RESUMEN
Intrauterine growth restriction (IUGR) is associated with increased perinatal mortality and morbidity, and plays an important role in the development of adult cardiovascular diseases. This study brings forward a hypothesis that Human umbilical vein endothelial cells (HUVECs) from IUGR newborns present dysfunctions and varying changes of signaling pathways as compared to the Control group. Similar pathways may also be present in pulmonary or systemic vasculatures. HUVECs were derived from newborns. There were three groups according to the different fetal origins: normal newborns (Control), IUGR from poor maternal nutrition (IUGR1), and pregnancy-induced hypertension (IUGR2). We found that IUGR-derived HUVECs showed a proliferative phenotype compared to those from normal subjects. Interestingly, two types IUGR could cause varying degrees of cellular dysfunction. Meanwhile, the Notch1 signaling pathway showed enhanced activation in the two IUGR-induced HUVECs, with subsequent activation of Akt or extracellular signal regulated protein kinases1/2 (ERK1/2). Pharmacological inhibition or gene silencing of Notch1 impeded the proliferative phenotype of IUGR-induced HUVECs and reduced the activation of ERK1/2 and AKT. In summary, elevated Notch1 levels might play a crucial role in IUGR-induced HUVECs disorders through the activation of ERK1/2 and AKT. These pathways could be potential therapeutic targets for prevention of the progression of IUGR associated diseases later in life.
Asunto(s)
Retardo del Crecimiento Fetal/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Neovascularización Patológica , Receptor Notch1/metabolismo , Adulto , Apoptosis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteínas de Ciclo Celular/metabolismo , Movimiento Celular , Proliferación Celular , Células Cultivadas , Diaminas/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Retardo del Crecimiento Fetal/patología , Inhibidores y Moduladores de Gamma Secretasa/farmacología , Silenciador del Gen , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Recién Nacido , Fenotipo , Fosforilación , Embarazo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor Notch1/antagonistas & inhibidores , Receptor Notch1/genética , Transducción de Señal , Tiazoles/farmacologíaRESUMEN
In this study, we established the predictive model for lung adenocarcinoma (LUAD) depending on immune-related gene pairs (IRGPs) signature, which could not consider the technical bias of different platforms. Furthermore, we explored the predictive model with regard to the immune microenvironment and response to immunotherapy and identified specific drugs targeting the IRGPs model. Twenty-three IRGPs were identified and comprised the predictive model. When compared with the high-risk group, the low-risk group displayed a distinctly favorable prognosis and was characterized by increased immune score and decreased tumor purity. In addition, the low-risk group exhibited higher expression of immune checkpoint molecules, lower tumor stemness index, and was much more sensitive to immunotherapy. Lastly, candidate drugs that aimed at LUAD subtype differentiation were identified. The derived IRGPs model is an adverse independent biomarker for estimating oncologic outcomes in LUAD patients, and may be helpful to formulate personalized immunotherapy strategy.
Asunto(s)
Adenocarcinoma del Pulmón/terapia , Inmunoterapia , Neoplasias Pulmonares/terapia , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/metabolismo , Antineoplásicos , Análisis por Conglomerados , Supervivencia sin Enfermedad , Humanos , Proteínas de Punto de Control Inmunitario/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Pronóstico , Resultado del Tratamiento , Microambiente Tumoral/inmunologíaRESUMEN
Increased levels of cytosolic DNA in lung tissues play an important role in acute lung injury. However, the detailed mechanisms involved remain elusive. Here, we found that cyclic GMP-AMP synthase (cGAS, a cytosolic DNA sensor) expression was increased in airway epithelium in response to increased cytosolic DNA. Conditional deletion of airway epithelial cGAS exacerbated acute lung injury in mice, cGAS knockdown augmented LPS-induced production of interleukin (IL)-6 and IL-8. Mechanically, deletion of cGAS augmented expression of phosphorylated CREB (cAMP response element-binding protein), and cGAS directly interacted with CREB via its C-terminal domain. Furthermore, CREB knockdown rescued the LPS-induced excessive inflammatory response caused by cGAS deletion. Our study demonstrates that airway epithelial cGAS plays a protective role in acute lung injury and confirms a non-canonical cGAS-CREB pathway that regulates the inflammatory responses in airway epithelium to mediate LPS-induced acute lung injury.
