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1.
Am J Respir Crit Care Med ; 201(10): 1230-1239, 2020 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-32011901

RESUMEN

Rationale: The preclinical natural history of progressive lung fibrosis is poorly understood.Objectives: Our goals were to identify risk factors for interstitial lung abnormalities (ILA) on high-resolution computed tomography (HRCT) scans and to determine progression toward clinical interstitial lung disease (ILD) among subjects in a longitudinal cohort of self-reported unaffected first-degree relatives of patients with familial interstitial pneumonia.Methods: Enrollment evaluation included a health history and exposure questionnaire and HRCT scans, which were categorized by visual assessment as no ILA, early/mild ILA, or extensive ILA. The study endpoint was met when ILA were extensive or when ILD was diagnosed clinically. Among subjects with adequate study time to complete 5-year follow-up HRCT, the proportion with ILD events (endpoint met or radiographic ILA progression) was calculated.Measurements and Main Results: Among 336 subjects, the mean age was 53.1 (SD, 9.9) years. Those with ILA (early/mild [n = 74] or extensive [n = 3]) were older, were more likely to be ever smokers, had shorter peripheral blood mononuclear cell telomeres, and were more likely to carry the MUC5B risk allele. Self-reported occupational or environmental exposures, including aluminum smelting, lead, birds, and mold, were independently associated with ILA. Among 129 subjects with sufficient study time, 25 (19.4%) had an ILD event by 5 years after enrollment; of these, 12 met the study endpoint and another 13 had radiologic progression of ILA. ILD events were more common among those with early/mild ILA at enrollment (63.3% vs. 6.1%; P < 0.0001).Conclusions: Rare and common environmental exposures are independent risk factors for radiologic abnormalities. In 5 years, progression of ILA occurred in most individuals with early ILA detected at enrollment.


Asunto(s)
Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Adulto , Anciano , Fumar Cigarrillos/epidemiología , Estudios de Cohortes , Progresión de la Enfermedad , Exposición a Riesgos Ambientales/estadística & datos numéricos , Femenino , Volumen Espiratorio Forzado , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Estudios Longitudinales , Pulmón/fisiopatología , Enfermedades Pulmonares Intersticiales/epidemiología , Enfermedades Pulmonares Intersticiales/genética , Enfermedades Pulmonares Intersticiales/fisiopatología , Masculino , Persona de Mediana Edad , Mucina 5B/genética , Capacidad de Difusión Pulmonar , Tomografía Computarizada por Rayos X , Capacidad Pulmonar Total , Capacidad Vital
2.
J Allergy Clin Immunol ; 142(5): 1515-1528.e8, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29331643

RESUMEN

BACKGROUND: IL-33 is one of the most consistently associated gene candidates for asthma identified by using a genome-wide association study. Studies in mice and in human cells have confirmed the importance of IL-33 in inducing type 2 cytokine production from both group 2 innate lymphoid cells (ILC2s) and TH2 cells. However, there are no pharmacologic agents known to inhibit IL-33 release from airway cells. OBJECTIVE: We sought to determine the effect of glucagon-like peptide 1 receptor (GLP-1R) signaling on aeroallergen-induced airway IL-33 production and release and on innate type 2 airway inflammation. METHODS: BALB/c mice were challenged intranasally with Alternaria extract for 4 consecutive days. GLP-1R agonist or vehicle was administered starting either 2 days before the first Alternaria extract challenge or 1 day after the first Alternaria extract challenge. RESULTS: GLP-1R agonist treatment starting 2 days before the first Alternaria extract challenge decreased IL-33 release in the bronchoalveolar lavage fluid and dual oxidase 1 (Duox1) mRNA expression 1 hour after the first Alternaria extract challenge and IL-33 expression in lung epithelial cells 24 hours after the last Alternaria extract challenge. Furthermore, GLP-1R agonist significantly decreased the number of ILC2s expressing IL-5 and IL-13, lung protein expression of type 2 cytokines and chemokines, the number of perivascular eosinophils, mucus production, and airway responsiveness compared with vehicle treatment. GLP-1R agonist treatment starting 1 day after the first Alternaria extract challenge also significantly decreased eosinophilia and type 2 cytokine and chemokine expression in the airway after 4 days of Alternaria extract challenge. CONCLUSION: These results reveal that GLP-1R signaling might be a therapy to reduce IL-33 release and inhibit the ILC2 response to protease-containing aeroallergens, such as Alternaria.


