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OBJECTIVE: Asthma stands as one of the most prevalent chronic respiratory conditions in children, with its pathogenesis tied to the actived antigen presentation by dendritic cells (DCs) and the imbalance within T cell subgroups. This study seeks to investigate the role of the transcription factor EB (TFEB) in modulating the antigen presentation process of DCs and its impact on the differentiation of T cell subgroups. METHODS: Bone marrow dendritic cells (BMDCs) were activated using house dust mites (HDM) and underwent RNA sequencing (RNA-seq) to pinpoint differentially expressed genes. TFEB mRNA expression levels were assessed in the peripheral blood mononuclear cells (PBMCs) of both healthy children and those diagnosed with asthma. In an asthma mouse model induced by HDM, the TFEB expression in lung tissue DCs was evaluated. Further experiments involved LV-shTFEB BMDCs co-cultured with T cells to explore the influence of TFEB on DCs' antigen presentation, T cell subset differentiation, and cytokine production. RESULTS: Transcriptomic sequencing identified TFEB as a significantly differentially expressed gene associated with immune system pathways and antigen presentation. Notably, TFEB expression showed a significant increase in the PBMCs of children diagnosed with asthma compared to healthy counterparts. Moreover, TFEB exhibited heightened expression in lung tissue DCs of HDM-induced asthmatic mice and HDM-stimulated BMDCs. Silencing TFEB resulted in the downregulation of MHC II, CD80, CD86, and CD40 on DCs. This action reinstated the equilibrium among Th1/Th2 and Th17/Treg cell subgroups, suppressed the expression of pro-inflammatory cytokines like IL-4, IL-5, IL-13, and IL-17, while augmenting the expression of the anti-inflammatory cytokine IL-10. CONCLUSION: TFEB might have a vital role in asthma's development by impacting the antigen presentation of DCs, regulating T cell subgroup differentiation, and influencing cytokine secretion. Its involvement could be pivotal in rebalancing the immune system in asthma. These research findings could potentially unveil novel therapeutic avenues for treating asthma.
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Apresentação de Antígeno , Asma , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Células Dendríticas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Asma/imunologia , Asma/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Camundongos , Apresentação de Antígeno/imunologia , Humanos , Criança , Feminino , Masculino , Células Cultivadas , Camundongos Endogâmicos BALB CRESUMO
OBJECTIVE: This study aims to investigate the role of Acyl-CoA synthetase 4 (ACSL4) in mediating mitochondrial fatty acid metabolism and dendritic cell (DC) antigen presentation in the immune response associated with asthma. METHODS: RNA sequencing was employed to identify key genes associated with mitochondrial function and fatty acid metabolism in DCs. ELISA was employed to assess the levels of fatty acid metabolism in DCs. Mitochondrial morphology was evaluated using laser confocal microscopy, structured illumination microscopy, and transmission electron microscopy. Flow cytometry and immunofluorescence were utilized to detect changes in mitochondrial superoxide generation in DCs, followed by immunofluorescence co-localization analysis of ACSL4 and the mitochondrial marker protein COXIV. Subsequently, pathological changes and immune responses in mouse lung tissue were observed. ELISA was conducted to measure the levels of fatty acid metabolism in lung tissue DCs. qRT-PCR and western blotting were employed to respectively assess the expression levels of mitochondrial-associated genes (ATP5F1A, VDAC1, COXIV, TFAM, iNOS) and proteins (ATP5F1A, VDAC1, COXIV, TOMM20, iNOS) in lung tissue DCs. Flow cytometry was utilized to analyze changes in the expression of surface antigens presented by DCs in lung tissue, specifically the MHCII molecule and the co-stimulatory molecules CD80/86. RESULTS: The sequencing results reveal that ACSL4 is a crucial gene regulating mitochondrial function and fatty acid metabolism in DCs. Inhibiting ACSL4 reduces the levels of fatty acid oxidases in DCs, increases arachidonic acid levels, and decreases A-CoA synthesis. Simultaneously, ACSL4 inhibition leads to an increase in mitochondrial superoxide production (MitoSOX) in DCs, causing mitochondrial rupture, vacuolization, and sparse mitochondrial cristae. In mice, ACSL4 inhibition exacerbates pulmonary pathological changes and immune responses, reducing the fatty acid metabolism levels within lung tissue DCs and the expression of mitochondria-associated genes and proteins. This inhibition induces an increase in the expression of MHCII antigen presentation molecules and co-stimulatory molecules CD80/86 in DCs. CONCLUSIONS: The research findings indicate that ACSL4-mediated mitochondrial fatty acid metabolism and dendritic cell antigen presentation play a crucial regulatory role in the immune response of asthma. This discovery holds promise for enhancing our understanding of the mechanisms underlying asthma pathogenesis and potentially identifying novel targets for its prevention and treatment.
