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1.
Nat Cell Biol ; 23(10): 1060-1072, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34616019

RESUMO

Eosinophilic inflammation is a feature of allergic asthma. Despite mounting evidence showing that chromatin filaments released from neutrophils mediate various diseases, the understanding of extracellular DNA from eosinophils is limited. Here we show that eosinophil extracellular traps (EETs) in bronchoalveolar lavage fluid are associated with the severity of asthma in patients. Functionally, we find that EETs augment goblet-cell hyperplasia, mucus production, infiltration of inflammatory cells and expressions of type 2 cytokines in experimental non-infection-related asthma using both pharmaceutical and genetic approaches. Multiple clinically relevant allergens trigger EET formation at least partially via thymic stromal lymphopoietin in vivo. Mechanically, EETs activate pulmonary neuroendocrine cells via the CCDC25-ILK-PKCα-CRTC1 pathway, which is potentiated by eosinophil peroxidase. Subsequently, the pulmonary neuroendocrine cells amplify allergic immune responses via neuropeptides and neurotransmitters. Therapeutically, inhibition of CCDC25 alleviates allergic inflammation. Together, our findings demonstrate a previously unknown role of EETs in integrating immunological and neurological cues to drive asthma progression.


Assuntos
Asma/patologia , Líquido da Lavagem Broncoalveolar/imunologia , Eosinófilos/patologia , Armadilhas Extracelulares/fisiologia , Inflamação/patologia , Pulmão/patologia , Células Neuroendócrinas/patologia , Adulto , Animais , Asma/etiologia , Asma/metabolismo , Estudos de Casos e Controles , Eosinófilos/imunologia , Eosinófilos/metabolismo , Feminino , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Neuroendócrinas/imunologia , Células Neuroendócrinas/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Proteína Quinase C-alfa/genética , Proteína Quinase C-alfa/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
2.
Int J Mol Sci ; 22(18)2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34576307

RESUMO

In the era of personalized medicine, insights into the molecular mechanisms that differentially contribute to disease phenotypes, such as asthma phenotypes including obesity-associated asthma, are urgently needed. Peripheral blood was drawn from 10 obese, non-atopic asthmatic adults with a high body mass index (BMI; 36.67 ± 6.90); 10 non-obese, non-atopic asthmatic adults with normal BMI (23.88 ± 2.73); and 10 healthy controls with normal BMI (23.62 ± 3.74). All asthmatic patients were considered to represent a low type-2 asthma phenotype according to selective clinical parameters. RNA sequencing (RNA-Seq) was conducted on peripheral blood CD4+ T cells. Thousands of differentially expressed genes were identified in both asthma groups compared with heathy controls. The expression of interferon (IFN)-stimulated genes associated with IFN-related signaling pathways was specifically affected in obese asthmatics, while the gap junction and G protein-coupled receptor (GPCR) ligand binding pathways were enriched in both asthma groups. Furthermore, obesity gene markers were also upregulated in CD4+ T cells from obese asthmatics compared with the two other groups. Additionally, the enriched genes of the three abovementioned pathways showed a unique correlation pattern with various laboratory and clinical parameters. The specific activation of IFN-related signaling and viral infection pathways might provide a novel view of the molecular mechanisms associated with the development of the low type-2 obesity-associated asthma phenotype, which is a step ahead in the development of new stratified therapeutic approaches.


Assuntos
Asma/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Interferons/metabolismo , Obesidade/metabolismo , Transdução de Sinais , Adulto , Asma/complicações , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Receptores Acoplados a Proteínas G/metabolismo
3.
Biomed Res Int ; 2021: 9956078, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34541002