Asunto(s)
Asma/inmunología , Péptido 1 Similar al Glucagón/inmunología , Receptor del Péptido 1 Similar al Glucagón/inmunología , Interleucina-33/inmunología , Alérgenos/inmunología , Alternaria/inmunología , Animales , Citocinas/inmunología , Dermatophagoides pteronyssinus/inmunología , Eosinofilia/inmunología , Femenino , Receptor del Péptido 1 Similar al Glucagón/agonistas , Inmunidad Innata , Pulmón/citología , Pulmón/inmunología , Linfocitos/inmunología , Ratones Endogámicos BALB C , Ratones Transgénicos , Moco/inmunología , Transducción de Señal
3.
Artículo en Inglés | MEDLINE | ID: mdl-29660395

RESUMEN

Endogenous prostaglandin I2 (PGI2) has inhibitory effects on immune responses against pathogens or allergens; however, the immunomodulatory activity of endogenous PGI2 signaling in endotoxin-induced inflammation is unknown. To test the hypothesis that endogenous PGI2 down-regulates endotoxin-induced lung inflammation, C57BL/6 wild type (WT) and PGI2 receptor (IP) KO mice were challenged intranasally with LPS. Urine 6-keto-PGF1α, a stable metabolite of PGI2, was significantly increased following the LPS-challenge, suggesting that endogenous PGI2 signaling modulates the host response to LPS-challenge. IPKO mice had a significant increase in neutrophils in the BAL fluid as well as increased proteins of KC, LIX, and TNF-α in lung homogenates compared with WT mice. In contrast, IL-10 was decreased in LPS-challenged IPKO mice compared with WT mice. The PGI2 analog cicaprost significantly decreased LPS-induced KC, and TNF-α, but increased IL-10 and AREG in bone marrow-derived dendritic cells (BMDCs) and bone marrow-derived macrophages (BMMs) compared with vehicle-treatment. These results indicated that endogenous PGI2 signaling attenuated neutrophilic lung inflammation through the reduced inflammatory cytokine and chemokine and enhanced IL-10.


Asunto(s)
Lesión Pulmonar Aguda/metabolismo , Epoprostenol/metabolismo , Lipopolisacáridos/toxicidad , Infiltración Neutrófila , Neutrófilos/metabolismo , Transducción de Señal , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/patología , Animales , Modelos Animales de Enfermedad , Epoprostenol/genética , Ratones , Ratones Noqueados , Neutrófilos/patología
4.
Thorax ; 71(7): 633-45, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27071418

RESUMEN

BACKGROUND: Group 2 innate lymphoid cells (ILC2) are an important source of the type 2 cytokines interleukin (IL)-5 and IL-13 that are critical to the allergic airway phenotype. Previous studies reported that histone deacetylase (HDAC) inhibition by trichostatin A (TSA) downregulated adaptive allergic immune responses; however, the effect of HDAC inhibition on the early innate allergic immune response is unknown. Therefore, we investigated the effect of TSA on innate airway inflammation mediated by ILC2 activation. METHODS: BALB/c mice were challenged intranasally with Alternaria extract, exogenous recombinant mouse IL-33 (rmIL-33) or the respective vehicles for four consecutive days following TSA or vehicle treatment. Bronchoalveolar lavage (BAL) fluids and lungs were harvested 24 h after the last challenge. RESULTS: We found that TSA treatment significantly decreased the number of ILC2 expressing IL-5 and IL-13 in the lungs challenged with Alternaria extract or rmIL-33 compared with vehicle treatment (p<0.05). TSA treatment significantly decreased protein expression of IL-5, IL-13, CCL11 and CCL24 in the lung homogenates from Alternaria extract-challenged mice or rmIL-33-challenged mice compared with vehicle treatment (p<0.05). Further, TSA treatment significantly decreased the number of perivascular eosinophils and mucus production in the large airways that are critical components of the asthma phenotype (p<0.05). TSA did not change early IL-33 release in the BAL fluids; however, TSA decreased lung IL-33 expression from epithelial cells 24 h after last Alternaria extract challenge compared with vehicle treatment (p<0.05). CONCLUSIONS: These results reveal that TSA reduces allergen-induced ILC2 activation and the early innate immune responses to an inhaled protease-containing aeroallergen.