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Apresentação de Antígeno , Asma , Coenzima A Ligases , Células Dendríticas , Ácidos Graxos , Mitocôndrias , Animais , Feminino , Camundongos , Asma/imunologia , Asma/metabolismo , Coenzima A Ligases/metabolismo , Coenzima A Ligases/genética , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Ácidos Graxos/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Superóxidos/metabolismoRESUMO
BACKGROUND: Pediatric bronchiectasis is a common respiratory disease in children. The use of video-assisted thoracoscopic surgery (VATS) for its treatment remains controversial. OBJECTIVES: The objective of our study was to compare and analyze the clinical efficacy of thoracoscopic surgery and thoracotomy in the treatment of pediatric bronchiectasis and summarize the surgical treatment experience of VATS in children with bronchiectasis. DESIGN: Retrospective single-center cohort study. METHODS: A retrospective analysis was conducted on the clinical data of 46 pediatric patients who underwent surgery with bronchiectasis at the Children's Hospital of Chongqing Medical University from May 2015 to May 2023. The patients were divided into two groups: the VATS group (25 cases) and the thoracotomy group (21 cases). Comparative analysis was performed on various parameters including basic clinical data, surgical methods, operation time, intraoperative blood loss, transfusion status, postoperative pain, postoperative mechanical ventilation time, chest tube drainage time, length of hospital stay, incidence of complications, and follow-up information. RESULTS: There were no statistically significant differences between the two groups of patients in terms of age, weight, gender, etiology, duration of symptoms, site of onset, and comorbidities (p > 0.05). The operation time in the VATS group was longer than that in the thoracotomy group (p < 0.001). However, the VATS group had better outcomes in terms of intraoperative blood loss, transfusion status, postoperative pain, postoperative mechanical ventilation time, chest tube drainage time, and length of hospital stay (p < 0.05). The incidence of postoperative complications in the VATS group was lower than that in the thoracotomy group, although the difference was not statistically significant (p = 0.152). Follow-up data showed no statistically significant difference in the surgical treatment outcomes between the two groups (p = 0.493). CONCLUSION: The incidence of complications and mortality in surgical treatment of bronchiectasis is acceptable. Compared with thoracotomy surgery, VATS has advantages such as smaller trauma, less pain, faster recovery, and fewer complications. For suitable pediatric patients with bronchiectasis, VATS is a safe and effective surgical method.
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Bronquiectasia , Cirurgia Torácica Vídeoassistida , Humanos , Criança , Cirurgia Torácica Vídeoassistida/efeitos adversos , Estudos Retrospectivos , Estudos de Coortes , Perda Sanguínea Cirúrgica , Bronquiectasia/cirurgia , Dor Pós-Operatória/etiologia , Tempo de Internação , FibroseRESUMO
Objective: This study aimed to investigate the role of pyroptosis in alveolar macrophages regarding the immune microenvironment of acute respiratory distress syndrome (ARDS) and its prognosis. Methods: ARDS Microarray data were downloaded from Gene Expression Omnibus (GEO). Support vector machine (SVM) and random forest (RF) models were applied to identify hub pyroptosis-related genes (PRGs) with prognostic significance in ARDS. RT-PCR was used to detect the relative expression of PRGs mRNA in alveolar macrophages of ARDS mice. Consensus clustering analysis was conducted based on the expression of the PRGs to identify pyroptosis modification patterns. Bioinformatic algorithms were used to study the immune traits and biological functions of the pyroptosis patterns. Finally, protein-protein interaction (PPI) networks were established to identify hub regulatory proteins with implications for the pyroptosis patterns. Results: In our study, a total of 12 PRGs with differential expression were obtained. Four hub PRGs, including GPX4, IL6, IL18 and NLRP3, were identified and proven to be predictive of ventilator-free days (VFDS) in ARDS patients. The AUC values of the 4 PRGs were 0.911 (GPX4), 0.879 (IL18), 0.851 (IL6) and 0.841 (NLRP3), respectively. In ARDS mice, GPX4 mRNA decreased significantly, while IL6, IL18, and NLRP3 mRNA increased. Functional analysis revealed that IL6 had the strongest positive correlation with the CCR pathway, while GPX4 exhibited the strongest negative correlation with the T co-inhibition pathway. Based on the expression of the 4 PRGs, three pyroptosis modification patterns representing different immune states were obtained, and pattern C might represent immune storm. Conclusion: The results showed that pyroptosis plays an important regulatory role in the immune microenvironment of ARDS. This finding provides new insights into the pathogenesis, diagnosis, and treatment of ARDS.