RESUMO

Background: Respiratory syncytial virus (RSV) infects infants and children, predisposing them to development of asthma during adulthood. Epithelial neuroendocrine phenotypes may be associated with development of asthma. This study hopes to ascertain if RSV infection promotes epithelial neuroendocrine phenotypes through the NODAL signaling pathway. Methods: The GSE6802 data set was obtained from the GEO database, and the differential genes were analyzed using the R language. An in vitro model was constructed with RSV infected human respiratory epithelial cells, and then real-time qPCR and immunofluorescence were used to detect the expression of different epithelial biomarkers and airway neuropeptides. The acute and chronic infection model of RSV infection was established by intranasal injection of RSV into guinea pigs. Immunohistochemistry and Western blot were used to detect the expression of pulmonary neuroendocrine cells markers ENO2 and neuropeptides. Results: The expression levels of ENO2, SP, CGRP, and NODAL/ACTRII were significantly higher in the RSV infection group than those of the control group, which were abrogated by siRNA-NODAL. In vivo, we found that the expression levels of ENO2, SP, and CGRP were significantly higher than that of the control group. Conclusion: RSV promotes epithelial neuroendocrine phenotypes through the NODAL signaling pathway.


Assuntos
Células Neuroendócrinas/metabolismo , Ligantes da Sinalização Nodal/metabolismo , Infecções por Vírus Respiratório Sincicial/fisiopatologia , Animais , Asma/metabolismo , Diferenciação Celular , Linhagem Celular , China , Bases de Dados Factuais , Bases de Dados Genéticas , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Cobaias , Células HeLa , Humanos , Pulmão/metabolismo , Células Neuroendócrinas/virologia , Neuropeptídeos/metabolismo , Proteína Nodal/genética , Proteína Nodal/metabolismo , Proteína Nodal/fisiologia , Ligantes da Sinalização Nodal/genética , Fenótipo , Infecções por Vírus Respiratório Sincicial/metabolismo , Vírus Sinciciais Respiratórios/patogenicidade , Transdução de Sinais
4.
Sci Rep ; 11(1): 17788, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493738

RESUMO

Bile acid profiles are altered in obese individuals with asthma. Thus, we sought to better understand how obesity-related systemic changes contribute to lung pathophysiology. We also test the therapeutic potential of nitro-oleic acid (NO2-OA), a regulator of metabolic and inflammatory signaling pathways, to mitigate allergen and obesity-induced lung function decline in a murine model of asthma. Bile acids were measured in the plasma of healthy subjects and individuals with asthma and serum and lung tissue of mice with and without allergic airway disease (AAD). Lung function, indices of inflammation and hepatic bile acid enzyme expression were measured in obese mice with house dust mite-induced AAD treated with vehicle or NO2-OA. Serum levels of glycocholic acid and glycoursodeoxycholic acid clinically correlate with body mass index and airway hyperreactivity whereas murine levels of ß-muricholic acid and tauro-ß-muricholic acid were significantly increased and positively correlated with impaired lung function in obese mice with AAD. NO2-OA reduced murine bile acid levels by modulating hepatic expression of bile acid synthesis enzymes, with a concomitant reduction in small airway resistance and tissue elastance. Bile acids correlate to body mass index and lung function decline and the signaling actions of nitroalkenes can limit AAD by modulating bile acid metabolism, revealing a potential pharmacologic approach to improving the current standard of care.


Assuntos
Asma/metabolismo , Asma/fisiopatologia , Ácidos e Sais Biliares/metabolismo , Ácidos Graxos/fisiologia , Pulmão/fisiopatologia , Nitrocompostos/uso terapêutico , Obesidade/metabolismo , Ácidos Oleicos/uso terapêutico , Adolescente , Adulto , Animais , Antiasmáticos/uso terapêutico , Antígenos de Dermatophagoides/toxicidade , Asma/tratamento farmacológico , Asma/etiologia , Dieta Hiperlipídica/efeitos adversos , Avaliação Pré-Clínica de Medicamentos , Ácidos Graxos/química , Feminino , Volume Expiratório Forçado , Ácido Glicocólico/sangue , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/fisiopatologia , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/metabolismo , Magreza , Ácido Ursodesoxicólico/análogos & derivados , Ácido Ursodesoxicólico/sangue , Capacidade Vital , Adulto Jovem
5.
Am J Hum Genet ; 108(10): 1836-1851, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34582791

RESUMO

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.


