabolismo , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Pyroglyphidae , Células Th2
2.
J Immunol ; 208(9): 2085-2097, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35396219

RESUMO

Asthma is a common and ubiquitous chronic respiratory disease that is associated with airway inflammation and hyperreactivity resulting in airway obstruction. It is now accepted that asthma is controlled by a combination of host genetics and environment in a rather complex fashion; however, the link between sensing of the environment and development and exacerbation of allergic lung inflammation is unclear. Human populations expressing cosegregating D299G and T399I polymorphisms in the TLR4 gene are associated with a decreased risk for asthma in adults along with hyporesponsiveness to inhaled LPS, the TLR4 ligand. However, these data do not account for other human genetic or environmental factors. Using a novel mouse strain that expresses homologous human TLR4 polymorphisms (TLR4-single nucleotide polymorphism [SNP]), we directly tested the effect of these TLR4 polymorphisms on in vivo responses to allergens using two models of induction. We report that intact TLR4 is required for allergic inflammation when using the OVA and LPS model of induction, as cellular and pathological benchmarks were diminished in both TLR4-SNP and TLR4-deficent mice. However, in the more clinically relevant model using house dust mite extract for induction, responses were enhanced in the TLR4-SNP mice, as evidenced by greater levels of eosinophilic inflammation, Th2 cytokine production, and house dust mite-specific IgG1 production compared with wild-type mice; however, mucus production and airway hyperreactivity were not affected. These results suggest that the TLR4 polymorphic variants (genes) interact differently with the allergic stimulation (environment).


Assuntos
Antígenos de Dermatophagoides , Asma , Eosinofilia Pulmonar , Receptor 4 Toll-Like , Alérgenos , Animais , Antígenos de Dermatophagoides/imunologia , Asma/genética , Asma/patologia , Inflamação , Lipopolissacarídeos , Camundongos , Polimorfismo de Nucleotídeo Único , Pyroglyphidae , Receptor 4 Toll-Like/genética
3.
Clin Transl Med ; 12(4): e816, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35474304

RESUMO

BACKGROUND: Exacerbation-prone asthma is a feature of severe disease. However, the basis for its persistency remains unclear. OBJECTIVES: To determine the clinical and transcriptomic features of frequent exacerbators (FEs) and persistent FEs (PFEs) in the U-BIOPRED cohort. METHODS: We compared features of FE (≥2 exacerbations in past year) to infrequent exacerbators (IE, <2 exacerbations) and of PFE with repeat ≥2 exacerbations during the following year to persistent IE (PIE). Transcriptomic data in blood, bronchial and nasal epithelial brushings, bronchial biopsies and sputum cells were analysed by gene set variation analysis for 103 gene signatures. RESULTS: Of 317 patients, 62.4% had FE, of whom 63.6% had PFE, while 37.6% had IE, of whom 61.3% had PIE. Using multivariate analysis, FE was associated with short-acting beta-agonist use, sinusitis and daily oral corticosteroid use, while PFE was associated with eczema, short-acting beta-agonist use and asthma control index. CEA cell adhesion molecule 5 (CEACAM5) was the only differentially expressed transcript in bronchial biopsies between PE and IE. There were no differentially expressed genes in the other four compartments. There were higher expression scores for type 2, T-helper type-17 and type 1 pathway signatures together with those associated with viral infections in bronchial biopsies from FE compared to IE, while there were higher expression scores of type 2, type 1 and steroid insensitivity pathway signatures in bronchial biopsies of PFE compared to PIE. CONCLUSION: The FE group and its PFE subgroup are associated with poor asthma control while expressing higher type 1 and type 2 activation pathways compared to IE and PIE, respectively.


