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1.
Ann Allergy Asthma Immunol ; 130(3): 298-304, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36509407

RESUMEN

BACKGROUND: Severe asthma impacts quality of life (QoL), including dyspnea, sleep, and activity limitation. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukins-4 and -13, which are key and central drivers of type 2 inflammation. Phase 3 LIBERTY ASTHMA VENTURE (NCT02528214) and LIBERTY ASTHMA TRAVERSE open-label extension (NCT02134028) evaluated dupilumab 300 mg vs placebo every 2 weeks for 24 weeks (VENTURE) and dupilumab only for an additional 48 to 96 weeks (TRAVERSE) in patients with oral corticosteroid (OCS)-dependent severe asthma. OBJECTIVE: To assess dupilumab's impact on Asthma QoL Questionnaire (AQLQ) items related to breathing symptoms, sleep, and activity limitation, and on OCS reduction. METHODS: The proportion of patients with AQLQ scores of 6 or 7 for breathing symptoms-, sleeping-, and activity-related items in VENTURE and TRAVERSE, together with OCS dose reductions in VENTURE. RESULTS: In VENTURE, significantly greater proportions of dupilumab- vs placebo-treated patients achieved scores of 6 or 7 by week 24 in breathing symptoms-related (42.7%-60.2% vs 22.4%-39.3%), sleeping-related (45.6%-65.0% vs 27.1%-47.7%), and activity-related (44.7%-51.5% vs 22.4%-34.6%) AQLQ items. Improvements were maintained through TRAVERSE in the dupilumab/dupilumab group and increased to dupilumab treatment levels in the placebo/dupilumab group. Significant OCS dose reductions were observed in VENTURE; up to 90% and 60% of dupilumab-treated vs 65% and 41% of placebo-treated patients with AQLQ scores of 6 or 7 in breathing symptoms-, sleeping-, and activity-related items achieved greater than or equal to 50% dose reduction and eliminated OCS at week 24, respectively. CONCLUSION: In patients with severe OCS-dependent asthma, dupilumab improved QoL related to breathing symptoms, sleep, and activity limitation, and reduced OCS use. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02528214 and NCT02134028.


Asunto(s)
Asma , Calidad de Vida , Humanos , Inyecciones Subcutáneas , Asma/tratamiento farmacológico , Corticoesteroides/uso terapéutico , Disnea/tratamiento farmacológico , Resultado del Tratamiento , Sueño , Método Doble Ciego
2.
Eur Respir J ; 58(5)2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-33958427

RESUMEN

BACKGROUND: Acute pulmonary exacerbations (AE) are episodes of clinical worsening in cystic fibrosis (CF), often precipitated by infection. Timely detection is critical to minimise morbidity and lung function declines associated with acute inflammation during AE. Based on our previous observations that airway protein short palate lung nasal epithelium clone 1 (SPLUNC1) is regulated by inflammatory signals, we investigated the use of SPLUNC1 fluctuations to diagnose and predict AE in CF. METHODS: We enrolled CF participants from two independent cohorts to measure AE markers of inflammation in sputum and recorded clinical outcomes for a 1-year follow-up period. RESULTS: SPLUNC1 levels were high in healthy controls (n=9, 10.7 µg·mL-1), and significantly decreased in CF participants without AE (n=30, 5.7 µg·mL-1; p=0.016). SPLUNC1 levels were 71.9% lower during AE (n=14, 1.6 µg·mL-1; p=0.0034) regardless of age, sex, CF-causing mutation or microbiology findings. Cytokines interleukin-1ß and tumour necrosis factor-α were also increased in AE, whereas lung function did not decrease consistently. Stable CF participants with lower SPLUNC1 levels were much more likely to have an AE at 60 days (hazard ratio (HR)±se 11.49±0.83; p=0.0033). Low-SPLUNC1 stable participants remained at higher AE risk even 1 year after sputum collection (HR±se 3.21±0.47; p=0.0125). SPLUNC1 was downregulated by inflammatory cytokines and proteases increased in sputum during AE. CONCLUSION: In acute CF care, low SPLUNC1 levels could support a decision to increase airway clearance or to initiate pharmacological interventions. In asymptomatic, stable patients, low SPLUNC1 levels could inform changes in clinical management to improve long-term disease control and clinical outcomes in CF.