Assuntos
Asma/epidemiologia , Biomarcadores/metabolismo , Dermatite Atópica/epidemiologia , Leucócitos/patologia , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Locos de Características Quantitativas , Asma/genética , Asma/metabolismo , Asma/patologia , Dermatite Atópica/genética , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , National Heart, Lung, and Blood Institute (U.S.) , Fenótipo , Prognóstico , Proteoma/análise , Proteoma/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Reino Unido/epidemiologia , Estados Unidos/epidemiologia , Sequenciamento Completo do Genoma
6.
Int J Mol Sci ; 22(18)2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34576313

RESUMO

Asthma is now recognized as a heterogeneous disease, encompassing different phenotypes driven by distinct pathophysiological mechanisms called endotypes. Common phenotypes of asthma, referred to as eosinophilic asthma, are characterized by the presence of eosinophilia. Eosinophils are usually considered invariant, terminally differentiated effector cells and have become a primary therapeutic target in severe eosinophilic asthma (SEA) and other eosinophil-associated diseases (EADs). Biological treatments that target eosinophils reveal an unexpectedly complex role of eosinophils in asthma, including in SEA, suggesting that "not all eosinophils are equal". In this review, we address our current understanding of the role of eosinophils in asthma with regard to asthma phenotypes and endotypes. We further address the possibility that different SEA phenotypes may involve differences in eosinophil biology. We discuss how these differences could arise through eosinophil "endotyping", viz. adaptations of eosinophil function imprinted during their development, or through tissue-induced plasticity, viz. local adaptations of eosinophil function through interaction with their lung tissue niches. In doing so, we also discuss opportunities, technical challenges, and open questions that, if addressed, might provide considerable benefits in guiding the choice of the most efficient precision therapies of SEA and, by extension, other EADs.


Assuntos
Asma/metabolismo , Eosinófilos/metabolismo , Animais , Humanos , Imunoterapia/métodos
7.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445677

RESUMO

Adiponectin is an adipokine associated with the healthy obese phenotype. Adiponectin increases insulin sensitivity and has cardio and vascular protection actions. Studies related to adiponectin, a modulator of the innate and acquired immunity response, have suggested a role of this molecule in asthma. Studies based on various asthma animal models and on the key cells involved in the allergic response have provided important insights about this relation. Some of them indicated protection and others reversed the balance towards negative effects. Many of them described the cellular pathways activated by adiponectin, which are potentially beneficial for asthma prevention or for reduction in the risk of exacerbations. However, conclusive proofs about their efficiency still need to be provided. In this article, we will, briefly, present the general actions of adiponectin and the epidemiological studies supporting the relation with asthma. The main focus of the current review is on the mechanisms of adiponectin and the impact on the pathobiology of asthma. From this perspective, we will provide arguments for and against the positive influence of this molecule in asthma, also indicating the controversies and sketching out the potential directions of research to complete the picture.


Assuntos
Adiponectina/metabolismo , Asma/metabolismo , Asma/fisiopatologia , Adipocinas/metabolismo , Adiponectina/fisiologia , Humanos , Resistência à Insulina/fisiologia , Leptina/metabolismo , Obesidade/metabolismo
8.
Nat Commun ; 12(1): 5029, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413303

RESUMO

Dendritic cells (DC) in the lung that induce Th17 differentiation remain incompletely understood, in part because conventional CD11b+ DCs (cDC2) are heterogeneous. Here, we report a population of cDCs that rapidly accumulates in lungs of mice following house dust extract inhalation. These cells are Ly-6C+, are developmentally and phenotypically similar to cDC2, and strongly promote Th17 differentiation ex vivo. Single cell RNA-sequencing (scRNA-Seq) of lung cDC2 indicates 5 distinct clusters. Pseudotime analysis of scRNA-Seq data and adoptive transfer experiments with purified cDC2 subpopulations suggest stepwise developmental progression of immature Ly-6C+Ly-6A/E+ cDC2 to mature Ly-6C-CD301b+ lung resident cDC2 lacking Ccr7 expression, which then further mature into CD200+ migratory cDC2 expressing Ccr7. Partially mature Ly-6C+Ly-6A/E-CD301b- cDC2, which express Il1b, promote Th17 differentiation. By contrast, CD200+ mature cDC2 strongly induce Th2, but not Th17, differentiation. Thus, Th17 and Th2 differentiation are promoted by lung cDC2 at distinct stages of maturation.