Assuntos
Asma , Transcriptoma , Asma/genética , Asma/metabolismo , Asma/patologia , Brônquios/patologia , Estudos de Coortes , Humanos , Escarro/metabolismo , Transcriptoma/genética
4.
Biomed Pharmacother ; 149: 112904, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35367759

RESUMO

Airway hyperresponsiveness(AHR) is a major clinical phenomenon in lung diseases (asthma, COPD and pulmonary fibrosis) and not only a high-risk factor for perioperative airway spasm leading to hypoxaemia, haemodynamic instability and even "silent lung", but also a potential risk for increased mortality from underlying diseases (e.g. asthma, COPD). Airway reactivity is closely linked to airway inflammation, remodelling and increased mucus secretion, and endoplasmic reticulum stress is an important mechanism for the development of these pathologies. This review, therefore, focuses on the effects of endoplasmic reticulum stress on the immune cells involved in airway hyperreactivity (epithelial cells, dendritic cells, eosinophils and neutrophils) in inflammation and mucus & sputum secretion; and on the differentiation and remodelling of airway smooth muscle cells and epithelial cells. The aim is to clarify the mechanisms associated with endoplasmic reticulum stress in airway hyperresponsiveness and to find new ideas and methods for the prevention of airway hyperresponsiveness in the perioperative period.


Assuntos
Asma , Doença Pulmonar Obstrutiva Crônica , Hipersensibilidade Respiratória , Asma/patologia , Estresse do Retículo Endoplasmático , Humanos , Inflamação/patologia
5.
Toxins (Basel) ; 14(4)2022 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-35448876

RESUMO

Glucocorticoid-resistant asthma, which predominates with neutrophils instead of eosinophils, is an increasing health concern. One potential source for the induction of neutrophil-predominant asthma is aerosolized lipopolysaccharide (LPS). Cyanobacteria have recently caused significant tidal blooms, and aerosolized cyanobacterial LPS has been detected near the cyanobacterial overgrowth. We hypothesized that cyanobacterial LPS contributes to lung inflammation by increasing factors that promote lung inflammation and neutrophil recruitment. To test this hypothesis, c57Bl/6 mice were exposed intranasally to LPS from the cyanobacterium member, Geitlerinema sp., in vivo to assess neutrophil infiltration and the production of pro-inflammatory cytokines and chemokines from the bronchoalveolar fluid by ELISA. Additionally, we exposed the airway epithelial cell line, A549, to Geitlerinema sp. LPS in vitro to confirm that airway epithelial cells were stimulated by this LPS to increase cytokine production and the expression of the adhesion molecule, ICAM-1. Our data demonstrate that Geitlerinema sp. LPS induces lung neutrophil infiltration, the production of pro-inflammatory cytokines such as Interleukin (IL)-6, Tumor necrosis factor-alpha, and Interferongamma as well as the chemokines IL-8 and RANTES. Additionally, we demonstrate that Geitlerinema sp. LPS directly activates airway epithelial cells to produce pro-inflammatory cytokines and the adhesion molecule, Intercellular Adhesion Molecule-1 (ICAM-1), in vitro using the airway epithelial cell line, A549. Based on our findings that use Geitlerinema sp. LPS as a model system, the data indicate that cyanobacteria LPS may contribute to the development of glucocorticoid-resistant asthma seen near water sources that contain high levels of cyanobacteria.


Assuntos
Asma , Cianobactérias , Pneumonia , Animais , Asma/patologia , Quimiocinas/metabolismo , Cianobactérias/metabolismo , Citocinas/metabolismo , Glucocorticoides/metabolismo , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/toxicidade , Pulmão/patologia , Camundongos , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Pneumonia/patologia
6.
Am J Physiol Lung Cell Mol Physiol ; 322(5): L683-L698, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35348023

RESUMO

Excessive production, secretion, and retention of abnormal mucus is a pathological feature of many obstructive airways diseases including asthma. Azithromycin is an antibiotic that also possesses immunomodulatory and mucoregulatory activities, which may contribute to the clinical effectiveness of azithromycin in asthma. The current study investigated these nonantibiotic activities of azithromycin in mice exposed daily to intranasal house dust mite (HDM) extract for 10 days. HDM-exposed mice exhibited airways hyperresponsiveness to aerosolized methacholine, a pronounced mixed eosinophilic and neutrophilic inflammatory response, increased airway smooth muscle (ASM) thickness, and elevated levels of epithelial mucin staining. Azithromycin (50 mg/kg sc, 2 h before each HDM exposure) attenuated HDM-induced airways hyperresponsiveness to methacholine, airways inflammation (bronchoalveolar lavage eosinophil and neutrophils numbers, and IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, and RANTES levels), and epithelial mucin staining (mucous metaplasia) by at least 50% (compared with HDM-exposed mice, P < 0.05). Isolated tracheal segments of HDM-exposed mice secreted Muc5ac and Muc5b (above baseline levels) in response to exogenous ATP. Moreover, ATP-induced secretion of mucins was attenuated in segments obtained from azithromycin-treated, HDM-exposed mice (P < 0.05). In additional ex vivo studies, ATP-induced secretion of Muc5ac (but not muc5b) from HDM-exposed tracheal segments was inhibited by in vitro exposure to azithromycin. In vitro azithromycin also inhibited ATP-induced secretion of Muc5ac and Muc5b in tracheal segments from IL-13-exposed mice. In summary, azithromycin inhibited ATP-induced mucin secretion and airways inflammation in HDM-exposed mice, both of which are likely to contribute to suppression of airways hyperresponsiveness.