Asunto(s)
Fibrosis Quística , Glicoproteínas , Humanos , Pulmón , Mucosa Nasal , Fosfoproteínas
3.
Am J Respir Crit Care Med ; 202(1): 51-64, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32255668

RESUMEN

Rationale: MicroRNAs are potent regulators of biologic systems that are critical to tissue homeostasis. Individual microRNAs have been identified in airway samples. However, a systems analysis of the microRNA-mRNA networks present in the sputum that contribute to airway inflammation in asthma has not been published.Objectives: Identify microRNA and mRNA networks in the sputum of patients with asthma.Methods: We conducted a genome-wide analysis of microRNA and mRNA in the sputum from patients with asthma and correlated expression with clinical phenotypes. Weighted gene correlation network analysis was implemented to identify microRNA networks (modules) that significantly correlate with clinical features of asthma and mRNA expression networks. MicroRNA expression in peripheral blood neutrophils and lymphocytes and in situ hybridization of the sputum were used to identify the cellular sources of microRNAs. MicroRNA expression obtained before and after ozone exposure was also used to identify changes associated with neutrophil counts in the airway.Measurements and Main Results: Six microRNA modules were associated with clinical features of asthma. A single module (nely) was associated with a history of hospitalizations, lung function impairment, and numbers of neutrophils and lymphocytes in the sputum. Of the 12 microRNAs in the nely module, hsa-miR-223-3p was the highest expressed microRNA in neutrophils and was associated with increased neutrophil counts in the sputum in response to ozone exposure. Multiple microRNAs in the nely module correlated with two mRNA modules enriched for TLR (Toll-like receptor) and T-helper cell type 17 (Th17) signaling and endoplasmic reticulum stress. hsa-miR-223-3p was a key regulator of the TLR and Th17 pathways in the sputum of subjects with asthma.Conclusions: This study of sputum microRNA and mRNA expression from patients with asthma demonstrates the existence of microRNA networks and genes that are associated with features of asthma severity. Among these, hsa-miR-223-3p, a neutrophil-derived microRNA, regulates TLR/Th17 signaling and endoplasmic reticulum stress.


Asunto(s)
Asma/inmunología , Redes Reguladoras de Genes , MicroARNs/metabolismo , Neutrófilos/metabolismo , Índice de Severidad de la Enfermedad , Esputo/metabolismo , Adulto , Anciano , Asma/diagnóstico , Asma/genética , Biomarcadores/metabolismo , Estudios de Casos y Controles , Estudios Transversales , Femenino , Estudio de Asociación del Genoma Completo , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , ARN Mensajero/metabolismo
4.
J Allergy Clin Immunol ; 145(2): 550-562, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32035607

RESUMEN

BACKGROUND: Airway eosinophilia is a prominent feature of asthma and chronic rhinosinusitis (CRS), and the endothelium plays a key role in eosinophil trafficking. To date, microRNA-1 (miR-1) is the only microRNA known to be regulated in the lung endothelium in asthma models. OBJECTIVE: We sought to determine the role of endothelial miR-1 in allergic airway inflammation. METHODS: We measured microRNA and mRNA expression using quantitative RT-PCR. We used ovalbumin and house dust mite models of asthma. Endothelium-specific overexpression of miR-1 was achieved through lentiviral vector delivery or induction of a transgene. Tissue eosinophilia was quantified by using Congo red and anti-eosinophil peroxidase staining. We measured eosinophil binding with a Sykes-Moore adhesion chamber. Target recruitment to RNA-induced silencing complex was assessed by using anti-Argonaute2 RNA immunoprecipitation. Surface P-selectin levels were measured by using flow cytometry. RESULTS: Serum miR-1 levels had inverse correlations with sputum eosinophilia, airway obstruction, and number of hospitalizations in asthmatic patients and sinonasal tissue eosinophilia in patients with CRS. IL-13 stimulation decreased miR-1 levels in human lung endothelium. Endothelium-specific overexpression of miR-1 reduced airway eosinophilia and asthma phenotypes in murine models and inhibited IL-13-induced eosinophil binding to endothelial cells. miR-1 recruited P-selectin, thymic stromal lymphopoietin, eotaxin-3, and thrombopoietin receptor to the RNA-induced silencing complex; downregulated these genes in the lung endothelium; and reduced surface P-selectin levels in IL-13-stimulated endothelial cells. In our asthma and CRS cohorts, miR-1 levels correlated inversely with its target genes. CONCLUSION: Endothelial miR-1 regulates eosinophil trafficking in the setting of allergic airway inflammation. miR-1 has therapeutic potential in asthmatic patients and patients with CRS.