Asunto(s)
Asma/inmunología , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Inmunidad Innata , Linfocitos/inmunología , Alérgenos/inmunología , Alternaria , Animales , Lavado Broncoalveolar , Quimiocina CCL11/metabolismo , Quimiocina CCL24/metabolismo , Interleucina-13/metabolismo , Interleucina-33/farmacología , Interleucina-5/metabolismo , Pulmón/inmunología , Ratones , Ratones Endogámicos BALB C
5.
J Virol ; 88(17): 9655-72, 2014 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-24920804

RESUMEN

UNLABELLED: Immune-mediated lung injury is a hallmark of lower respiratory tract illness caused by respiratory syncytial virus (RSV). STAT4 plays a critical role in CD4+ Th1 lineage differentiation and gamma interferon (IFN-γ) protein expression by CD4+ T cells. As CD4+ Th1 differentiation is associated with negative regulation of CD4+ Th2 and Th17 differentiation, we hypothesized that RSV infection of STAT4-/- mice would result in enhanced lung Th2 and Th17 inflammation and impaired lung Th1 inflammation compared to wild-type (WT) mice. We performed primary and secondary RSV challenges in WT and STAT4-/- mice and used STAT1-/- mice as a positive control for the development of RSV-specific lung Th2 and Th17 inflammation during primary challenge. Primary RSV challenge of STAT4-/- mice resulted in decreased T-bet and IFN-γ expression levels in CD4+ T cells compared to those of WT mice. Lung Th2 and Th17 inflammation did not develop in primary RSV-challenged STAT4-/- mice. Decreased IFN-γ expression by NK cells, CD4+ T cells, and CD8+ T cells was associated with attenuated weight loss and enhanced viral clearance with primary challenge in STAT4-/- mice compared to WT mice. Following secondary challenge, WT and STAT4-/- mice also did not develop lung Th2 or Th17 inflammation. In contrast to primary challenge, secondary RSV challenge of STAT4-/- mice resulted in enhanced weight loss, an increased lung IFN-γ expression level, and an increased lung RSV-specific CD8+ T cell response compared to those of WT mice. These data demonstrate that STAT4 regulates the RSV-specific CD8+ T cell response to secondary infection but does not independently regulate lung Th2 or Th17 immune responses to RSV challenge. IMPORTANCE: STAT4 is a protein critical for both innate and adaptive immune responses to viral infection. Our results show that STAT4 regulates the immune response to primary and secondary challenge with RSV but does not restrain RSV-induced lung Th2 or Th17 immune responses. These findings suggest that STAT4 expression may influence lung immunity and severity of illness following primary and secondary RSV infections.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Pulmón/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitiales Respiratorios/inmunología , Factor de Transcripción STAT4/inmunología , Células Th17/inmunología , Células Th2/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Pulmón/patología , Ratones Endogámicos BALB C , Ratones Noqueados , Factor de Transcripción STAT4/deficiencia
6.
BMC Med Genet ; 16: 82, 2015 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-26369942