Assuntos
Asma , Pyroglyphidae , Trifosfato de Adenosina , Alérgenos , Animais , Asma/patologia , Azitromicina/farmacologia , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Interleucina-13 , Metaplasia , Cloreto de Metacolina , Camundongos , Mucinas , Muco
7.
Front Immunol ; 13: 818017, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35281012

RESUMO

Unified airway disease, including concurrent asthma and chronic rhinosinusitis (CRS), is a common, but poorly understood disorder with no curative treatment options. To establish a murine model of chronic unified eosinophilic airway inflammation, mice were challenged with Aspergillus niger, and sinonasal mucosa and lung tissue were evaluated by immunohistochemistry, flow cytometry, and gene expression. Inhalation of A niger conidia resulted in a Th2-biased lung and sinus inflammation that typifies allergic asthma and CRS. Gene network and pathway analysis correlated with human disease with upregulation of not only the JAK-STAT and helper T-cell pathways, but also less expected pathways governing the spliceosome, osteoclast differentiation, and coagulation pathways. Utilizing a specific inhibitor and gene-deficient mice, we demonstrate that STAT6 is required for mycosis-induced sinus inflammation. These findings confirm the relevance of this new model and portend future studies that further extend our understanding of the immunopathologic basis of airway mycosis and unified airway disease.


Assuntos
Asma , Eosinofilia , Sinusite , Animais , Aspergillus , Asma/patologia , Eosinofilia/patologia , Inflamação , Pulmão/patologia , Camundongos , Fator de Transcrição STAT6
8.
Int Immunopharmacol ; 106: 108603, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35123286

RESUMO

Dendritic cells (DCs) are professional antigen-presenting cells that play a key role in directing T-cell responses and are involved in the pathogenesis of allergic asthma. Acteoside, an active phenylethanoid glycoside, is widely distributed in many medicinal plants. Herein, we explored the immunomodulatory effects of acteoside on bone marrow-derived DCs in vitro, and further investigated the immunosuppressive ability of acteoside to manipulate T helper type 2 (Th2)-mediated allergic asthma in mice. Following lipopolysaccharide activation, 50 µM of acteoside significantly reduced the production of proinflammatory mediators, including interleukin (IL)-12 and tumor necrosis factor (TNF)-α, whereas it enhanced secretion of the anti-inflammatory cytokine, IL-10, by DCs. However, these effects of acteoside on DCs were reversed by pretreatment with CH223191, an aryl hydrocarbon receptor (AhR) antagonist. Additionally, coculture of acteoside-treated DCs with CD4+ T cells promoted the generation of forkhead box P3-positive (Foxp3+) regulatory T cells (Tregs) via AhR activation. Using a murine asthma model, our results demonstrated that oral administration of 50 mg/kg of acteoside decreased levels of Th2-type cytokines, such as IL-4, IL-5, and IL-13, whereas the level of IL-10 and the frequency of CD4+Foxp3+ Tregs were augmented. Moreover, acteoside treatment markedly inhibited the elevated serum level of ovalbumin-specific immunoglobulin E, attenuated the development of airway hyperresponsiveness, and reduced inflammatory cell counts in bronchoalveolar lavage fluid. Additionally, histological results reveled that acteoside ameliorated pulmonary inflammation in asthmatic mice. Taken together, these results indicated that acteoside exhibits immunomodulatory effects on DCs and plays an anti-inflammatory role in the treatment of allergic asthma.