Asunto(s)
Asma/inmunología , Quimiotaxis de Leucocito/inmunología , MicroARNs/inmunología , MicroARNs/metabolismo , Rinitis Alérgica Perenne/inmunología , Sinusitis/inmunología , Animales , Asma/metabolismo , Asma/patología , Células Endoteliales/metabolismo , Eosinófilos , Humanos , Ratones , Eosinofilia Pulmonar/inmunología , Eosinofilia Pulmonar/metabolismo , Eosinofilia Pulmonar/patología , Rinitis Alérgica Perenne/metabolismo , Rinitis Alérgica Perenne/patología , Sinusitis/metabolismo , Sinusitis/patología
5.
Am J Physiol Lung Cell Mol Physiol ; 316(2): L321-L333, 2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30461288

RESUMEN

Bpifa1 (BPI fold-containing group A member 1) is an airway host-protective protein with immunomodulatory properties that binds to LPS and is regulated by infectious and inflammatory signals. Differential expression of Bpifa1 has been widely reported in lung disease, yet the biological significance of this observation is unclear. We sought to understand the role of Bpifa1 fluctuations in modulating lung inflammation. We treated wild-type (WT) and Bpifa1-/- mice with intranasal LPS and performed immunological and transcriptomic analyses of lung tissue to determine the immune effects of Bpifa1 deficiency. We show that neutrophil (polymorphonuclear cells, PMNs) lung recruitment and transmigration to the airways in response to LPS is impaired in Bpifa1-/- mice. Transcriptomic analysis revealed a signature of 379 genes that differentiated Bpifa1-/- from WT mice. During acute lung inflammation, the most downregulated genes in Bpifa1-/- mice were Cxcl9 and Cxcl10. Bpifa1-/- mice had lower bronchoalveolar lavage concentrations of C-X-C motif chemokine ligand 10 (Cxcl10) and Cxcl9, interferon-inducible PMN chemokines. This was consistent with lower expression of IFNγ, IFNλ, downstream IFN-stimulated genes, and IFN-regulatory factors, which are important for the innate immune response. Administration of Cxcl10 before LPS treatment restored the inflammatory response in Bpifa1-/- mice. Our results identify a novel role for Bpifa1 in the regulation of Cxcl10-mediated PMN recruitment to the lungs via IFNγ and -λ signaling during acute inflammation.


Asunto(s)
Glicoproteínas/efectos de los fármacos , Glicoproteínas/genética , Inflamación/tratamiento farmacológico , Infiltración Neutrófila/efectos de los fármacos , Fosfoproteínas/efectos de los fármacos , Fosfoproteínas/genética , Enfermedad Aguda , Animales , Lipopolisacáridos/farmacología , Pulmón/efectos de los fármacos , Ratones Endogámicos C57BL , Infiltración Neutrófila/fisiología
6.
Am J Physiol Lung Cell Mol Physiol ; 314(5): L882-L892, 2018 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-29345196

RESUMEN

Surfactant protein C (SPC), a key component of pulmonary surfactant, also plays a role in regulating inflammation. SPC deficiency in patients and mouse models is associated with increased inflammation and delayed repair, but the key drivers of SPC-regulated inflammation in response to injury are largely unknown. This study focuses on a new mechanism of SPC as an anti-inflammatory molecule using SPC-TK/SPC-KO (surfactant protein C-thymidine kinase/surfactant protein C knockout) mice, which represent a novel sterile injury model that mimics clinical acute respiratory distress syndrome (ARDS). SPC-TK mice express the inducible suicide gene thymidine kinase from by the SPC promoter, which targets alveolar type 2 (AT2) cells for depletion in response to ganciclovir (GCV). We compared GCV-induced injury and repair in SPC-TK mice that have normal endogenous SPC expression with SPC-TK/SPC-KO mice lacking SPC expression. In contrast to SPC-TK mice, SPC-TK/SPC-KO mice treated with GCV exhibited more severe inflammation, resulting in over 90% mortality; there was only 8% mortality of SPC-TK animals. SPC-TK/SPC-KO mice had highly elevated inflammatory cytokines and granulocyte infiltration in the bronchoalveolar lavage (BAL) fluid. Consistent with a proinflammatory phenotype, immunofluorescence revealed increased phosphorylated signal transduction and activation of transcription 3 (pSTAT3), suggesting enhanced Janus kinase (JAK)/STAT activation in inflammatory and AT2 cells of SPC-TK/SPC-KO mice. The level of suppressor of cytokine signaling 3, an anti-inflammatory mediator that decreases pSTAT3 signaling, was significantly decreased in the BAL fluid of SPC-TK/SPC-KO mice. Hyperactivation of pSTAT3 and inflammation were rescued by AZD1480, a JAK1/2 inhibitor. Our findings showing a novel role for SPC in regulating inflammation via JAK/STAT may have clinical applications.