RESUMEN

BACKGROUND: Despite the significant interest in ß2-Adrenergic receptor (ADRB2) polymorphisms related to asthma, whether ADRB2 genetic variants are similarly associated with acute respiratory tract infections have not been studied. We hypothesized that genetic variants in ADRB2 associated with a response to asthma therapy during an asthma exacerbation were also associated with severity of acute respiratory tract infections. METHODS: To test this hypothesis, we genotyped 5 common polymorphisms in the promoter region and coding block of the ADRB2 gene (loci -2387, -2274, -1343, +46, and +79) from 374 Caucasian and African American term infants who were enrolled at the time of acute respiratory illness over four respiratory viral seasons. Severity of respiratory tract infections was measured using a bronchiolitis severity score (BSS; range = 0-12, clinically significant difference = 0.5) with a higher score indicating more severe disease. We assigned the promoter, coding and combined promoter and coding haplotypes to the unphased genotype data. The associations between each of these five single-nucleotide polymorphisms (SNPs) as well as the haplotypes and infant BSS were analyzed using nonparametric univariate analysis and multivariable proportional odds model separately in Caucasians and African Americans. RESULTS: There was no significant association between infant BSS and each of the SNPs in both Caucasians and African Americans. However, promoter haplotype CCA was associated with a decreased BSS in African Americans in a dose dependent manner. The median (interquartile range) BSS of infants with no copies of the CCA haplotype, one copy, and two copies of the CCA haplotype were 5.5 (2.0, 8.0), 4.0 (1.0, 7.5), and 3.0 (1.0, 4.0), respectively. This dose dependent relationship persisted after adjusting for infant age, gender, daycare exposure, secondhand smoke exposure, prior history of breastfeeding, siblings at home, and enrollment season (adjusted odds ratio: 0.59, 95% confidence interval: 0.36, 0.98). There was no similar protective relationship of haplotype CCA on severity of respiratory tract infections identified in Caucasians. CONCLUSIONS: ADRB2 genotype may be predictive of severity of acute respiratory tract infections in African Americans, and potentially identify a subset of infants who may respond to beta-agonist therapy.


Asunto(s)
Regiones Promotoras Genéticas/genética , Receptores Adrenérgicos beta 2/genética , Infecciones del Sistema Respiratorio/genética , Infecciones del Sistema Respiratorio/patología , Infecciones del Sistema Respiratorio/virología , Negro o Afroamericano/genética , Estudios de Cohortes , Femenino , Genotipo , Haplotipos/genética , Humanos , Recién Nacido , Desequilibrio de Ligamiento , Masculino , Estudios Prospectivos , Estadísticas no Paramétricas , Estados Unidos , Población Blanca/genética
7.
Infect Immun ; 82(9): 3723-39, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24958709

RESUMEN

The Th17 cytokines interleukin-17A (IL-17A), IL-17F, and IL-22 are critical for the lung immune response to a variety of bacterial pathogens, including Klebsiella pneumoniae. Th2 cytokine expression in the airways is a characteristic feature of asthma and allergic airway inflammation. The Th2 cytokines IL-4 and IL-13 diminish ex vivo and in vivo IL-17A protein expression by Th17 cells. To determine the effect of IL-4 and IL-13 on IL-17-dependent lung immune responses to acute bacterial infection, we developed a combined model in which allergic airway inflammation and lung IL-4 and IL-13 expression were induced by ovalbumin sensitization and challenge prior to acute lung infection with K. pneumoniae. We hypothesized that preexisting allergic airway inflammation decreases lung IL-17A expression and airway neutrophil recruitment in response to acute K. pneumoniae infection and thereby increases the lung K. pneumoniae burden. As hypothesized, we found that allergic airway inflammation decreased the number of K. pneumoniae-induced airway neutrophils and lung IL-17A, IL-17F, and IL-22 expression. Despite the marked reduction in postinfection airway neutrophilia and lung expression of Th17 cytokines, allergic airway inflammation significantly decreased the lung K. pneumoniae burden and postinfection mortality. We showed that the decreased lung K. pneumoniae burden was independent of IL-4, IL-5, and IL-17A and partially dependent on IL-13 and STAT6. Additionally, we demonstrated that the decreased lung K. pneumoniae burden associated with allergic airway inflammation was both neutrophil and CCL8 dependent. These findings suggest a novel role for CCL8 in lung antibacterial immunity against K. pneumoniae and suggest new mechanisms of orchestrating lung antibacterial immunity.