Assuntos
Asma , Linfócitos T Reguladores , Animais , Asma/patologia , Líquido da Lavagem Broncoalveolar , Citocinas/farmacologia , Células Dendríticas , Fatores de Transcrição Forkhead , Glucosídeos , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Fenóis , Receptores de Hidrocarboneto Arílico , Células Th2
9.
Int J Mol Sci ; 23(3)2022 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-35163010

RESUMO

Repurposing of the anthelminthic drug niclosamide was proposed as an effective treatment for inflammatory airway diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Niclosamide may also be effective for the treatment of viral respiratory infections, such as SARS-CoV-2, respiratory syncytial virus, and influenza. While systemic application of niclosamide may lead to unwanted side effects, local administration via aerosol may circumvent these problems, particularly when the drug is encapsulated into small polyethylene glycol (PEG) hydrospheres. In the present study, we examined whether PEG-encapsulated niclosamide inhibits the production of mucus and affects the pro-inflammatory mediator CLCA1 in mouse airways in vivo, while effects on mucociliary clearance were assessed in excised mouse tracheas. The potential of encapsulated niclosamide to inhibit TMEM16A whole-cell Cl- currents and intracellular Ca2+ signalling was assessed in airway epithelial cells in vitro. We achieved encapsulation of niclosamide in PEG-microspheres and PEG-nanospheres (Niclo-spheres). When applied to asthmatic mice via intratracheal instillation, Niclo-spheres strongly attenuated overproduction of mucus, inhibited secretion of the major proinflammatory mediator CLCA1, and improved mucociliary clearance in tracheas ex vivo. These effects were comparable for niclosamide encapsulated in PEG-nanospheres and PEG-microspheres. Niclo-spheres inhibited the Ca2+ activated Cl- channel TMEM16A and attenuated mucus production in CFBE and Calu-3 human airway epithelial cells. Both inhibitory effects were explained by a pronounced inhibition of intracellular Ca2+ signals. The data indicate that poorly dissolvable compounds such as niclosamide can be encapsulated in PEG-microspheres/nanospheres and deposited locally on the airway epithelium as encapsulated drugs, which may be advantageous over systemic application.


Assuntos
Niclosamida/administração & dosagem , Pneumonia/tratamento farmacológico , Sistema Respiratório/efeitos dos fármacos , Animais , Asma/tratamento farmacológico , Asma/metabolismo , Asma/patologia , COVID-19/complicações , COVID-19/tratamento farmacológico , Células Cultivadas , Modelos Animais de Doenças , Portadores de Fármacos/química , Composição de Medicamentos , Humanos , Hidrogéis/química , Instilação de Medicamentos , Camundongos , Microesferas , Muco/efeitos dos fármacos , Muco/metabolismo , Nanosferas/administração & dosagem , Nanosferas/química , Niclosamida/química , Niclosamida/farmacocinética , Pneumonia/patologia , Polietilenoglicóis/química , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Sistema Respiratório/metabolismo , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Traqueia
10.
Sci Rep ; 12(1): 2731, 2022 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-35177766

RESUMO

Allergic asthma is a chronic inflammatory respiratory disease. Psychiatric disorders, including anxiety are associated with poorer treatment response and disease control in asthmatic patients. To date, there is no experimental evidence describing the role of peripheral inflammation on the oscillatory activities in the anterior cingulate cortex (ACC) and basolateral amygdala (BLA), two major brain structures modulating anxiety. In the present work we evaluated lung and brain inflammatory responses, anxiety-like behavior, in association with oscillatory features of the ACC-BLA circuit in an animal model of allergic inflammation. Our data showed that allergic inflammation induced anxiety-like behavior and reactivation of microglia and astrocytes in ACC and BLA. Allergic inflammation also enhanced neuronal activities and functional connectivity of the ACC-BLA circuit which were correlated with the level of anxiety. Together, we suggest that disruption in the dynamic oscillatory activities of the ACC-BLA circuit, maybe due to regional inflammation, is an underlying mechanism of allergic asthma-induced anxiety-like behavior. Our findings could pave the way for better understanding the neuro-pathophysiology of the psychiatric disorders observed in asthmatic patients, possibly leading to develop novel treatment strategies.