Asunto(s)
Modelos Animales de Enfermedad , Janus Quinasa 1/metabolismo , Lesión Pulmonar/prevención & control , Péptidos/fisiología , Neumonía/prevención & control , Factor de Transcripción STAT3/metabolismo , Timidina Quinasa/fisiología , Animales , Péptidos y Proteínas de Señalización Intercelular , Janus Quinasa 1/genética , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Neumonía/metabolismo , Neumonía/patología , Proteína C Asociada a Surfactante Pulmonar , Factor de Transcripción STAT3/genética
9.
BMC Bioinformatics ; 18(1): 309, 2017 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-28637421

RESUMEN

BACKGROUND: Distance based unsupervised clustering of gene expression data is commonly used to identify heterogeneity in biologic samples. However, high noise levels in gene expression data and relatively high correlation between genes are often encountered, so traditional distances such as Euclidean distance may not be effective at discriminating the biological differences between samples. An alternative method to examine disease phenotypes is to use pre-defined biological pathways. These pathways have been shown to be perturbed in different ways in different subjects who have similar clinical features. We hypothesize that differences in the expressions of genes in a given pathway are more predictive of differences in biological differences compared to standard approaches and if integrated into clustering analysis will enhance the robustness and accuracy of the clustering method. To examine this hypothesis, we developed a novel computational method to assess the biological differences between samples using gene expression data by assuming that ontologically defined biological pathways in biologically similar samples have similar behavior. RESULTS: Pre-defined biological pathways were downloaded and genes in each pathway were used to cluster samples using the Gaussian mixture model. The clustering results across different pathways were then summarized to calculate the pathway-based distance score between samples. This method was applied to both simulated and real data sets and compared to the traditional Euclidean distance and another pathway-based clustering method, Pathifier. The results show that the pathway-based distance score performs significantly better than the Euclidean distance, especially when the heterogeneity is low and genes in the same pathways are correlated. Compared to Pathifier, we demonstrated that our approach achieves higher accuracy and robustness for small pathways. When the pathway size is large, by downsampling the pathways into smaller pathways, our approach was able to achieve comparable performance. CONCLUSIONS: We have developed a novel distance score that represents the biological differences between samples using gene expression data and pre-defined biological pathway information. Application of this distance score results in more accurate, robust, and biologically meaningful clustering results in both simulated data and real data when compared to traditional methods. It also has comparable or better performance compared to Pathifier.


Asunto(s)
Algoritmos , Expresión Génica , Redes y Vías Metabólicas , Asma/genética , Asma/metabolismo , Asma/patología , Análisis por Conglomerados , Humanos , Distribución Normal , Fenotipo
10.
Eur Respir J ; 50(2)2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28860266

RESUMEN

Bronchial thermoplasty is an endoscopic therapy for severe asthma. The previously reported, randomised sham-controlled AIR2 (Asthma Intervention Research 2) trial showed a significant reduction in severe asthma exacerbations, emergency department visits and hospitalisations after bronchial thermoplasty. More "real-world" clinical outcome data is needed.This article compares outcomes in bronchial thermoplasty subjects with 3 years of follow-up from the ongoing, post-market PAS2 (Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma) study with those from the AIR2 trial.279 subjects were treated with bronchial thermoplasty in the PAS2 study. We compared the first 190 PAS2 subjects with the 190 bronchial thermoplasty-treated subjects in the AIR2 trial at 3 years of follow-up. The PAS2 subjects were older (mean age 45.9 versus 40.7 years) and more obese (mean body mass index 32.5 versus 29.3 kg·m-2) and took higher doses of inhaled corticosteroids (mean dose 2301 versus 1961 µg·day-1). More PAS2 subjects had experienced severe exacerbations (74% versus 52%) and hospitalisations (15.3% versus 4.2%) in the 12 months prior to bronchial thermoplasty. At year 3 after bronchial thermoplasty, the percentage of PAS2 subjects with severe exacerbations, emergency department visits and hospitalisations significantly decreased by 45%, 55% and 40%, respectively, echoing the AIR2 results.The PAS2 study demonstrates similar improvements in asthma control after bronchial thermoplasty compared with the AIR2 trial despite enrolling subjects who may have had poorer asthma control.