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Acute lung injury (ALI) is a common clinical syndrome in the cardiac intensive care unit with a high mortality rate. Inflammation and oxidative stress have been reported to play a crucial role in the development of ALI. Previous studies have shown that human umbilical cord mesenchymal stem cells (hucMSCs) have anti-inflammatory and antioxidative effects in various diseases. However, the anti-inflammatory and antioxidative effects of the hucMSC conditioned medium (CM) on LPS-induced ALI remain unclear. Therefore, in this study, we assessed whether the hucMSC conditioned medium could attenuate LPS-induced ALI and the underlying mechanisms. Mice were randomly divided into four groups: the control group, PBS group, LPS+PBS group, and LPS+CM group. The lung histopathology and bronchoalveolar lavage fluid (BALF) were analyzed after intervention. The Nrf2/NF-κB signaling pathway and its downstream target genes were tested, and the cytokines and growth factors in CM were also measured. The results showed that CM significantly attenuated the histological alterations; decreased the wet/dry weight ratio; reduced the levels of MPO, MDA and ROS; increased SOD and GSH activity; and downregulated the level of proinflammatory cytokines such as IL-1ß, IL-6, and TNF-α. Furthermore, CM promoted the expression of Nrf2 and its target genes NQ01, HO-1, and GCLC and inhibited the expression of NF-κB and its target genes IL-6, IL-1ß, and TNF-α. These effects may be closely related to the large amounts of cytokines and growth factors in the CM. In conclusion, our results demonstrated that CM could attenuate LPS-induced ALI, probably due to inhibition of inflammation and oxidative stress via the Nrf2/NF-κB signaling pathway.
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Lesão Pulmonar Aguda/prevenção & controle , Antioxidantes/farmacologia , Meios de Cultivo Condicionados/farmacologia , Pulmão/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pneumonia/prevenção & controle , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Células Cultivadas , Meios de Cultivo Condicionados/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Lipopolissacarídeos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Pneumonia/patologia , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Edema Pulmonar/prevenção & controle , Espécies Reativas de Oxigênio/metabolismo , Transdução de SinaisRESUMO
OBJECTIVE: Regulatory T cells (Tregs) and T helper (Th) 17 cells are two subsets of CD4 + T cells with opposite effects which play a crucial role in the pathogenesis of lung injury. In this study, we aim to investigate the protective effect of Pseudomonas aeruginosa outer membrane vesicles (OMVs) preconditioning on lung ischemia-reperfusion (I/R) injury and potential mechanisms. METHODS: Pathogen-free C57BL/6 mice were randomly divided into four groups: control, Control + OMVs, I/R and I/R + OMVs groups. Bronchoalveolar lavage fluid (BALF), serum, and lung tissues were collected and analyzed for pathophysiology and immune mechanism. RESULTS: OMVs not only attenuated tissue injury and respiratory physiologic function but also mediated the downregulation of lung wet-to-dry weight ratio and the reduction of total protein concentration. The numbers of total cells, macrophages, neutrophils, and lymphocytes were markedly decreased in the I/R mice following OMVs preconditioning. OMVs also decreased inflammatory cytokines associated with CD4 + T cells in both BALF and serum. In addition, the level of Tregs and its transcription factor forkhead box P3 (Foxp3) were significantly increased, while the level of Th17 cells and its transcription factor retinoid-related orphan receptor γ (RORγt) were significantly decreased following OMVs preconditioning. In the process of exploring the underlying protection mechanisms of OMVs, we found that OMVs preconditioning significantly reduced protein expression of Toll-like receptor 4 (TLR4), which in turn not only inactivated myeloid differentiation factor 88 (MyD88) and Phosphorylated nuclear factor kappa B (p-NF-κB), but also simultaneously increased the levels of T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3). CONCLUSIONS: These results suggest that OMVs preconditioning may ameliorate lung I/R injury by regulating the balance of Tregs and Th17 cells through Tim-3 and TLR4/NF-κB pathway.
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Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Pulmão/patologia , Subunidade p50 de NF-kappa B/metabolismo , Pseudomonas aeruginosa , Traumatismo por Reperfusão/fisiopatologia , Linfócitos T Reguladores/imunologia , Receptor 4 Toll-Like/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Linfócitos T CD4-Positivos/citologia , Citocinas/metabolismo , Humanos , Lipopolissacarídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Células Th17/metabolismoRESUMO
GITRL/GITR signaling pathway plays an important role in allergy, inflammation, transplantation and autoimmunity. However, its role in asthma remains unclear. Thus, the present study aimed to investigate changes in this pathway and observe the therapeutic effect of its blocking on asthma. By using house dust mite-induced asthma model, changes of GITRL/GITR and its downstream molecules MAPKs (e.g., p38 MAPK, JNK and Erk) and NF-κB were observed. After that, GITRL in lung of mice was knocked down by recombinant adeno-associated virus to observe the impact on its downstream molecules and assess the therapeutic effect on asthma. These results showed that GITRL/GITR and its downstream molecules MAPKs/NF-κB were activated in asthmatic mice. This activation was suppressed after GITRL knockdown, and allergic airway inflammation and airway hyperresponsiveness were alleviated. These results demonstrate that GITRL/GITR-MAPKs/NF-κB signaling pathway participates in the pathogenesis of asthma. Blockade of GITRL/GITR signaling pathway exhibits protective effects in a mouse model of house dust mite-induced allergic asthma.