Assuntos
Ansiedade/metabolismo , Asma/metabolismo , Complexo Nuclear Basolateral da Amígdala/metabolismo , Giro do Cíngulo/metabolismo , Animais , Ansiedade/patologia , Asma/patologia , Complexo Nuclear Basolateral da Amígdala/patologia , Giro do Cíngulo/patologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Ratos , Ratos Wistar
11.
J Immunol ; 208(5): 1007-1020, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35181641

RESUMO

E-protein transcription factors limit group 2 innate lymphoid cell (ILC2) development while promoting T cell differentiation from common lymphoid progenitors. Inhibitors of DNA binding (ID) proteins block E-protein DNA binding in common lymphoid progenitors to allow ILC2 development. However, whether E-proteins influence ILC2 function upon maturity and activation remains unclear. Mice that overexpress ID1 under control of the thymus-restricted proximal Lck promoter (ID1tg/WT) have a large pool of primarily thymus-derived ILC2s in the periphery that develop in the absence of E-protein activity. We used these mice to investigate how the absence of E-protein activity affects ILC2 function and the genomic landscape in response to house dust mite (HDM) allergens. ID1tg/WT mice had increased KLRG1- ILC2s in the lung compared with wild-type (WT; ID1WT/WT) mice in response to HDM, but ID1tg/WT ILC2s had an impaired capacity to produce type 2 cytokines. Analysis of WT ILC2 accessible chromatin suggested that AP-1 and C/EBP transcription factors but not E-proteins were associated with ILC2 inflammatory gene programs. Instead, E-protein binding sites were enriched at functional genes in ILC2s during development that were later dynamically regulated in allergic lung inflammation, including genes that control ILC2 response to cytokines and interactions with T cells. Finally, ILC2s from ID1tg/WT compared with WT mice had fewer regions of open chromatin near functional genes that were enriched for AP-1 factor binding sites following HDM treatment. These data show that E-proteins shape the chromatin landscape during ILC2 development to dictate the functional capacity of mature ILC2s during allergic inflammation in the lung.


Assuntos
Antígenos de Dermatophagoides/imunologia , Asma/imunologia , Proteína 1 Inibidora de Diferenciação/metabolismo , Linfócitos T/imunologia , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Alérgenos/imunologia , Animais , Asma/patologia , Diferenciação Celular/imunologia , Cromatina/metabolismo , Citocinas/imunologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Feminino , Lectinas Tipo C/genética , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pyroglyphidae/imunologia , Receptores Imunológicos/genética , Células-Tronco/citologia , Linfócitos T/citologia , Fator de Transcrição AP-1/metabolismo
12.
Respir Res ; 23(1): 31, 2022 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-35172835

RESUMO

BACKGROUND: Toll-interacting protein (Tollip) is one of the key negative regulators in host innate immunity. Genetic variation of Tollip has been associated with less Tollip expression and poor lung function in asthmatic patients, but little is known about the role of Tollip in human airway type 2 inflammatory response, a prominent feature in allergic asthma. OBJECTIVE: Our goal was to determine the role and underlying mechanisms of Tollip in human airway epithelial responses such as eotaxin to type 2 cytokine IL-13. METHODS: Tollip deficient primary human airway epithelial cells from 4 healthy donors were generated by the gene knockdown approach and stimulated with IL-13 to measure activation of transcription factor STAT3, and eotaxin-3, an eosinophilic chemokine. RESULTS: Following IL-13 treatment, Tollip deficient cells had significantly higher levels of STAT3 activation and eotaxin-3 than the scrambled control counterpart, which was reduced by a STAT3 inhibitor. Interaction between Tollip and STAT3 proteins was identified by co-immunoprecipitation. CONCLUSION: Our results, for the first time, suggest that Tollip inhibits excessive eotaxin-3 induction by IL-13, in part through the interaction and inhibition of STAT3. These findings lend evidence to the potential of a STAT3 inhibitor as a therapeutic target, especially for type 2 inflammation-high asthmatics with Tollip deficiency.