Asunto(s)
Asma , Termoplastia Bronquial , Glucocorticoides/uso terapéutico , Efectos Adversos a Largo Plazo , Complicaciones Posoperatorias , Calidad de Vida , Adulto , Asma/diagnóstico , Asma/psicología , Asma/terapia , Termoplastia Bronquial/efectos adversos , Termoplastia Bronquial/métodos , Termoplastia Bronquial/estadística & datos numéricos , Servicio de Urgencia en Hospital/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Hospitalización/estadística & datos numéricos , Humanos , Efectos Adversos a Largo Plazo/diagnóstico , Efectos Adversos a Largo Plazo/etiología , Efectos Adversos a Largo Plazo/psicología , Efectos Adversos a Largo Plazo/terapia , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/psicología , Complicaciones Posoperatorias/terapia , Vigilancia de Productos Comercializados , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Índice de Severidad de la Enfermedad
11.
Eur Respir J ; 50(4)2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-29025889

RESUMEN

The chitinase-like protein YKL-40 mediates airway inflammation and serum levels are associated with asthma severity. However, asthma phenotypes associated with YKL-40 levels have not been precisely defined.We conducted an unsupervised cluster analysis of asthma patients treated at the Yale Center for Asthma and Airways Disease (n=156) to identify subgroups according to YKL-40 level. The resulting YKL-40 clusters were cross-validated in cohorts from the Severe Asthma Research Programme (n=167) and the New York University/Bellevue Asthma Repository (n=341). A sputum transcriptome analysis revealed molecular pathways associated with YKL-40 subgroups.Four YKL-40 clusters (C1-C4) were identified. C3 and C4 had high serum YKL-40 levels compared with C1 and C2. C3 was associated with earlier onset and longer duration of disease, severe airflow obstruction, and near-fatal asthma exacerbations. C4 had the highest serum YKL-40 levels, adult onset and less airflow obstruction, but frequent exacerbations. An airway transcriptome analysis in C3 and C4 showed activation of non-type 2 inflammatory pathways.Elevated serum YKL-40 levels were associated with two distinct clinical asthma phenotypes: one with irreversible airway obstruction and another with severe exacerbations. The YKL-40 clusters are potentially useful for identification of individuals with severe or exacerbation-prone asthma.


Asunto(s)
Obstrucción de las Vías Aéreas/inmunología , Asma , Proteína 1 Similar a Quitinasa-3 , Inflamación/inmunología , Sistema Respiratorio , Adolescente , Adulto , Edad de Inicio , Asma/sangre , Asma/diagnóstico , Asma/fisiopatología , Proteína 1 Similar a Quitinasa-3/análisis , Proteína 1 Similar a Quitinasa-3/sangre , Análisis por Conglomerados , Estudios Transversales , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Sistema Respiratorio/inmunología , Sistema Respiratorio/fisiopatología , Índice de Severidad de la Enfermedad , Esputo/metabolismo , Estadística como Asunto , Brote de los Síntomas
12.
Am J Respir Crit Care Med ; 191(10): 1116-25, 2015 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-25763605

RESUMEN

RATIONALE: The airway transcriptome includes genes that contribute to the pathophysiologic heterogeneity seen in individuals with asthma. OBJECTIVES: We analyzed sputum gene expression for transcriptomic endotypes of asthma (TEA), gene signatures that discriminate phenotypes of disease. METHODS: Gene expression in the sputum and blood of patients with asthma was measured using Affymetrix microarrays. Unsupervised clustering analysis based on pathways from the Kyoto Encyclopedia of Genes and Genomes was used to identify TEA clusters. Logistic regression analysis of matched blood samples defined an expression profile in the circulation to determine the TEA cluster assignment in a cohort of children with asthma to replicate clinical phenotypes. MEASUREMENTS AND MAIN RESULTS: Three TEA clusters were identified. TEA cluster 1 had the most subjects with a history of intubation (P = 0.05), a lower prebronchodilator FEV1 (P = 0.006), a higher bronchodilator response (P = 0.03), and higher exhaled nitric oxide levels (P = 0.04) compared with the other TEA clusters. TEA cluster 2, the smallest cluster, had the most subjects that were hospitalized for asthma (P = 0.04). TEA cluster 3, the largest cluster, had normal lung function, low exhaled nitric oxide levels, and lower inhaled steroid requirements. Evaluation of TEA clusters in children confirmed that TEA clusters 1 and 2 are associated with a history of intubation (P = 5.58 × 10(-6)) and hospitalization (P = 0.01), respectively. CONCLUSIONS: There are common patterns of gene expression in the sputum and blood of children and adults that are associated with near-fatal, severe, and milder asthma.