Asunto(s)
Quimiocina CCL8/inmunología , Hipersensibilidad/inmunología , Inflamación/inmunología , Infecciones por Klebsiella/inmunología , Klebsiella pneumoniae/inmunología , Pulmón/inmunología , Neutrófilos/inmunología , Animales , Eosinófilos/inmunología , Eosinófilos/microbiología , Femenino , Hipersensibilidad/microbiología , Inflamación/microbiología , Interleucinas/inmunología , Infecciones por Klebsiella/microbiología , Pulmón/microbiología , Ratones , Ratones Endogámicos BALB C , Neutrófilos/microbiología , Ovalbúmina/inmunología , Neumonía Bacteriana/inmunología , Neumonía Bacteriana/microbiología
8.
J Immunol ; 188(3): 1027-35, 2012 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-22210911

RESUMEN

IL-13 is a central mediator of airway hyperresponsiveness and mucus expression, both hallmarks of asthma. IL-13 is found in the sputum of patients with asthma; therefore, IL-13 is an attractive drug target for treating asthma. We have shown previously that IL-13 inhibits Th17 cell production of IL-17A and IL-21 in vitro. Th17 cells are associated with autoimmune diseases, host immune responses, and severe asthma. In this study, we extend our in vitro findings and determine that IL-13 increases IL-10 production from Th17-polarized cells and that IL-13-induced IL-10 production negatively regulates the secretion of IL-17A and IL-21. To determine if IL-13 negatively regulates lung IL-17A expression via an IL-10-dependent mechanism in vivo, we used a model of respiratory syncytial virus (RSV) strain A2 infection in STAT1 knockout (KO) mice that increases lung IL-17A and IL-13 expression, cytokines not produced during RSV infection in wild-type mice. To test the hypothesis that IL-13 negatively regulates lung IL-17A expression, we created STAT1/IL-13 double KO (DKO) mice. We found that RSV-infected STAT1/IL-13 DKO mice had significantly greater lung IL-17A expression compared with that of STAT1 KO mice and that increased IL-17A expression was abrogated by anti-IL-10 Ab treatment. RSV-infected STAT1/IL-13 DKO mice also had increased neutrophil infiltration compared with that of RSV-infected STAT1 KO mice. Neutralizing IL-10 increased the infiltration of inflammatory cells into the lungs of STAT1 KO mice but not STAT1/IL-13 DKO mice. These findings are vital to understanding the potential side effects of therapeutics targeting IL-13. Inhibiting IL-13 may decrease IL-10 production and increase IL-17A production, thus potentiating IL-17A-associated diseases.


Asunto(s)
Interleucina-10/fisiología , Interleucina-13/fisiología , Interleucina-17/metabolismo , Neumonía/virología , Células Th17/metabolismo , Animales , Movimiento Celular , Pulmón/inmunología , Pulmón/metabolismo , Ratones , Ratones Noqueados , Infiltración Neutrófila/inmunología , Neumonía/inmunología , Neumonía/patología , Infecciones por Virus Sincitial Respiratorio/inmunología
9.
Am J Respir Crit Care Med ; 187(1): 34-41, 2013 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-23204253