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Asma/imunologia , Proteína Relacionada a TNFR Induzida por Glucocorticoide/imunologia , Hipersensibilidade/imunologia , Proteínas Quinases Ativadas por Mitógeno/imunologia , NF-kappa B/imunologia , Pyroglyphidae/imunologia , Fatores de Necrose Tumoral/imunologia , Animais , Dermatophagoides pteronyssinus/imunologia , Modelos Animais de Doenças , Feminino , Inflamação/imunologia , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Hipersensibilidade Respiratória/imunologia , Transdução de Sinais/imunologiaRESUMO
BACKGROUND: Glucocorticoid-induced tumor necrosis factor receptor family-related protein ligand (GITRL) plays an important role in tumors, autoimmunity and inflammation. However, GITRL is not known to modulate the pathogenesis of allergic asthma. In this study, we investigated whether regulating GITRL expressed on dendritic cells (DCs) can prevent asthma and to elucidate its mechanism of action. METHODS: In vivo, the role of GITRL in modulating house dust mite (HDM)-induced asthma was assessed in adeno-associated virus (AAV)-shGITRL mice. In vitro, the role of GITRL expression by DCs was evaluated in LV-shGITRL bone marrow dendritic cells (BMDCs) under HDM stimulation. And the direct effect of GITRL was observed by stimulating splenocytes with GITRL protein. The effect of regulating GITRL on CD4+ T cell differentiation was detected. Further, GITRL mRNA in the peripheral blood of asthmatic children was tested. RESULTS: GITRL was significantly increased in HDM-challenged mice. In GITRL knockdown mice, allergen-induced airway inflammation, serum total IgE levels and airway hyperresponsiveness (AHR) were reduced. In vitro, GITRL expression on BMDCs was increased after HDM stimulation. Further, knocking down GITRL on DCs partially restored the balance of Th1/Th2 and Th17/Treg cells. Moreover, GITRL stimulation in vitro inhibited Treg cell differentiation and promoted Th2 and Th17 cell differentiation. Similarly, GITRL mRNA expression was increased in the peripheral blood from asthmatic children. CONCLUSIONS: This study identified a novel role for GITRL expressed by DCs as a positive regulator of CD4+ T cells responses in asthma, which implicates that GITRL inhibitors may be a potential immunotherapy for asthma.
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Asma/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Células Dendríticas/metabolismo , Pyroglyphidae , Hipersensibilidade Respiratória/metabolismo , Fatores de Necrose Tumoral/biossíntese , Animais , Asma/sangue , Diferenciação Celular/fisiologia , Criança , Técnicas de Cocultura , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Hipersensibilidade Respiratória/sangue , Fatores de Necrose Tumoral/sangueRESUMO
BACKGROUND: The purpose of our study was to assess the frequency of occult foreign body aspiration (FBA) and to evaluate the diagnostic difficulties and therapeutic methods for these patients. METHODS: Between May 2000 and May 2020, 3557 patients with the diagnosis of FBA were treated in our department. Thirty-five patients with occult FBA were included in this study. A retrospective analysis of medical records was performed. RESULTS: Twenty-three male patients (65.7%) and 12 female patients (34.3%) were hospitalized due to occult FBA. The average age was 3.60 years (range 9 months-12 years). Most of the patients were younger than 3 years old (n = 25, 71.4%). Coughing (n = 35, 100%) and wheezing (n = 18, 51.4%) were the main symptoms and signs. All the patients were found to have a FBA under the fiberoptic bronchoscope. The most common organic foreign bodies were peanuts (n = 10) and the most common inorganic foreign bodies were pen caps (n = 5). The extraction of foreign bodies under rigid bronchoscopy was applied successfully in 34 patients. Only one patient needed a surgical intervention. CONCLUSIONS: Occult FBA should always be considered in the differential diagnosis of chronic or recurrent respiratory diseases that are poorly explained, even in the absence of a previous history of aspiration.