Asunto(s)
Asma/genética , Perfilación de la Expresión Génica , Esputo , Transcriptoma/genética , Adolescente , Adulto , Edad de Inicio , Asma/sangre , Asma/fisiopatología , Análisis Químico de la Sangre , Estudios de Casos y Controles , Niño , Estudios Transversales , Femenino , Marcadores Genéticos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Fenotipo , ARN/sangre , ARN/genética , Encuestas y Cuestionarios , Adulto Joven
13.
J Allergy Clin Immunol ; 136(1): 51-58.e10, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25592985

RESUMEN

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 (CHI3L1) promoter, the gene encoding YKL-40, are associated with circulating YKL-40 levels and asthma prevalence. However, the effects of gene polymorphisms on asthma severity and airway expression of YKL-40 have not been examined. OBJECTIVE: We sought to determine the effect of genetic variation in CHI3L1 on asthma severity and YKL-40 expression in subjects from the Yale Center for Asthma and Airways Disease and the Severe Asthma Research Program. METHODS: SNPs spanning the CHI3L1 gene were genotyped in 259 Yale Center for Asthma and Airways Disease and 919 Severe Asthma Research Program subjects. Association and haplotype analyses were conducted to identify effects on airflow obstruction, YKL-40 levels, and asthma severity. RESULTS: Fifteen SNPs in CHI3L1 were associated with FEV1, serum YKL-40 levels, or both. rs12141494 (intron 6) was the only SNP in subjects of European ancestry in both cohorts that was associated with serum YKL-40 levels and postbronchodilator FEV1. Conditional analysis demonstrated that the effect on lung function was independent of the promoter SNP rs4950928, and haplotype analysis demonstrated that G alleles at rs12141494 and rs4950928 are associated with lower YKL-40 expression and higher FEV1 percent predicted values. In asthmatic subjects the risk allele A at rs12141494 was associated with severe asthma and higher YKL-40 expression in the airway (P ≤ .05). CONCLUSION: In contrast to the promoter SNP rs4950928, the intronic SNP rs12141494 in CHI3L1 is associated with asthma severity, lung function, and YKL-40 expression in the blood and airway. These data suggest that SNP rs12141494 modulates YKL-40 expression in the airway and contributes to airway remodeling and asthma severity.


Asunto(s)
Adipoquinas/genética , Asma/genética , Lectinas/genética , Adulto , Anciano , Remodelación de las Vías Aéreas (Respiratorias) , Proteína 1 Similar a Quitinasa-3 , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Regulación de la Expresión Génica/genética , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple
14.
Am J Respir Cell Mol Biol ; 52(5): 525-34, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25265466

RESUMEN

Bactericidal/permeability-increasing protein fold-containing family member A1 (BPIFA1), formerly known as SPLUNC1, is one of the most abundant proteins in respiratory secretions and has been identified with increasing frequency in studies of pulmonary disease. Its expression is largely restricted to the respiratory tract, being highly concentrated in the upper airways and proximal trachea. BPIFA1 is highly responsive to airborne pathogens, allergens, and irritants. BPIFA1 actively participates in host protection through antimicrobial, surfactant, airway surface liquid regulation, and immunomodulatory properties. Its expression is modulated in multiple lung diseases, including cystic fibrosis, chronic obstructive pulmonary disease, respiratory malignancies, and idiopathic pulmonary fibrosis. However, the role of BPIFA1 in pulmonary pathogenesis remains to be elucidated. This review highlights the versatile properties of BPIFA1 in antimicrobial protection and its roles as a sensor of environmental exposure and regulator of immune cell function. A greater understanding of the contribution of BPIFA1 to disease pathogenesis and activity may clarify if BPIFA1 is a biomarker and potential drug target in pulmonary disease.


Asunto(s)
Glicoproteínas/metabolismo , Enfermedades Pulmonares/microbiología , Fosfoproteínas/metabolismo , Mucosa Respiratoria/metabolismo , Animales , Regulación de la Expresión Génica , Glicoproteínas/genética , Interacciones Huésped-Patógeno , Humanos , Inmunidad Innata , Mediadores de Inflamación/metabolismo , Enfermedades Pulmonares/genética , Enfermedades Pulmonares/inmunología , Enfermedades Pulmonares/virología , Fosfoproteínas/genética , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/microbiología , Mucosa Respiratoria/virología , Transducción de Señal
16.
Am J Respir Cell Mol Biol ; 48(6): 717-24, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23470624