Assuntos
Asma/metabolismo , Citocinas/metabolismo , Células Epiteliais/metabolismo , Imunidade Inata , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mucosa Respiratória/metabolismo , Fator de Transcrição STAT3/metabolismo , Adulto , Idoso , Asma/imunologia , Asma/patologia , Células Cultivadas , Células Epiteliais/patologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia
13.
J Ethnopharmacol ; 290: 115093, 2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35149129

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Acalypha indica Linn (Euphorbiaceae), a popular traditional medicine, is an erect herb found throughout various parts of India. In Ayurveda, Acalypha indica was commonly used in asthma and allergy. However, no attempts were made in past to validate the antiasthmatic potential of Acalypha indica. AIM OF THE STUDY: The present study was aimed to assess the anti-asthmatic potential of ethanolic extracts of Acalypha indica leaves (EAIL) using various experimental animal models. MATERIALS AND METHODS: EAIL was analyzed using different screening methods such as acetylcholine and histamine-induced contraction of goat tracheal chain, clonidine-induced catalepsy in mice, milk-induced leucocytosis and eosinophilia in mice, clonidine-induced mast cell degranulation in rats, passive paw anaphylaxis in rats, histamine-induced bronchoconstriction in guinea pigs, and ovalbumin (OVA)-induced histopathological alterations in mice. RESULTS: Data received in the present study showed that EAIL drastically antagonized acetylcholine and histamine-induced contraction of goat tracheal chain, suggesting its anticholinergic and antihistaminic activity respectively. The duration of immobility, produced by clonidine, was found to be decreased in mice which showed its H1 receptor blocking activity. In milk-induced leucocytosis and eosinophilia in mice, EAIL significantly reduced the number of leucocytes and eosinophils suggesting its adaptogenic and anti-allergic potential. Inhibition of clonidine-induced mast cell degranulation in rats displayed its mast cell stabilizing potential. Reduction of paw edema in passive paw anaphylaxis exhibited antianaphylactic activity of EAIL. Guinea pigs were protected from histamine-induced bronchoconstriction by EAIL which revealed its bronchodilator potential. Furthermore, the histopathological architecture of lung tissue was near to normal. CONCLUSION: Our results contribute towards validation of the traditional use of Acalypha indica in the treatment of asthma due to the presence of a wide range of phytoconstituents. Hence our investigation revealed that EAIL possessed strong antiasthmatic property by virtue of various mechanisms.


Assuntos
Acalypha , Asma/patologia , Broncoconstrição/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Antialérgicos/farmacologia , Antiasmáticos/farmacologia , Anti-Inflamatórios/farmacologia , Broncodilatadores/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células Caliciformes/efeitos dos fármacos , Cobaias , Hipersensibilidade/patologia , Mediadores da Inflamação/metabolismo , Mastócitos/efeitos dos fármacos , Camundongos , Folhas de Planta , Ratos , Ratos Wistar
15.
Rev Mal Respir ; 39(2): 100-103, 2022 Feb.
Artigo em Francês | MEDLINE | ID: mdl-35183407

RESUMO

Asthma is a chronic airway condition defined by hyperresponsiveness, bronchial remodeling and chronic inflammation. A significant proportion of severe asthmatic patients remain uncontrolled despite recent therapeutic breakthroughs (biotherapies). Better understanding of the signaling pathways involved in the pathophysiological mechanisms underlying severe asthma could successfully address this unmet need. Rac GTPase acts as a molecular switch and has already been convincingly associated with airway hyperresponsiveness and bronchial remodeling in asthma. Having been elucidated by acquired knowledge regarding other pathologies. Its role in the inflammation mechanisms characterizing asthma is currently under specific evaluation.


Assuntos
Asma , GTP Fosfo-Hidrolases , Hipersensibilidade Respiratória , Asma/patologia , Brônquios/patologia , Humanos , Inflamação
16.
J Immunol ; 208(5): 1272-1279, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35110420

RESUMO

Interstitial macrophages (IMs) are key regulators of allergic inflammation. We previously showed that the absence of semaphorin 3E (Sema3E) exacerbates asthma features in both acute and chronic asthma models. However, it has not been studied whether Sema3E, via its receptor plexinD1, regulates IM function in allergic asthma. Therefore, we investigated the role of plexinD1 deficiency on IMs in allergic asthma. We found that the absence of plexinD1 in IMs increased airway hyperresponsiveness, airway leukocyte numbers, allergen-specific IgE, goblet cell hyperplasia, and Th2/Th17 cytokine response in the house dust mite (HDM)-induced allergic asthma model. Muc5ac, Muc5b, and α-SMA genes were increased in mice with Plxnd1-deficient IMs compared with wild-type mice. Furthermore, plexinD1-deficient bone marrow-derived macrophages displayed reduced IL-10 mRNA expression, at both the baseline and following HDM challenge, compared with their wild-type counterpart mice. Our data suggest that Sema3E/plexinD1 signaling in IMs is a critical pathway that modulates airway inflammation, airway resistance, and tissue remodeling in the HDM murine model of allergic asthma. Reduced IL-10 expression by plexinD1-deficient macrophages may account for these enhanced allergic asthma features.