RESUMEN

RATIONALE: Asthma is a heterogeneous lung disorder characterized by airway inflammation and airway dysfunction, manifesting as hyperresponsiveness and obstruction. Glutathione S-transferase M1 (GSTM1) is a multifunctional phase II enzyme and regulator of stress-activated cellular signaling relevant to asthma pathobiology. A common homozygous deletion polymorphism of the GSTM1 gene eliminates enzyme activity. OBJECTIVES: To determine the effect of GSTM1 on airway inflammation and reactivity in adults with established atopic asthma in vivo. METHODS: Nineteen GSTM1 wild-type and eighteen GSTM1-null individuals with mild atopic asthma underwent methacholine and inhaled allergen challenges, and endobronchial allergen provocations through a bronchoscope. MEASUREMENTS AND MAIN RESULTS: The influx of inflammatory cells, panels of cytokines and chemokines linked to asthmatic inflammation, F(2)-isoprostanes (markers of oxidative stress), and IgE were measured in bronchoalveolar lavage fluid at baseline and 24 hours after allergen instillation. Individuals with asthma with the GSTM1 wild-type genotype had greater baseline and allergen-provoked airway neutrophilia and concentrations of myeloperoxidase than GSTM1-null patients. In contrast, the eosinophilic inflammation was unaffected by GSTM1. The allergen-stimulated generation of acute-stress and proneutrophilic mediators, tumor necrosis factor-α, CXCL-8, IL-1ß, and IL-6, was also greater in the GSTM1 wild-type patients. Moreover, post-allergen airway concentrations of IgE and neutrophil-generated mediators, matrix metalloproteinase-9, B-cell activating factor, transforming growth factor-ß1, and elastase were higher in GSTM1 wild-type individuals with asthma. Total airway IgE correlated with B-cell activating factor concentrations. In contrast, levels of F(2)-isoprostane were comparable in both groups. Finally, GSTM1 wild-type individuals with asthma required lower threshold concentrations of allergen to produce bronchoconstriction. CONCLUSIONS: The functional GSTM1 genotype promotes neutrophilic airway inflammation in humans with atopic asthma in vivo.


Asunto(s)
Asma/genética , Glutatión Transferasa/genética , Neutrófilos/metabolismo , Adulto , Pruebas de Provocación Bronquial , Broncoconstricción/inmunología , Femenino , Genotipo , Humanos , Masculino , Adulto Joven
10.
Thorax ; 68(8): 717-23, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23422214

RESUMEN

BACKGROUND: Viral infections are the most frequent cause of asthma exacerbations and are linked to increased airway reactivity (AR) and inflammation. Mice infected with respiratory syncytial virus (RSV) during ovalbumin (OVA)-induced allergic airway inflammation (OVA/RSV) had increased AR compared with OVA or RSV mice alone. Furthermore, interleukin 17A (IL-17A) was only increased in OVA/RSV mice. OBJECTIVE: To determine whether IL-17A increases AR and inflammation in the OVA/RSV model. METHODS: Wild-type (WT) BALB/c and IL-17A knockout (KO) mice underwent mock, RSV, OVA or OVA/RSV protocols. Lungs, bronchoalveolar lavage (BAL) fluid and/or mediastinal lymph nodes (MLNs) were harvested after infection. Cytokine expression was determined by ELISA in the lungs or BAL fluid. MLNs were restimulated with either OVA (323-229) peptide or RSV M2 (127-135) peptide and IL-17A protein expression was analysed. AR was determined by methacholine challenge. RESULTS: RSV increased IL-17A protein expression by OVA-specific T cells 6 days after infection. OVA/RSV mice had decreased interferon-ß protein expression compared with RSV mice. OVA/RSV mice had increased IL-23p19 mRNA expression in lung homogenates compared with mock, OVA or RSV mice. Unexpectedly, IL-17A KO OVA/RSV mice had increased AR compared with WT OVA/RSV mice. Furthermore, IL-17A KO OVA/RSV mice had increased eosinophils, lymphocytes and IL-13 protein expression in BAL fluid compared with WT OVA/RSV mice. CONCLUSIONS: IL-17A negatively regulated AR and airway inflammation in OVA/RSV mice. This finding is important because IL-17A has been identified as a potential therapeutic target in asthma, and inhibiting IL-17A in the setting of virally-induced asthma exacerbations may have adverse consequences.