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Brônquios/lesões , Broncoscopia/métodos , Corpos Estranhos/diagnóstico , Criança , Pré-Escolar , China/epidemiologia , Tosse/etiologia , Diagnóstico Diferencial , Feminino , Corpos Estranhos/epidemiologia , Corpos Estranhos/terapia , Humanos , Lactente , Masculino , Aspiração Respiratória , Sons Respiratórios/etiologia , Estudos RetrospectivosRESUMO
The mechanism(s) underlying endotoxin tolerance in asthma remain elusive. As the endotoxin lipopolysaccharide (LPS) affects the expression of the regulatory T-cell (Treg)-suppressive glucocorticoid-induced tumor necrosis factor receptor ligand (GITRL) on antigen-presenting dendritic cells (DCs), we hypothesized that LPS-induced changes in DC GITRL expression may impact Treg-mediated T-helper (Th) cell suppression and the induction of endotoxin tolerance. Here, we propose a novel mechanism by which low-dose LPS inhalation in neonatal mice induces endotoxin tolerance, thereby offering protection from later asthma development. Three-day old wild-type and Toll-like receptor 4 (TLR4)-deficient neonatal mice were exposed to low-dose LPS (1 µg) intranasally for 10 consecutive days prior to ovalbumin (OVA)-induced asthma to better understand the tolerogenic mechanism(s) of low-dose LPS pre-exposure. In vivo findings were validated using in vitro co-culturing studies of primary CD11c+ DCs and CD4+ T-cells with or without low-dose LPS pre-exposure before OVA stimulation. Low-dose LPS pre-exposure upregulated the Treg response and downregulated pathogenic Th2 and Th17 responses through promoting apoptosis of Th2 and Th17 cells. Low-dose LPS pre-exposure downregulated DC GITRL expression and T-cell GITR expression. Artificial DC GITRL expression abrogated the tolerogenic Treg-skewing effect of low-dose LPS pre-exposure. Low-dose LPS pre-exposure inhibited TRIF/IRF3/IFNß signaling and upregulated expression of tolerogenic TRIF/IRF3/IFNß negative regulators in a TLR4-dependent manner. This tolerogenic DC GITRL downregulation was attributable to TRIF/IRF3/IFNß signaling inhibition. Low-dose LPS pre-exposure produces tolerogenic Treg skewing in neonatal asthmatic mice, a phenomenon attributable to TLR4-dependent TRIF/IRF3/IFNß-mediated DC GITRL downregulation.
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Asma/imunologia , Tolerância Imunológica/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Asma/etiologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta Imunológica , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Relacionada a TNFR Induzida por Glucocorticoide/biossíntese , Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética , Humanos , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/farmacologia , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Transdução de Sinais/efeitos dos fármacos , Organismos Livres de Patógenos Específicos , Células Th17/efeitos dos fármacos , Células Th17/patologia , Células Th2/imunologia , Células Th2/patologia , Receptor 4 Toll-Like/deficiência , Fatores de Necrose Tumoral/biossíntese , Fatores de Necrose Tumoral/genéticaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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BACKGROUND: Multiple randomized controlled trials have assessed hand-foot skin reaction (HFSR) caused by vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). OBJECTIVE: We performed a meta-analysis to determine the incidence and the relative risk (RR) of HFSR associated with these agents. METHODS: Databases were searched for relevant studies. Statistical analyses were conducted to calculate the summary incidences, RR, and 95% confidence intervals (CIs) by using random-effects or fixed-effects models according to the heterogeneity of the included studies. RESULTS: A total of 24,956 patients from 57 studies were included. The overall incidence of all-grade and high-grade HFSR associated with VEGFR-TKIs was 35.0% (95% CI, 28.6%-41.6%) and 9.7% (95% CI, 7.3%-12.3%), respectively. The use of VEGFR-TKIs significantly increased the risk of developing all-grade (RR, 5.09; 95% CI, 3.52-7.35; P < .001) and high-grade (RR, 9.42; 95% CI, 5.59-15.90; P < .001) HFSR. Subgroup analyses revealed that the risk of HFSR was significantly increased according to tumor type, VEGFR-TKI, trial phase, treatment regimen, and control therapy. No evidence of publication bias was observed. LIMITATION: High heterogeneity in most studies. CONCLUSION: High risk of HFSR is prone to develop in cancer patients receiving VEGFR-TKIs.