Assuntos
Asma/imunologia , Antígeno CD11b/imunologia , Células Dendríticas/imunologia , Pulmão/imunologia , Células Th17/imunologia , Células Th2/imunologia , Transferência Adotiva/métodos , Animais , Asma/metabolismo , Asma/patologia , Sequência de Bases , Antígeno CD11b/metabolismo , Diferenciação Celular/fisiologia , Células Cultivadas , Técnicas de Cocultura , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise de Célula Única/métodos , Células Th17/citologia , Células Th2/citologia
9.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360618

RESUMO

Activation of the Ca2+ activated Cl- channel TMEM16A is proposed as a treatment in inflammatory airway disease. It is assumed that activation of TMEM16A will induce electrolyte secretion, and thus reduce airway mucus plugging and improve mucociliary clearance. A benefit of activation of TMEM16A was shown in vitro and in studies in sheep, but others reported an increase in mucus production and airway contraction by activation of TMEM16A. We analyzed expression of TMEM16A in healthy and inflamed human and mouse airways and examined the consequences of activation or inhibition of TMEM16A in asthmatic mice. TMEM16A was found to be upregulated in the lungs of patients with asthma or cystic fibrosis, as well as in the airways of asthmatic mice. Activation or potentiation of TMEM16A by the compounds Eact or brevenal, respectively, induced acute mucus release from airway goblet cells and induced bronchoconstriction in mice in vivo. In contrast, niclosamide, an inhibitor of TMEM16A, blocked mucus production and mucus secretion in vivo and in vitro. Treatment of airway epithelial cells with niclosamide strongly inhibited expression of the essential transcription factor of Th2-dependent inflammation and goblet cell differentiation, SAM pointed domain-containing ETS-like factor (SPDEF). Activation of TMEM16A in people with inflammatory airway diseases is likely to induce mucus secretion along with airway constriction. In contrast, inhibitors of TMEM16A may suppress pulmonary Th2 inflammation, goblet cell metaplasia, mucus production, and bronchoconstriction, partially by inhibiting expression of SPDEF.


Assuntos
Anoctamina-1/metabolismo , Asma/patologia , Constrição Patológica/complicações , Fibrose Cística/patologia , Inflamação/patologia , Muco/metabolismo , Mucosa Respiratória/patologia , Animais , Anoctamina-1/genética , Asma/etiologia , Asma/metabolismo , Fibrose Cística/etiologia , Fibrose Cística/metabolismo , Células HEK293 , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Camundongos , Mucosa Respiratória/metabolismo
10.
Clin Immunol ; 231: 108822, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34400320

RESUMO

Lung surfactant protein A (SP-A) is critical for immunomodulation. Thymic stromal lymphopoietin (TSLP)-activated dendritic cells (DCs) drive T follicular helper (Tfh) cells differentiation in allergic asthma. We employed wild-type (WT) and SP-A-/- mice injected with TSLP and ovalbumin (OVA)-activated DCs and challenged with OVA. Compared with WT mice, we showed that allergic inflammation was dramatically increased in SP-A-/- mice. In parallel, both IL-4-producing CD45RA-CXCR5+PD-1+CD4+ cells (Tfh2) and IgE were markedly increased in SP-A-/- mice. Further study showed that SP-A prohibited TSLP activated-DCs from expressing OX40L. When we blocked OX40L-OX40 and IL-4R signaling, the differentiation of Tfh2 and IgE responses in SP-A-/- mice was significantly inhibited. In severe asthma patients, SP-A is dysfunctional in modulating the TSLP-DCs-mediated differentiation of Tfh cells. This study suggests that SP-A acts as a modulator of Tfh differentiation and IgE generation in asthma.