Assuntos
Asma/patologia , Dermatophagoides pteronyssinus/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Macrófagos/imunologia , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Semaforinas/genética , Actinas/genética , Actinas/metabolismo , Resistência das Vias Respiratórias/imunologia , Animais , Asma/imunologia , Modelos Animais de Doenças , Feminino , Células Caliciformes/imunologia , Imunoglobulina E/imunologia , Interleucina-10/genética , Contagem de Leucócitos , Leucócitos/imunologia , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Knockout , Mucina-5AC/genética , Mucina-5AC/metabolismo , Mucina-5B/genética , Mucina-5B/metabolismo , RNA Mensageiro/genética , Células Th17/imunologia , Células Th2/imunologia
17.
Respir Res ; 23(1): 17, 2022 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-35093061

RESUMO

BACKGROUND: Type 2-high asthma is a prominent endotype of asthma which is characterized by airway eosinophilic inflammation. Airway epithelial cells play a critical role in the pathogenesis of asthma. Our previous miRNA profiling data showed that miR-30a-3p was downregulated in bronchial epithelial cells from asthma patients. We hypothesize that epithelial miR-30a-3p plays a role in asthma airway inflammation. METHODS: We measured miR-30a-3p expression in bronchial brushings of asthma patients (n = 51) and healthy controls (n = 16), and analyzed the correlations between miR-30a-3p expression and airway eosinophilia. We examined whether Runt-related transcription factor 2 (RUNX2) was a target of miR-30a-3p and whether RUNX2 bound to the promoter of high mobility group box 1 (HMGB1) by using luciferase reporter assay and chromatin immunoprecipitation (ChIP)-PCR. The role of miR-30a-3p was also investigated in a murine model of allergic airway inflammation. RESULTS: We found that miR-30a-3p expression were significantly decreased in bronchial brushings of asthma patients compared to control subjects. Epithelial miR-30a-3p expression was negatively correlated with parameters reflecting airway eosinophilia including eosinophils in induced sputum and bronchial biopsies, and fraction of exhaled nitric oxide in asthma patients. We verified that RUNX2 is a target of miR-30a-3p. Furthermore, RUNX2 bound to the promoter of HMGB1 and upregulated HMGB1 expression. RUNX2 and HMGB1 expression was both enhanced in airway epithelium and was correlated with each other in asthma patients. Inhibition of miR-30a-3p enhanced RUNX2 and HMGB1 expression, and RUNX2 overexpression upregulated HMGB1 in BEAS-2B cells. Intriguingly, airway overexpression of mmu-miR-30a-3p suppressed Runx2 and Hmgb1 expression, and alleviated airway eosinophilia in a mouse model of allergic airway inflammation. CONCLUSIONS: Epithelial miR-30a-3p could possibly target RUNX2/HMGB1 axis to suppress airway eosinophilia in asthma.


Assuntos
Asma/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Eosinofilia/genética , Regulação da Expressão Gênica , Proteína HMGB1/genética , Inflamação/genética , MicroRNAs/genética , Animais , Asma/complicações , Asma/patologia , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/biossíntese , Modelos Animais de Doenças , Eosinofilia/complicações , Eosinofilia/patologia , Feminino , Proteína HMGB1/biossíntese , Humanos , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/biossíntese , Escarro/metabolismo , Regulação para Cima
18.
Sci Transl Med ; 14(627): eabf8188, 2022 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-35020406

RESUMO

Exacerbations of symptoms represent an unmet need for people with asthma. Bacterial dysbiosis and opportunistic bacterial infections have been observed in, and may contribute to, more severe asthma. However, the molecular mechanisms driving these exacerbations remain unclear. We show here that bacterial lipopolysaccharide (LPS) induces oncostatin M (OSM) and that airway biopsies from patients with severe asthma present with an OSM-driven transcriptional profile. This profile correlates with activation of inflammatory and mucus-producing pathways. Using primary human lung tissue or human epithelial and mesenchymal cells, we demonstrate that OSM is necessary and sufficient to drive pathophysiological features observed in severe asthma after exposure to LPS or Klebsiella pneumoniae. These findings were further supported through blockade of OSM with an OSM-specific antibody. Single-cell RNA sequencing from human lung biopsies identified macrophages as a source of OSM. Additional studies using Osm-deficient murine macrophages demonstrated that macrophage-derived OSM translates LPS signals into asthma-associated pathologies. Together, these data provide rationale for inhibiting OSM to prevent bacterial-associated progression and exacerbation of severe asthma.