RESUMEN

Short palate, lung, and nasal epithelial clone-1 (SPLUNC1) is a protein abundantly expressed by the respiratory epithelium of the proximal lower respiratory tract, a site of great environmental exposure. Previous studies showed that SPLUNC1 exerts antimicrobial effects, regulates airway surface liquid and mucociliary clearance, and suppresses allergic airway inflammation. We studied SPLUNC1 to gain insights into its role in host defense. In the lower respiratory tract, concentrations of SPLUNC1 are high under basal conditions. In models of pneumonia caused by common respiratory pathogens, and in Th1-induced and Th2-induced airway inflammation, SPLUNC1 secretion is markedly reduced. Pathogen-associated molecular patterns and IFN-γ act directly on airway epithelial cells to inhibit SPLUNC1 mRNA expression. Thus, SPLUNC1 is quickly suppressed during infection, in response to an insult on the epithelial surface. These experiments highlight the finely tuned fluctuations of SPLUNC1 in response to exposures in the respiratory tract, and suggest that the loss of SPLUNC1 is a crucial feature of host defense across air-breathing animal species.


Asunto(s)
Inmunidad Adaptativa , Regulación de la Expresión Génica , Glicoproteínas/inmunología , Inmunidad Innata , Fosfoproteínas/inmunología , Animales , Línea Celular Tumoral , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Inmunohistoquímica , Inflamación/patología , Virus de la Influenza A/inmunología , Interferón gamma/inmunología , Lipopolisacáridos/inmunología , Pulmón/inmunología , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Neumonía Bacteriana/inmunología , Neumonía Bacteriana/patología , Pseudomonas aeruginosa/inmunología , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/microbiología , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/metabolismo , Streptococcus pneumoniae/inmunología
17.
J Immunol ; 187(7): 3815-20, 2011 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-21873527

RESUMEN

Inhibiting allergic airway inflammation is the goal of therapy in persistent asthma. Administration of medication via the airways delivers drug directly to the site of inflammation and avoids systemic side effects but often fails to modulate systemic features of asthma. We have shown that Th1 cells, through production of IFN-γ, inhibit many Th2-induced effector functions that promote disease. Using a newly generated mouse that expresses IFN-γR only on airway epithelial cells, we show that the airway epithelium controls a range of pathological responses in asthma. IFN-γ acting only through the airway epithelium inhibits mucus, chitinases, and eosinophilia, independent of Th2 cell activation. IFN-γ signaling through the airway epithelium inhibits eosinophil generation in the bone marrow, indicating that signals on the airway mucosal surface can regulate distant functions to inhibit disease. IFN-γ actions through the airway epithelium will limit airway obstruction and inflammation and may be therapeutic in refractory asthma.


Asunto(s)
Asma/inmunología , Asma/patología , Hipersensibilidad/inmunología , Hipersensibilidad/patología , Interferón gamma/inmunología , Mucosa Respiratoria/inmunología , Animales , Asma/metabolismo , Hipersensibilidad/metabolismo , Interferón gamma/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/inmunología , Células TH1/inmunología , Células TH1/metabolismo , Células Th2/inmunología , Células Th2/metabolismo
18.
J Allergy Clin Immunol Pract ; 11(11): 3383-3390.e3, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37454926

RESUMEN

BACKGROUND: It remains unclear whether patients with asthma and/or chronic obstructive pulmonary disease (COPD) are at increased risk for severe coronavirus disease 2019 (COVID-19). OBJECTIVE: Compare in-hospital COVID-19 outcomes among patients with asthma, COPD, and no airway disease. METHODS: A retrospective cohort study was conducted on 8,395 patients admitted with COVID-19 between March 2020 and April 2021. Airway disease diagnoses were defined using International Classification of Diseases, 10th Revision codes. Mortality and sequential organ failure assessment (SOFA) scores were compared among groups. Logistic regression analysis was used to identify and adjust for confounding clinical features associated with mortality. RESULTS: The median SOFA score in patients without airway disease was 0.32 and mortality was 11%. In comparison, asthma patients had lower SOFA scores (median 0.15; P < .01) and decreased mortality, even after adjusting for age, diabetes, and other confounders (odds ratio 0.65; P = .01). Patients with COPD had higher SOFA scores (median 0.86; P < .01) and increased adjusted odds of mortality (odds ratio 1.40; P < .01). Blood eosinophil count of 200 cells/µL or greater, a marker of type 2 inflammation, was associated with lower mortality across all groups. Importantly, patients with asthma showed improved outcomes even after adjusting for eosinophilia, indicating that noneosinophilic asthma was associated with protection as well. CONCLUSIONS: COVID-19 severity was increased in patients with COPD and decreased in those with asthma, eosinophilia, and noneosinophilic asthma, independent of clinical confounders. These findings suggest that COVID-19 severity may be influenced by intrinsic immunological factors in patients with airway diseases, such as type 2 inflammation.