Assuntos
Asma/imunologia , Citocinas/imunologia , Imunoglobulina E/biossíntese , Proteína A Associada a Surfactante Pulmonar/imunologia , Células T Auxiliares Foliculares/imunologia , Adulto , Idoso , Animais , Asma/metabolismo , Diferenciação Celular/imunologia , Citocinas/metabolismo , Células Dendríticas/imunologia , Feminino , Humanos , Imunoglobulina E/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Proteína A Associada a Surfactante Pulmonar/metabolismo , Células T Auxiliares Foliculares/metabolismo
11.
Sci Rep ; 11(1): 16664, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404870

RESUMO

Asthma-chronic obstructive pulmonary disease (COPD) overlap, termed as ACO, is a complex heterogeneous disease characterised by persistent airflow limitation, which manifests features of both asthma and COPD. These patients have a worse prognosis, in terms of more frequent and severe exacerbations, more frequent symptoms, worse quality of life, increased comorbidities and a faster lung function decline. In absence of clear diagnostic or therapeutic guidelines, ACO presents as a challenge to clinicians. The present study aims to investigate whether ACO patients have a distinct exhaled breath condensate (EBC) metabolic profile in comparison to asthma and COPD. A total of 132 age and BMI matched male smokers were recruited in the exploratory phase which consisted of (i) controls = 33 (ii) asthma = 34 (iii) COPD = 30 and (iv) ACO = 35. Using nuclear magnetic resonance (NMR) metabolomics, 8 metabolites (fatty acid, propionate, isopropanol, lactate, acetone, valine, methanol and formate) were identified to be significantly dysregulated in ACO subjects when compared to both, asthma and COPD. The expression of these dysregulated metabolites were further validated in a fresh patient cohort consisting of (i) asthma = 32 (ii) COPD = 32 and (iii) ACO = 40, which exhibited a similar expression pattern. Multivariate receiver operating characteristic (ROC) curves generated using these metabolites provided a robust ACO classification model. The findings were also integrated with previously identified serum metabolites and inflammatory markers to develop a robust predictive model for differentiation of ACO. Our findings suggest that NMR metabolomics of EBC holds potential as a platform to identify robust, non-invasive biomarkers for differentiating ACO from asthma and COPD.


Assuntos
Asma/metabolismo , Metaboloma , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fumar/metabolismo , Adulto , Asma/diagnóstico , Testes Respiratórios , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Prognóstico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Fumantes
12.
Cells ; 10(8)2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34440746

RESUMO

Fibroblasts are an integral part of connective tissue and play a crucial role in developing and modulating the structural framework of tissues by acting as the primary source of extracellular matrix (ECM). A precise definition of the fibroblast remains elusive. Lung fibroblasts orchestrate the assembly and turnover of ECM to facilitate gas exchange alongside performing immune functions including the secretion of bioactive molecules and antigen presentation. DNA methylation is the covalent attachment of a methyl group to primarily cytosines within DNA. DNA methylation contributes to diverse cellular phenotypes from the same underlying genetic sequence, with DNA methylation profiles providing a memory of cellular origin. The lung fibroblast population is increasingly viewed as heterogeneous with between 6 and 11 mesenchymal populations identified across health and lung disease to date. DNA methylation has been associated with different lung fibroblast populations in health and with alterations in lung disease, but to varying extents. In this review, we will discuss lung fibroblast heterogeneity and the evidence for a contribution from DNA methylation to defining cell populations and alterations in disease.