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Inibidores da Angiogênese/efeitos adversos , Síndrome Mão-Pé/epidemiologia , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores da Angiogênese/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Síndrome Mão-Pé/diagnóstico , Síndrome Mão-Pé/etiologia , Síndrome Mão-Pé/prevenção & controle , Humanos , Incidência , Metanálise em Rede , Inibidores de Proteínas Quinases/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Medição de Risco/estatística & dados numéricos , Índice de Gravidade de Doença , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
The PI3K/Akt/mTOR pathway is thought to be closely associated with airway inflammation and is regulated by various upstream proteins. Brahma-related gene 1 (Brg1) plays an important role in chromatin remodeling and facilitates recruitment of essential transcription factors, leading to regulation of gene expression. Thus, the present study aimed at evaluating the anti-inflammatory role of Brg1 on house dust mite (HDM)-induced asthma through regulating the PI3K/Akt/mTOR pathway. The Brgfl/fl mice were crossbred with the SFTPC-Cre mice to generate bronchial epithelial cell specific Brg1 knockout mice, and LY294002 was used to inhibit PI3K. Western blot, immunofluorescence, immunoprecipitation, and immunohistochemical staining were used to detect the expression of proteins. An increase in Brg1 and a decrease in the PI3K/Akt/mTOR pathway activity were detected in asthmatic mice, but not in control mice. When Brg1 was knocked out, the asthma severity was ameliorated and the PI3K/Akt/mTOR pathway was activated. However, this protective effect could be suppressed by LY294002. Additionally, we observed that Brg1 was co-localized and co-immunoprecipitated with PI3K, using immunofluorescence and immunoprecipitation assays. Our results suggest that Brg1 might play an essential role in maintaining airway inflammation and affect the PI3K/Akt/mTOR pathway in asthma.
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Asma/imunologia , DNA Helicases/imunologia , Proteínas Nucleares/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Transdução de Sinais , Serina-Treonina Quinases TOR/imunologia , Fatores de Transcrição/imunologia , Animais , Asma/patologia , Feminino , Inflamação/imunologia , Inflamação/patologia , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND It is generally believed that endotoxin exposure exacerbates risk of developing asthmatic symptoms. However, recent studies have indicated that prior bacterial exposure may prevent future symptoms of asthma. Here, we evaluated the influence of pre-exposure to different concentrations of lipopolysaccharide (LPS) to subsequent ovalbumin (OVA) allergen sensitization and challenge. MATERIAL AND METHODS Four-week-old Balb/c mice were treated intranasally with varying concentrations of LPS (1 ug, 10 ug, and 100 ug) or sterile PBS for 10 days, then 2 weeks later they were exposed to OVA. Both the molecular and functional airway responses to OVA administration were assessed following prior exposure to different doses of LPS or controls. Additionally, the Th1/Th2 and Treg/Th17 balance was measured. RESULTS Airway responsiveness and immune cell recruitment in the bronchoalveolar lavage (BALF) were decreased in animals exposed to a low dose of LPS (1 ug) treatment compared with the asthma group. Moderate-dose (10 ug) and high-dose (100 ug) LPS administration showed no differences from controls. Further, low-dose LPS (1 ug) exposure was associated with increased Th1 cytokines, T-bet, Treg cytokine (IL-10, TGF-ß), and Foxp3 expression, but decreased Th2 cytokines (IL-4,5,13), GATA3, Th17, and ROR-gt expression compared with the asthma group. Finally, higher numbers of CD4+CD25+Foxp3+Treg cells, and CD4+INF-γ+T cells, and lower CD4+IL-4+T cells and CD4+IL-17+T cells were observed in the low-dose LPS-treated groups compared to controls. CONCLUSIONS Our findings suggest that prior exposure to low doses of LPS may protect from OVA-induced airway hyperresponsiveness (AHR) and histopathologic changes through regulation of the Th1/Th2 and Treg/Th17 balance.
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Asma/tratamento farmacológico , Asma/imunologia , Lipopolissacarídeos/uso terapêutico , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos CD/metabolismo , Asma/genética , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Células , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Granulócitos/efeitos dos fármacos , Granulócitos/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/farmacologia , Pulmão/patologia , Camundongos Endogâmicos BALB C , Ovalbumina , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Hipersensibilidade Respiratória , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologiaRESUMO
BACKGROUND: Exosomes are nanovesicles originating from multivesicular bodies that have complex functions and significant therapeutic effects in many diseases. In the present study, we successfully extracted exosomes from Pseudomonas aeruginosa and assessed the effect of those exosomes on the development of the allergic response in two types of classic asthma models. METHODS: Female BALB/c mice were administrated with P. aeruginosa-derived exosomes 1 week before ovalbumin (OVA) or house dust mite (HDM) sensitization. Bronchoalveolar lavage fluid, serums and lung tissues were collected and analyzed for pathophysiology and immune responses. RESULTS: Our results demonstrated that P. aeruginosa-derived exosomes inhibited the development of airway hyper-responsiveness (AHR), peribronchial and perivascular inflammation in lung tissues and the level of serum IgE. Moreover, this protective effect was associated with an increase in the regulatory T cell (Treg) response and a concomitant decreased Th2 response. CONCLUSIONS: In conclusion, these observations demonstrated that P. aeruginosa-derived exosomes could induce protection against allergic sensitization in asthma mice, and our study provided a new insight to prevent allergic diseases.