Asunto(s)
Asma , COVID-19 , Diabetes Mellitus Tipo 2 , Eosinofilia , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Estudios Retrospectivos , COVID-19/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Asma/diagnóstico , Inflamación , Eosinofilia/complicaciones
19.
Proc Natl Acad Sci U S A ; 106(22): 9099-104, 2009 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-19458046

RESUMEN

Asthma is an inflammatory disorder caused by airway exposures to allergens and chemical irritants. Studies focusing on immune, smooth muscle, and airway epithelial function revealed many aspects of the disease mechanism of asthma. However, the limited efficacies of immune-directed therapies suggest the involvement of additional mechanisms in asthmatic airway inflammation. TRPA1 is an irritant-sensing ion channel expressed in airway chemosensory nerves. TRPA1-activating stimuli such as cigarette smoke, chlorine, aldehydes, and scents are among the most prevalent triggers of asthma. Endogenous TRPA1 agonists, including reactive oxygen species and lipid peroxidation products, are potent drivers of allergen-induced airway inflammation in asthma. Here, we examined the role of TRPA1 in allergic asthma in the murine ovalbumin model. Strikingly, genetic ablation of TRPA1 inhibited allergen-induced leukocyte infiltration in the airways, reduced cytokine and mucus production, and almost completely abolished airway hyperreactivity to contractile stimuli. This phenotype is recapitulated by treatment of wild-type mice with HC-030031, a TRPA1 antagonist. HC-030031, when administered during airway allergen challenge, inhibited eosinophil infiltration and prevented the development of airway hyperreactivity. Trpa1(-/-) mice displayed deficiencies in chemically and allergen-induced neuropeptide release in the airways, providing a potential explanation for the impaired inflammatory response. Our data suggest that TRPA1 is a key integrator of interactions between the immune and nervous systems in the airways, driving asthmatic airway inflammation following inhaled allergen challenge. TRPA1 may represent a promising pharmacological target for the treatment of asthma and other allergic inflammatory conditions.


Asunto(s)
Asma/fisiopatología , Hiperreactividad Bronquial/fisiopatología , Células Receptoras Sensoriales/fisiología , Canales de Potencial de Receptor Transitorio/fisiología , Animales , Asma/inmunología , Hiperreactividad Bronquial/inmunología , Sistema Inmunológico/inmunología , Sistema Inmunológico/fisiopatología , Inflamación/inmunología , Inflamación/fisiopatología , Ratones , Ratones Noqueados , Células Receptoras Sensoriales/inmunología , Canal Catiónico TRPA1 , Canales de Potencial de Receptor Transitorio/genética
20.
Patient Prefer Adherence ; 16: 2649-2661, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36176349

RESUMEN

Purpose: Multiple biologics are available for moderate to severe asthma. Given the important relationship between patient engagement in healthcare decision-making and health outcomes, patient preference is an increasingly important consideration. This study elicited patients' preferences for attributes of biologic therapies for moderate to severe asthma. Patient and Methods: A discrete choice experiment (DCE) questionnaire was designed to collect data from an existing survey panel of adults with moderate to severe asthma in the United States. Patients were asked to select their preferred hypothetical treatment from profiles with varying attributes related to efficacy, safety, and administration convenience. Conditional logit regression models were used to quantify patient preferences. Results: Of 301 eligible patients who completed the survey, the mean age was 46.7±15.1 years and 71.8% were female. Patients had asthma for 22.5±16.3 years on average, and most (97.3%) had experienced ≥1 asthma attack in the past 12 months. Among treatment attributes examined, patients most valued the absence of a black box warning for the risk of a life-threatening allergic reaction, effectiveness of reducing severe asthma exacerbations, and improvement in lung function (all p < 0.001). Home administration setting for subcutaneous injections (vs doctor's office/clinic) (p = 0.009) and ability of a biologic to treat additional chronic condition(s) (p < 0.05) were also considered important. Dosing frequency and type of injection device were not significant factors. Conclusion: Patients with moderate to severe asthma valued efficacy and safety over convenience attributes when selecting biologic treatments. Awareness of these preferences can facilitate patient-physician shared decision-making when managing moderate to severe asthma in clinical practice.

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