Assuntos
Metilação de DNA , Fibrose Pulmonar/patologia , Asma/metabolismo , Asma/patologia , Fibrose Cística/metabolismo , Fibrose Cística/patologia , Matriz Extracelular/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Fenótipo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Fibrose Pulmonar/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/patologia
13.
Cells ; 10(8)2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34440807

RESUMO

Allergic asthma is a chronic and heterogeneous pulmonary disease in which platelets can be activated in an IgE-mediated pathway and migrate to the airways via CCR3-dependent mechanism. Activated platelets secrete IL-33, Dkk-1, and 5-HT or overexpress CD40L on the cell surfaces to induce Type 2 immune response or interact with TSLP-stimulated myeloid DCs through the RANK-RANKL-dependent manner to tune the sensitization stage of allergic asthma. Additionally, platelets can mediate leukocyte infiltration into the lungs through P-selectin-mediated interaction with PSGL-1 and upregulate integrin expression in activated leukocytes. Platelets release myl9/12 protein to recruit CD4+CD69+ T cells to the inflammatory sites. Bronchoactive mediators, enzymes, and ROS released by platelets also contribute to the pathogenesis of allergic asthma. GM-CSF from platelets inhibits the eosinophil apoptosis, thus enhancing the chronic inflammatory response and tissue damage. Functional alterations in the mitochondria of platelets in allergic asthmatic lungs further confirm the role of platelets in the inflammation response. Given the extensive roles of platelets in allergic asthma, antiplatelet drugs have been tested in some allergic asthma patients. Therefore, elucidating the role of platelets in the pathogenesis of allergic asthma will provide us with new insights and lead to novel approaches in the treatment of this disease.


Assuntos
Asma/patologia , Plaquetas/metabolismo , Imunidade Adaptativa , Asma/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/metabolismo , Integrinas/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Selectina-P/metabolismo , Espécies Reativas de Oxigênio/metabolismo
14.
Cells ; 10(7)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34359876

RESUMO

The lung extracellular matrix (ECM) plays a key role in the normal architecture of the lung, from embryonic lung development to mechanical stability and elastic recoil of the breathing adult lung. The lung ECM can modulate the biophysical environment of cells through ECM stiffness, porosity, topography and insolubility. In a reciprocal interaction, lung ECM dynamics result from the synthesis, degradation and organization of ECM components by the surrounding structural and immune cells. Repeated lung injury and repair can trigger a vicious cycle of aberrant ECM protein deposition, accompanied by elevated ECM stiffness, which has a lasting effect on cell and tissue function. The processes governing the resolution of injury repair are regulated by several pathways; however, in chronic lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary disease (IPF) these processes are compromised, resulting in impaired cell function and ECM remodeling. Current estimates show that more than 60% of the human coding transcripts are regulated by miRNAs. miRNAs are small non-coding RNAs that regulate gene expressions and modulate cellular functions. This review is focused on the current knowledge of miRNAs in regulating ECM synthesis, degradation and topography by cells and their dysregulation in asthma, COPD and IPF.


Assuntos
Asma/genética , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Fibrose Pulmonar Idiopática/genética , MicroRNAs/genética , Doença Pulmonar Obstrutiva Crônica/genética , Asma/metabolismo , Asma/patologia , Colágeno/genética , Colágeno/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Matriz Extracelular/química , Fibroblastos/patologia , Fibronectinas/genética , Fibronectinas/metabolismo , Regulação da Expressão Gênica , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Laminina/genética , Laminina/metabolismo , Pulmão/metabolismo , Pulmão/patologia , MicroRNAs/classificação , MicroRNAs/metabolismo , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Transdução de Sinais , Sindecanas/genética , Sindecanas/metabolismo , Versicanas/genética , Versicanas/metabolismo
15.
Respir Investig ; 59(5): 651-660, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34244107