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Asma/imunologia , Exossomos/metabolismo , Hipersensibilidade/imunologia , Pseudomonas aeruginosa/metabolismo , Linfócitos T Reguladores/imunologia , Alérgenos/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Feminino , Sistema Imunitário , Imunoglobulina E/sangue , Inflamação , Lipopolissacarídeos , Pulmão/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , OvalbuminaRESUMO
BACKGROUND/AIMS: Previous studies have shown that lipopolysaccharide (LPS) exposure may have a protective effect on asthma by reducing airway hyper-responsiveness, airway inflammation and serum IgE levels. However, there are few studies investigating the effect of LPS on mucous secretion in asthma. In this study, we evaluate the relationship between LPS pre-treatment in infant mice and airway mucus hypersecretion in an OVA (ovalbumin)-induced asthma model, and further explore the mechanisms behind this effect. METHODS: Mice were pre-treated with LPS by intranasal instillation (i.n.) from the 3rd day of life for 10 consecutive days before the OVA-induced asthma model was established. In order to detect mucus secretion, periodic acid-Schiff (PAS) staining was carried out, and the expression of Muc5ac was detected. The IL-13 levels in Bronchoalveolar lavage fluid (BALF) and lung tissue were also detected. In vitro, the expression of Muc5ac mRNA and protein was quantified in IL-13-stimulated 16HBE cells with or without LPS pre-treatment. In addition, proteins in the JAK2/STAT6 pathway, transcription factors (forkhead box transcription factor A2 (FOXA2), activation protein-1(AP-1), NF-κB), and the levels of reactive oxygen species (ROS) were also measured in vivo and in vitro. RESULTS: LPS pre-treatment reduced mucus secretion, as demonstrated by decreased PAS staining and muc5ac expression. Further exploration of the underlying mechanisms of this phenomenon revealed that LPS pre-treatment decreased the production of IL-13, IL-13 induced ROS synthesis was reduced, and the JAK2/STAT6 pathway was inhibited. Decreased stat6 increased transcription factor FOXA2, and the relatively increased FOXA2 further decreased the level of Muc5ac and mucous hypersecretion in OVA-induced asthma. CONCLUSIONS: LPS pre-treatment ameliorated mucus hypersecretion in an OVA-induced asthma model by inhibition of IL-13 production and by further inhibiting the JAK2/STAT6 pathway and ROS activity, and up-regulating expression of FOXA2.
Assuntos
Asma/induzido quimicamente , Regulação para Baixo/efeitos dos fármacos , Interleucina-13/genética , Janus Quinases/genética , Lipopolissacarídeos/farmacologia , Ovalbumina , Fator de Transcrição STAT6/genética , Administração Intranasal , Animais , Asma/imunologia , Asma/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Humanos , Interleucina-13/metabolismo , Janus Quinases/metabolismo , Lipopolissacarídeos/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Mucina-5AC/genética , Mucina-5AC/metabolismo , Muco/metabolismo , Substâncias Protetoras/farmacologia , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
The original article [1] contains an error whereby the corresponding authorship is mistakenly designated to the author Fengxia Ding.
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BACKGROUND: Renal fibrosis is characterized by infiltration of interstitial inflammatory cells and release of inflammatory mediators, activation and proliferation of fibroblasts, and deposition of excessive extracellular matrix (ECM). The aim of this study was to evaluate the effect of human umbilical cord-derived mesenchymal stem cell (hucMSC) conditioned medium (CM) on renal tubulointerstitial inflammation and fibrosis. METHODS: Renal interstitial fibrosis was prepared in vivo using the unilateral ureteral obstruction (UUO). Rats were divided randomly into Sham group, Sham group with CM, UUO group, and UUO group with CM. The effect of hucMSC-CM on kidney injury induced by UUO was assessed by detecting kidney histopathology, serum creatinine (SCr), and blood urea nitrogen (BUN). The levels of TNF-α, IL-6, and IL-1ß in serum and kidney tissues were detected by ELISA. The expression of proteins associated with fibrosis and renal inflammation was investigated using immunohistochemical staining and western blotting. The effects of hucMSC-CM on the TGF-ß1-induced epithelial-mesenchymal transition (EMT) process and on inflammation in NRK-52E cells were investigated by immunofluorescent staining, ELISA, and western blotting. RESULTS: hucMSC-CM reduced extracellular matrix deposition and inflammatory cell infiltration as well as release of inflammatory factors in UUO-induced renal fibrosis. Furthermore, hucMSC-CM markedly attenuated the EMT process and proinflammatory cytokines in rats with UUO and TGF-ß1-induced NRK-52E cells. hucMSC-CM also inhibited the TLR4/NF-κB signaling pathway in vivo and in vitro. CONCLUSIONS: Our results suggest that hucMSC-CM has protective effects against UUO-induced renal fibrosis and that hucMSC-CM exhibits its anti-inflammatory effects through inhibiting TLR4/NF-κB signaling pathway activation.