Assuntos
Asma , Oncostatina M/metabolismo , Animais , Asma/patologia , Humanos , Pulmão/patologia , Macrófagos/metabolismo , Camundongos , Muco , Oncostatina M/genética
19.
Respir Physiol Neurobiol ; 299: 103843, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35026480

RESUMO

Ganoderma, a fungal genus, is a traditional medicine with immuno-modulating effects. Asthma is an inflammatory disease of airways, and the main trigger of asthma is allergic inflammation. In this study, the effects of Ganoderma (an anti-inflammatory agent) given via oral administration (G/O) or intraperitoneal injection (G/IP) on asthma was evaluated. Forty BALB/c mice were divided into four groups, including the control, OVA-challenge, OVA-challenge + G/O, and OVA-challenge + G/IP. To determine AHR, the MCh challenge test was done. The levels of IL-1ß, -4, -5, -6, -8, -10, -12, -13, -17, -25, -33, -38, Cys-LT, LTB4, and hydroxyproline were measured. Finally, lung histopathology was evaluated to determine eosinophilic inflammation, goblet cell hyperplasia, and mucus hyper-secretion. Treatment with G/O and G/IP could significantly reduce the levels of IL-1ß, -5, -6, -8, -17, -25, -33, and -38; the levels of IL-4 and IL-13 had no significant changes, but the levels of IL-10 and IL-12 were enhanced. The mice treated with G/O and G/IP showed decreased levels of Cys-LT, LTB4, peribronchial and perivascular inflammation, but no significant changes were observed in AHR, hydroxyproline level, goblet cell hyperplasia, and mucus hyper-secretion. Ganoderma can be applied as an immunomodulatory and anti-inflammatory agent for managing asthma.


Assuntos
Asma , Ganoderma , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Asma/patologia , Líquido da Lavagem Broncoalveolar , Citocinas , Modelos Animais de Doenças , Hidroxiprolina/uso terapêutico , Hiperplasia/patologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Leucotrieno B4/uso terapêutico , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina
20.
Int Arch Allergy Immunol ; 183(5): 471-478, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35016174

RESUMO

BACKGROUND: We have previously showed rTgPI-1 tolerogenic adjuvant properties in asthma treatment, turning it a promising candidate for allergen-specific immunotherapy. This therapy is an alternative treatment to control asthma that still presents several concerns related to its formulation. rTgPI-1 contains independent inhibitory domains able to inhibit trypsin and neutrophil elastase, both involved in asthma pathology. OBJECTIVES: In view of the need to design rational therapies, herein we investigated the contribution of the different inhibitory domains in rTgPI-1 therapeutic effectiveness. METHODS: BALB/c mice were rendered allergic by intraperitoneal OVA-alum sensitization and airway challenged. Once the asthmatic phenotype was achieved, mice were intranasally treated with OVA combined with the full-length recombinant protein rTgPI-1 or its truncated versions, Nt (containing trypsin-inhibitory domains) or Ct (containing neutrophil elastase-inhibitory domains). Afterward, mice were aerosol re-challenged. RESULTS: Asthmatic mice treated with the neutrophil elastase- or the trypsin-inhibitory domains separately failed to improve allergic lung inflammation. Only when all inhibitory domains were simultaneously administered, an improvement was achieved. Still, a better outcome was obtained when mice were treated with the full-length rTgPI-1. CONCLUSIONS: Adjuvant ability depends on the presence of all its inhibitory domains in a single entity, so it should be included in potential asthma treatment formulations as a full-length protein.


Assuntos
Asma , Toxoplasma , Adjuvantes Imunológicos , Animais , Asma/patologia , Asma/terapia , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Elastase de Leucócito , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Inibidores de Serino Proteinase , Toxoplasma/genética , Tripsina , Vacinação
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