RESUMO

BACKGROUND: The role of the inflammatory secretory protein TNF-LIGHT (LIGHT) in the molecular mechanisms underlying persistent airflow limitation (PAL) in asthma remains unclear. We hypothesized that high airway LIGHT expression may be a feature of asthma with PAL associated with specific expression patterns of inflammatory molecules. METHODS: This hypothesis was tested in 16 patients with asthma on inhaled corticosteroid treatment. Induced sputum was collected, the expression of LIGHT and 3-nitrotyrosine (NT), which reflects the footprint of reactive nitrogen species content, was measured using immunohistochemical staining, and the inflammatory molecules in the sputum supernatant were analyzed using a magnetic bead array. RESULTS: LIGHT staining in the cells had a significantly higher intensity in participants with PAL than in participants without PAL (47.9 × 104/ml vs. 5.4 × 104/ml; p < 0.05). The array analysis indicated that IL-8, IL-19, matrix metalloproteinase 2, and osteopontin, were associated with high LIGHT immunoreactivity. The fractionation of 3-NT-positive cells was positively correlated with that of LIGHT-positive cells (r = 0.57, p < 0.05) and the TGF-ß1 level (r = 0.61, p < 0.05). LIGHT- and 3-NT-positive cells showed significant positive correlation with the differential cell counts of neutrophils, macrophages, and eosinophils in the induced sputum. Intense immunoreactivities of LIGHT (r = -0.54, p < 0.05) and 3-NT (r = -0.42, p = 0.1) were negatively associated with decreased forced expiratory volume in 1/forced vital capacity ratio. CONCLUSIONS: The findings suggest that LIGHT is a key component in the association between airway inflammation and airflow limitation in patients with asthma, and its expression may be persistently correlated with the abundance of inflammatory cells and inflammatory and profibrogenic radical/molecules.


Assuntos
Asma , Metaloproteinase 2 da Matriz , Asma/metabolismo , Eosinófilos , Volume Expiratório Forçado , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Sistema Respiratório , Escarro , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral
16.
Sci Rep ; 11(1): 13823, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226570

RESUMO

The prevalence of asthma is considerably high among women of childbearing age. Most asthmatic women also often have other atopic disorders. Therefore, the differentiation between patients with atopic diseases without asthma and asthmatics with coexisting diseases is essential to avoid underdiagnosis of asthma and to design strategies to reduce symptom severity and improve quality of life of patients. Hence, we aimed for the first time to conduct an analysis of volatile organic compounds in exhaled breath of women of childbearing age as a new approach to discriminate between asthmatics with other coexisting atopic diseases and non-asthmatics (with or without atopic diseases), which could be a helpful tool for more accurate asthma detection and monitoring using a noninvasive technique in the near future. In this study, exhaled air samples of 336 women (training set (n = 211) and validation set (n = 125)) were collected and analyzed by thermal desorption coupled with gas chromatography-mass spectrometry. ASCA (ANOVA (analysis of variance) simultaneous component analysis) and LASSO + LS (least absolute shrinkage and selection operator + logistic regression) were employed for data analysis. Fifteen statistically significant models (p-value < 0.05 in permutation tests) that discriminated asthma with other coexisting atopic diseases in women of childbearing age were generated. Acetone, 2-ethyl-1-hexanol and a tetrahydroisoquinoline derivative were selected as discriminants of asthma with other coexisting atopic diseases. In addition, carbon disulfide, a tetrahydroisoquinoline derivative, 2-ethyl-1-hexanol and decane discriminated asthma disease among patients with other atopic disorders. Results of this study indicate that refined metabolomic analysis of exhaled breath allows asthma with other coexisting atopic diseases discrimination in women of reproductive age.


Assuntos
Asma/diagnóstico , Expiração , Hipersensibilidade Imediata/diagnóstico , Compostos Orgânicos Voláteis/isolamento & purificação , Adulto , Asma/metabolismo , Asma/patologia , Testes Respiratórios , Diagnóstico Diferencial , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Hipersensibilidade Imediata/metabolismo , Hipersensibilidade Imediata/patologia , Masculino , Qualidade de Vida , Compostos Orgânicos Voláteis/metabolismo
18.
Mol Immunol ; 138: 31-37, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34332183