Asunto(s)
Asma/genética , Inflamación/metabolismo , Interleucina-17/genética , ARN Mensajero/genética , Infecciones por Virus Sincitial Respiratorio/genética , Animales , Asma/metabolismo , Asma/patología , Líquido del Lavado Bronquioalveolar/química , Citocinas/biosíntesis , Citocinas/genética , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Inflamación/genética , Inflamación/patología , Interleucina-17/biosíntesis , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , ARN Mensajero/biosíntesis , Reacción en Cadena en Tiempo Real de la Polimerasa , Infecciones por Virus Sincitial Respiratorio/metabolismo , Infecciones por Virus Sincitial Respiratorio/virología
11.
Biochem Biophys Res Commun ; 441(2): 418-24, 2013 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-24161390

RESUMEN

Mammalian cells contain two fatty acid synthesis pathways, the cytosolic FASI pathway, and the mitochondrial FASII pathway. The selection behind the conservation of the mitochondrial pathway is not completely understood, given the presence of the cytosolic FAS pathway. In this study, we show through heterologous gene reporter systems and PCR-based arrays that overexpression of MECR, the last step in the mtFASII pathway, causes modulation of gene expression through the PPAR pathway. Electromobility shift assays (EMSAs) demonstrate that overexpression of MECR causes increased binding of PPARs to DNA, while cell fractionation and imaging studies show that MECR remains localized to the mitochondria. Interestingly, knock down of the mtFASII pathway lessens the effect of MECR on this transcriptional modulation. Our data are most consistent with MECR-mediated transcriptional activation through products of the mtFASII pathway, although we cannot rule out MECR acting as a coactivator. Further investigation into the physiological relevance of this communication will be necessary to better understand some of the phenotypic consequences of deficits in this pathway observed in animal models and human disease.


Asunto(s)
Núcleo Celular/metabolismo , Ácidos Grasos/biosíntesis , Ácidos Grasos/genética , Mitocondrias/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Activación Transcripcional , Animales , Núcleo Celular/genética , Técnicas de Silenciamiento del Gen , Células HeLa , Humanos , Redes y Vías Metabólicas , Mitocondrias/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Receptores Activados del Proliferador del Peroxisoma/genética
13.
Hum Mutat ; 32(6): 579-89, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21120950

RESUMEN

Deficiency of carbamoyl phosphate synthetase I (CPSI) results in hyperammonemia ranging from neonatally lethal to environmentally induced adult-onset disease. Over 24 years, analysis of tissue and DNA samples from 205 unrelated individuals diagnosed with CPSI deficiency (CPSID) detected 192 unique CPS1 gene changes, of which 130 are reported here for the first time. Pooled with the already reported mutations, they constitute a total of 222 changes, including 136 missense, 15 nonsense, 50 changes of other types resulting in enzyme truncation, and 21 other changes causing in-frame alterations. Only ∼10% of the mutations recur in unrelated families, predominantly affecting CpG dinucleotides, further complicating the diagnosis because of the "private" nature of such mutations. Missense changes are unevenly distributed along the gene, highlighting the existence of CPSI regions having greater functional importance than other regions. We exploit the crystal structure of the CPSI allosteric domain to rationalize the effects of mutations affecting it. Comparative modeling is used to create a structural model for the remainder of the enzyme. Missense changes are found to directly correlate, respectively, with the one-residue evolutionary importance and inversely correlate with solvent accessibility of the mutated residue. This is the first large-scale report of CPS1 mutations spanning a wide variety of molecular defects highlighting important regions in this protein.