Asunto(s)
Lesión Pulmonar Aguda , Lipopolisacáridos , Animales , Ratones , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/genética , ADN , Interleucina-6 , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Transducción de SeñalRESUMEN
Asthma is a heterogeneous disease in which environmental factors play an important role, and the effect of particulate matter (PM) on the occurrence and severity of asthma is drawing more attention. This study aims to identify the correlation between PM and pediatric asthma exacerbation and explore the potential mechanisms. The asthma visits data (N = 16,779,739) in a university-based tertiary children's hospital from January 2013 to December 2017 were collected, and the relationship between asthma visits and local PM concentration was analyzed. For further study, we established a house dust mite (HDM)-induced allergic airway inflammation model with PM intervention. We detected a correlation between PM concentration and pediatric asthma visits, especially in children under 6 years old. The in vivo data showed that PM aggravated HDM-induced airway inflammation, and IL-33 neutralizing antibody exerted a protective role. Our study suggests that PM is a risk factor in promoting pediatric asthma exacerbation, in which IL-33 might be a promising target.
Asunto(s)
Contaminación del Aire/efectos adversos , Asma/epidemiología , Material Particulado/efectos adversos , Contaminación del Aire/análisis , Alérgenos , Animales , Anticuerpos Neutralizantes/farmacología , Asma/etiología , Asma/patología , Líquido del Lavado Bronquioalveolar/citología , Preescolar , China/epidemiología , Monitoreo del Ambiente , Femenino , Humanos , Lactante , Inflamación/patología , Interleucina-33/análisis , Interleucina-33/biosíntesis , Interleucina-33/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Tamaño de la Partícula , Material Particulado/análisis , Factores de Riesgo , Estaciones del AñoRESUMEN
Eosinophils are terminally differentiated cells derived from hematopoietic stem cells (HSCs) in the bone marrow. Several studies have confirmed the effective roles of eosinophils in asthmatic airway pathogenesis. However, their regulatory functions have not been well elucidated. Here, increased C-C chemokine ligand 6 (CCL6) in asthmatic mice and the human orthologs CCL15 and CCL23 that are highly expressed in asthma patients are described, which are mainly derived from eosinophils. Using Ccl6 knockout mice, further studies revealed CCL6-dependent allergic airway inflammation and committed eosinophilia in the bone marrow following ovalbumin (OVA) challenge and identified a CCL6-CCR1 regulatory axis in hematopoietic stem cells (HSCs). Eosinophil differentiation and airway inflammation were remarkably decreased by the specific CCR1 antagonist BX471. Thus, the study identifies that the CCL6-CCR1 axis is involved in the crosstalk between eosinophils and HSCs during the development of allergic airway inflammation, which also reveals a potential therapeutic strategy for targeting G protein-coupled receptors (GPCRs) for future clinical treatment of asthma.
Asunto(s)
Asma/genética , Quimiocinas CC/genética , Eosinófilos/metabolismo , Proteínas Inflamatorias de Macrófagos/genética , Receptores CCR1/genética , Adolescente , Adulto , Anciano , Animales , Asma/patología , Médula Ósea/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Eosinófilos/patología , Femenino , Voluntarios Sanos , Células Madre Hematopoyéticas/metabolismo , Humanos , Hipersensibilidad/genética , Hipersensibilidad/patología , Inflamación/genética , Inflamación/patología , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Ovalbúmina/farmacología , Compuestos de Fenilurea/farmacología , Piperidinas/farmacología , Transducción de Señal/efectos de los fármacos , Adulto JovenRESUMEN
INTRODUCTION: Asthma is a worldwide problem that is caused by complex underlying immune dysregulation. The identification of potential prognostic markers of asthma may provide information for treatment. The purpose of this study was to explore the key mechanisms involved in the development of asthma on the basis of microarray analysis. METHODS: The expression profile data of GSE43696, which contains 20 endobronchial epithelial brushing samples from healthy patients and 88 from asthma patients, were obtained from Gene Expression Omnibus. For the present study, we built co-expression modules by weighted gene co-expression network analysis (WGCNA). This new analysis strategy was applied to the data set to investigate the relationships underlying the modules and the pathogenesis of asthma. Functional enrichment analysis was performed on these co-expression genes from the modules, and a gene network was then constructed. In addition, mouse models of HDM-induced and OVA-induced asthma were established, and the expression of hub genes was measured. RESULTS: First, using WGCNA, 20 co-expression modules were constructed with 19,596 genes obtained from 108 human endobronchial epithelial brushing samples. The number of genes within the modules ranged from 41 to 845. According to the colours assigned by the system, the module positively correlated with asthma status was named 'red module', and the module positively correlated with asthma severity was named 'purple module'. The results of a functional enrichment analysis showed that the red module was mainly enriched in intracellular calcium-activated chloride channel activity, intracellular chloride channel activity and endopeptidase inhibitor activity. The purple module was mainly enriched in microtubule motor activity and microtubule-binding and motor activity. Moreover, the mRNA expression levels of the 15 hub genes were confirmed to be significantly upregulated in the HDM mouse model, and 12 hub genes were upregulated in the OVA model. CONCLUSIONS: The hub genes ANO7, PYCR1 and UBE2C might play potential roles in the pathogenesis of asthma. Our findings provided a framework of co-expression gene modules of asthma and led to the identification of some new markers that might be potential targets for the development of new drugs and diagnostic markers.