RESUMO

NOVA1 (neuro-oncological ventral antigen 1) is a neuron specific RNA binding protein, belonging to the Nova family, which plays an important role in various diseases. However, the role of NOVA1 in childhood asthma remains unclear. This study was aimed to investigate the role of NOVA1 in TGF-ß1-induced ASMCs proliferation and migration as well as the potential mechanisms. In our study, the NOVA1 expression was significantly increased in asthmatic tissues and TGF-ß1-induced ASMCs. Inhibition of NOVA1 significantly inhibited TGF-ß1-induced ASMCs cell proliferation and migration, and alleviates TGF-ß1-induced inflammation. NOVA1 positively regulated the PTBP1 expression and si-NOVA1 inhibited the activation of PTEN/AKT signal pathway. Importantly, the overexpression of PTBP1 partially reversed the effect of NOVA1 on cell viability, migration, inflammation and the activation of PTEN/AKT signal pathway. Generally, our study demonstrated that si-NOVA1 inhibited TGF-ß1-induced inflammation and migration in ASMCs through PTBP1/PTEN/AKT pathway. Therefore, inhibition of NOVA1 may be useful for the prevention or treatment of asthma airway remodeling.


Assuntos
Asma/patologia , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais/fisiologia , Adolescente , Remodelação das Vias Aéreas , Asma/metabolismo , Asma/fisiopatologia , Movimento Celular/fisiologia , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Miócitos de Músculo Liso/patologia , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
19.
Life Sci ; 282: 119792, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34229006

RESUMO

AIMS: Exercise training increases circulating and tissue levels of angiotensin-(1-7) [Ang-(1-7)], which was shown to attenuate inflammation and fibrosis in different diseases. Here, we evaluated whether Ang-(1-7)/Mas receptor is involved in the beneficial effects of aerobic training in a chronic model of asthma. MATERIAL AND METHODS: BALB/c mice were subjected to a protocol of asthma induced by ovalbumin sensitization (OVA; 4 i.p. injections) and OVA challenge (3 times/week for 4 weeks). Simultaneously to the challenge period, part of the animals was continuously treated with Mas receptor antagonist (A779, 1 µg/h; for 28 days) and trained in a treadmill (TRE; 60% of the maximal capacity, 1 h/day, 5 days/week during 4 weeks). PGC1-α mRNA expression (qRT-PCR), plasma IgE and lung cytokines (ELISA), inflammatory cells infiltration (enzymatic activity assay) and airway remodeling (by histology) were evaluated. KEY FINDINGS: Blocking the Mas receptor with A779 increased IgE and IL-13 levels and prevented the reduction in extracellular matrix deposition in airways in OVA-TRE mice. Mas receptor blockade prevented the reduction of myeloperoxidase activity, as well as, prevented exercise-induced IL-10 increase. These data show that activation of Ang-(1-7)/Mas receptor pathway is involved in the anti-inflammatory and anti-fibrotic effects of aerobic training in an experimental model of chronic asthma. SIGNIFICANCE: Our results support exercise training as a non-pharmacological tool to defeat lung remodeling induced by chronic pulmonary inflammation. Further, our result also supports development of new therapy based on Ang-(1-7) or Mas agonists as important tool for asthma treatment in those patients that cannot perform aerobic training.


Assuntos
Angiotensina I/metabolismo , Asma/terapia , Fragmentos de Peptídeos/metabolismo , Pneumonia/terapia , Angiotensina I/sangue , Animais , Asma/sangue , Asma/metabolismo , Modelos Animais de Doenças , Terapia por Exercício , Masculino , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/sangue , Pneumonia/sangue , Pneumonia/metabolismo
20.
Mayo Clin Proc ; 96(7): 1955-1969, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34218868

RESUMO

There are marked sex differences in asthma prevalence and severity. Sex hormones play a central role in these sex biases and directly interact with multiple key cells involved in the pathogenesis of asthma. Here we review the known effects of estrogen, progesterone, and testosterone on airway epithelial cells, airway smooth muscle cells, the mononuclear phagocyte system, innate lymphoid cells, eosinophils, mast cells, T cells, and B cells, all in the context of asthma. Furthermore, we explore unresolved clinical questions, such as the role of sex hormones in the link between asthma and obesity.


Assuntos
Asma , Hormônios Esteroides Gonadais/metabolismo , Mucosa Respiratória/metabolismo , Asma/imunologia , Asma/metabolismo , Asma/patologia , Humanos , Imunidade Celular , Imunidade Inata , Fatores Sexuais
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