Assuntos
Meios de Cultivo Condicionados/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose/terapia , Inflamação/terapia , Células-Tronco Mesenquimais/metabolismo , Nefrite Intersticial/terapia , Injúria Renal Aguda/patologia , Animais , Nitrogênio da Ureia Sanguínea , Linhagem Celular , Creatinina/sangue , Humanos , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Células-Tronco Mesenquimais/citologia , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/sangue , Cordão Umbilical/citologia , Obstrução Ureteral/patologiaRESUMO
OBJECTIVE: To investigate the effect of Brahma-related gene 1 (Brg1) on mucus hypersecretion in the airway of asthmatic mice and explore the mechanism. METHODS: Female C57bl/6 mice aged 6-8 weeks were randomized into wild-type control group, wild-type asthma group, Brg1-/- group with Brg1 gene knockdown in type â ¡ alveolar epithelial cells, and Brg1-/-+ asthma group (n=10). The mice in asthma group and Brg1-/-+asthma group were sensitized with ovalbumin (OVA) to establish asthmatic models. PAS staining was used to determine the number of goblet cells and mucus secretion in the airway. Real-time PCR was used to detect the expression of MUC5AC mRNA in the lung tissues. The levels of mucin MUC5AC and interleukin-13 (IL-13) in the bronchoalveolar lavage fluid (BALF) were detected with ELISA and immunohistochemistry, and the expressions of STAT6 and p-STAT6 in the lung tissue were detected using Western blotting. RESULTS: Compared with the control mice, wild-type asthmatic mice showed obvious mucus hypersecretion and increased MUC5AC mRNA in the airway with significantly increased IL-13 and MUC5AC levels in the BALF and activation of p-STAT6 in the lung tissues (P < 0.05). In the transgenic mice with Brg1 gene knockdown, airway mucus secretion and MUC5AC mRNA expression was significantly reduced following OVA challenge compared with those in the wild-type asthmatic mice; IL-13 and MUC5AC levels in the BALF and p-STAT6 expression in the lung tissues were also significantly decreased in the transgenic mice (P < 0.05). CONCLUSIONS: Brg1 gene knockdown in type â ¡ alveolar epithelial cells alleviates OVA-induced airway mucus hypersecretion and reduces the expression of MUC5AC in C57bl/6 mice possibly by inhibiting STAT6 activation, suggesting the role of Brg1 in promoting asthmatic airway mucus hypersecretion.
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AIM: The growing number of patients suffering from chronic renal disease (CKD) is a challenge for the development of innovative therapies. Researchers have studied the therapeutic effects of cell therapy in acute kidney injury (AKI). However, the therapeutic effect of conditional medium (CM) in the CKD models have been rarely reported. Here, we examined the effects of umbilical cord derived-mesenchymal stem cells (hUC-MSCs) CM on renal fibrosis in a rat model of unilateral ureteral obstruction (UUO). METHODS: Animals were randomly divided into three groups: sham-operated, UUO, UUO + CM. CM was administered via the left renal artery after total ligation of the left ureter. Rats were killed after 14 days of obstruction. Histological changes and oxidative stress parameters were assessed. Western blotting and immunohistochemistry analysis were used to measure epithelial-mesenchymal transition (EMT) markers, including epithelial cadherin (E-cadherin), α-smooth muscle actin (α-SMA), tumour necrosis factor-α (TNF-α), Collagen-I, and transforming growth factor ß1 (TGF-ß1). Proliferation and apoptosis of renal tubular epithelial cells (RTEs) were also measured. RESULTS: HucMSC-CM significantly reduced the levels of malondialdehyde (MDA) and reactive oxygen species (ROS), and increased the activity of glutathione (GSH) induced by UUO. Moreover, CM significantly reduced the expression of TGF-ß1, α-SMA, TNF-α and Collagen-I in UUO kidney, promoted the proliferation of RTEs and inhibited its apoptosis. In addition, the increased expression of E-cadherin also reflects the effective improvement of renal interstitial fibrosis. CONCLUSION: This study shows that CM protects UUO-induced kidney damage and therefore could be a potential tool to prevent CKD progression.