Asunto(s)
Asma/genética , Asma/patología , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Adulto , Animales , Biomarcadores/análisis , Bronquios/metabolismo , Bronquios/patología , Células Cultivadas , Estudios de Cohortes , Femenino , Regulación de la Expresión Génica , Estudios de Asociación Genética/métodos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Análisis por Micromatrices/métodos , Persona de Mediana Edad , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Índice de Severidad de la Enfermedad , Transducción de Señal/genética , Adulto JovenRESUMEN
The marked heterogeneity of lung adenocarcinoma (LUAD) makes its diagnosis and treatment difficult. In addition, the aberrant DNA methylation profile contributes to tumor heterogeneity and alters the immune response. We used DNA methylation array data from publicly available databases to establish a predictive model for LUAD prognosis. Thirty-three methylation sites were identified as specific prognostic biomarkers, independent of patients' clinical characteristics. These methylation profiles were used to identify potential drug candidates and study the immune microenvironment of LUAD and response to immunotherapy. When compared with the high-risk group, the low-risk group had a lower recurrence rate and favorable prognosis. The tumor microenvironment differed between the two groups as reflected by the higher number of resting dendritic cells and a lower number of monocytes and resting mast cells in the low-risk group. Moreover, low-risk patients reported higher immune and stromal scores, lower tumor purity, and higher expression of HLA genes. Low-risk patients responded well to immunotherapy due to higher expression of immune checkpoint molecules and lower stemness index. Thus, our model predicted a favorable prognosis and increased overall survival for patients in the low-risk methylation group. Further, this model could provide potential drug targets to develop effective immunotherapies for LUAD.
Asunto(s)
Adenocarcinoma del Pulmón/genética , Metilación de ADN/genética , Neoplasias Pulmonares/genética , Recurrencia Local de Neoplasia/genética , Microambiente Tumoral/inmunología , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/patología , Análisis por Conglomerados , Células Dendríticas/inmunología , Femenino , Antígenos HLA/genética , Antígenos HLA/inmunología , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Proteínas de Punto de Control Inmunitario/genética , Proteínas de Punto de Control Inmunitario/metabolismo , Inmunoterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Mastocitos/inmunología , Persona de Mediana Edad , Monocitos/inmunología , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
Several studies have reported that gut and lung microbiomes are involved in the process of asthma pathogenesis. However, it remains unclear how perinatal or early-life antibiotic intervention affect adult allergic airway inflammation. We assigned C57BL/6 mice randomly to four experimental groups: normal saline control (NS), ovalbumin (OVA), vancomycin pretreated NS (VAN-NS), and vancomycin pretreated OVA (VAN-OVA). The vancomycin groups were orally given the drug from gestational day 14 to 6 week. An OVA-induced asthma model was then established at 6 weeks of age, and airway inflammation was evaluated. In addition, total DNA was extracted from the feces and lung tissue and used for 16S rDNA gene sequencing, to detect the composition of the microbiome. In the VAN-OVA group, airway inflammation and Th2-related cytokines were found to be significantly increased versus the control groups. Gene sequencing showed that vancomycin treatment attenuated the richness and evenness, and altered the composition of the microbiome in the gut and lung. Micrococcaceae and Clostridiaceae-1 were potentially correlated to the severity of allergic airway inflammation. Our study suggests that perinatal and early-life vancomycin intervention aggravates allergic inflammation in adulthood, which might be correlated with imbalanced gut and lung microbiome homeostasis.