Asunto(s)
Carbamoil-Fosfato Sintasa (Amoniaco)/genética , Enfermedad por Deficiencia de Carbamoil-Fosfato Sintasa I/diagnóstico , Enfermedad por Deficiencia de Carbamoil-Fosfato Sintasa I/genética , Hiperamonemia/genética , Carbamoil-Fosfato Sintasa (Amoniaco)/química , Codón sin Sentido/genética , Análisis Mutacional de ADN , Humanos , Mutación INDEL/genética , Modelos Químicos , Mutación Missense/genética , Conformación Proteica , Isoformas de Proteínas/genética
14.
Pediatr Allergy Immunol Pulmonol ; 28(3): 158-164, 2015 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-26421213

RESUMEN

Background: Infants with lower respiratory tract infections (LRTIs) are at an increased risk of developing childhood wheezing illnesses (including asthma), but it is not currently possible to predict those at risk for these long-term outcomes. The current objective was to examine whether urine levels of club cell 16-kDa secretory protein (CC16) at the time of an infant LRTI are associated with the development of childhood wheezing illnesses. Methods: Prospective study of 133 previously healthy infants enrolled during a healthcare visit for a LRTI and followed longitudinally for childhood wheezing illnesses. Urine levels of CC16 at the time of enrollment were measured after validating a commercially available enzyme-linked immunosorbent assay kit for serum. The outcome of interest was parental report of subsequent childhood wheeze (defined as ≥1 episode of wheezing following the initial LRTI) at the 1-year follow-up visit. Logistic regression was used for the main analysis. Results: The median (interquartile range) urine levels of CC16 (ng/mg of creatinine) at the time of an infant LRTI were 11.1 (7.7-20.1) for infants with subsequent childhood wheeze and 13.4 (8.3-61.1) for those without (p = 0.11). In the main multivariate analysis using a logarithmic transformation of the urine levels of CC16, a twofold increase in urine levels of CC16 was associated with ∼30% decreased odds (OR = 0.74 [95% confidence interval (CI) 0.56-0.98], p = 0.04) of subsequent childhood wheeze after adjustment for potential confounders. Conclusions: An inverse association was found between urine levels of CC16 at the time of an infant LRTI and the odds of subsequent childhood wheeze. Urine CC16 may be a useful biomarker of the development of childhood wheezing illnesses after LRTIs in infancy.

15.
Neurotoxicology ; 32(6): 769-75, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21798283

RESUMEN

Autism is a common neurodevelopmental disorder with genetic and environmental components. Though unproven, genetic susceptibility to high mercury (Hg) body burden has been suggested as an autism risk factor in a subset of children. We hypothesized that exposure to "safe" Hg levels could be implicated in the etiology of autism if genetic susceptibility altered Hg's metabolism or intracellular compartmentalization. Genetic sequences of four genes implicated in the transport and response to Hg were screened for variation and association with autism. LAT1 and DMT1 function in Hg transport, and Hg exposure induces MTF1 and MT1a. We identified and characterized 74 variants in MT1a, DMT1, LAT1 and MTF1. Polymorphisms identified through screening 48 unrelated individuals from the general and autistic populations were evaluated for differences in allele frequencies using Fisher's exact test. Three variants with suggestive p-values <0.1 and four variants with significant p-values <0.05 were followed-up with TaqMan genotyping in a larger cohort of 204 patients and 323 control samples. The pedigree disequilibrium test was used to examine linkage and association. Analysis failed to show association with autism for any variant evaluated in both the initial screening set and the expanded cohort, suggesting that variations in the ability of the four genes studied to process and transport Hg may not play a significant role in the etiology of autism.


Asunto(s)
Trastorno Autístico/genética , Proteínas de Transporte de Catión/genética , Proteínas de Unión al ADN/genética , Transportador de Aminoácidos Neutros Grandes 1/genética , Mercurio/metabolismo , Metalotioneína/genética , Polimorfismo Genético , Factores de Transcripción/genética , Adolescente , Trastorno Autístico/metabolismo , Estudios de Casos y Controles , Proteínas de Transporte de Catión/metabolismo , Niño , Preescolar , Proteínas de Unión al ADN/metabolismo , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Desequilibrio de Ligamiento , Masculino , Metalotioneína/metabolismo , Fenotipo , Medición de Riesgo , Factores de Riesgo , Tennessee , Factores de Transcripción/metabolismo , Adulto Joven , Factor de Transcripción MTF-1
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