RESUMEN

ABSTRACT: Sleep-disordered breathing (SDB) is a contributor to atrial fibrillation (AF) and treatment of obstructive sleep apnea can reduce the recurrence of AF following catheter ablation. However, the effect of AF therapies on measures of SDB severity is less robustly described. We present the case of a middle-aged man with SDB and persistent AF who exhibited improvement in SDB metrics, as characterized by data downloaded from his auto-titrating continuous positive airway pressure (AutoCPAP) machine, very shortly following procedures that restored sinus rhythm. Between procedures, when his rhythm reverted to AF, the downloaded parameters suggested more SDB events. After catheter ablation, the patient maintained sinus rhythm and the improvement in SDB metrics was sustained as well. This case provides support in favor of a bidirectional relationship between SDB and AF and suggests that data available from PAP machines may be useful in serial assessment of SDB status relative to heart rhythm.

Asunto(s)

Fibrilación Atrial/terapia , Respiración con Presión Positiva , Síndromes de la Apnea del Sueño/terapia , Anciano , Ablación por Catéter , Cardioversión Eléctrica , Humanos , Masculino , Polisomnografía , Recurrencia

RESUMEN

RATIONALE: Effective therapeutic interventions for chronic, idiopathic lung diseases remain elusive. Normalized T-cell function is an important contributor to spontaneous resolution of pulmonary sarcoidosis. Up-regulation of inhibitor receptors, such as programmed death-1 (PD-1) and its ligand, PD-L1, are important inhibitors of T-cell function. OBJECTIVES: To determine the effects of PD-1 pathway blockade on sarcoidosis CD4(+) T-cell proliferative capacity. METHODS: Gene expression profiles of sarcoidosis and healthy control peripheral blood mononuclear cells were analyzed at baseline and follow-up. Flow cytometry was used to measure ex vivo expression of PD-1 and PD-L1 on systemic and bronchoalveolar lavage-derived cells of subjects with sarcoidosis and control subjects, as well as the effects of PD-1 pathway blockade on cellular proliferation after T-cell receptor stimulation. Immunohistochemistry analysis for PD-1/PD-L1 expression was conducted on sarcoidosis, malignant, and healthy control lung specimens. MEASUREMENTS AND MAIN RESULTS: Microarray analysis demonstrates longitudinal increase in PDCD1 gene expression in sarcoidosis peripheral blood mononuclear cells. Immunohistochemistry analysis revealed increased PD-L1 expression within sarcoidosis granulomas and lung malignancy, but this was absent in healthy lungs. Increased numbers of sarcoidosis PD-1(+) CD4(+) T cells are present systemically, compared with healthy control subjects (P < 0.0001). Lymphocytes with reduced proliferative capacity exhibited increased proliferation with PD-1 pathway blockade. Longitudinal analysis of subjects with sarcoidosis revealed reduced PD-1(+) CD4(+) T cells with spontaneous clinical resolution but not with disease progression. CONCLUSIONS: Analogous to the effects in other chronic lung diseases, these findings demonstrate that the PD-1 pathway is an important contributor to sarcoidosis CD4(+) T-cell proliferative capacity and clinical outcome. Blockade of the PD-1 pathway may be a viable therapeutic target to optimize clinical outcomes.

Asunto(s)

Antígeno B7-H1/metabolismo , Linfocitos T CD4-Positivos/fisiología , Receptor de Muerte Celular Programada 1/metabolismo , Sarcoidosis Pulmonar/inmunología , Adulto , Anciano , Anticuerpos , Antígeno B7-H1/inmunología , Biomarcadores/metabolismo , Estudios de Casos y Controles , Proliferación Celular , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/inmunología , Remisión Espontánea , Sarcoidosis Pulmonar/metabolismo , Regulación hacia Arriba

RESUMEN

OBJECTIVE: To determine the feasibility of administering iloprost by inhalation in patients with mild atopic asthma. METHODS: Volunteers underwent supervised inhalation of iloprost in the clinic with measurement of spirometry and blood pressure for 2 hours. The volunteers then inhaled iloprost four times daily at a dose of 2.5 or 5 µg for 14 days. Spirometry, asthma questionnaires, peak flow diaries, measurement of methacholine responsiveness, and exhaled nitric oxide concentrations were obtained prior to and after the treatment period. RESULTS: Chronic inhalation of iloprost (2.5-5 µg) did not alter spirometry or methacholine responsiveness. CONCLUSION: Inhaled iloprost in carefully selected volunteers with mild asthma appears to be a suitable intervention to explore the effects of prostacyclin in human asthma.

Asunto(s)

Asma/tratamiento farmacológico , Iloprost/uso terapéutico , Prostaglandinas I/uso terapéutico , Administración por Inhalación , Adulto , Presión Sanguínea/efectos de los fármacos , Hiperreactividad Bronquial , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Iloprost/administración & dosificación , Iloprost/efectos adversos , Masculino , Persona de Mediana Edad , Óxido Nítrico , Prostaglandinas I/administración & dosificación , Prostaglandinas I/efectos adversos , Espirometría

RESUMEN

BACKGROUND: Current asthma guidelines recommend assessing the level of a patient's asthma control. Consequently, there is increasing use of asthma control as an outcome measure in clinical research studies. Several composite assessment instruments have been developed to measure asthma control. OBJECTIVE: National Institutes of Health institutes and federal agencies convened an expert group to propose the most appropriate standardized composite score of asthma control instruments to be used in future asthma studies. METHODS: We conducted a comprehensive search of PubMed using both the National Library of Medicine's Medical Subject Headings and key terms to identify studies that attempted to develop and/or test composite score instruments for asthma control. We classified instruments as core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at a National Institutes of Health-organized workshop convened in March 2010 and finalized in September 2011. RESULTS: We identified 17 composite score instruments with published validation information; all had comparable content. Eight instruments demonstrated responsiveness over time; 3 demonstrated responsiveness to treatment. A minimal clinically important difference has been established for 3 instruments. The instruments have demographic limitations; some are proprietary, and their use could be limited by cost. CONCLUSION: Two asthma composite score instruments are sufficiently validated for use in adult populations, but additional research is necessary to validate their use in nonwhite populations. Gaps also exist in validating instruments for pediatric populations.

Asunto(s)

Asma/terapia , Evaluación de Resultado en la Atención de Salud/normas , Adolescente , Adulto , Asma/fisiopatología , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios/normas , Resultado del Tratamiento

RESUMEN

Acute asthma exacerbations are one of the most common reasons for paediatric emergency department visits and hospitalisations, and a relapse frequently necessitates repeat urgent care. While care plans exist, there are no acute asthma prediction rules (APRs) to assess severity and predict outcome. The primary objective of the Acute Asthma Severity Assessment Protocol study is to develop a multivariable APR for acute asthma exacerbations in paediatric patients. A prospective, convenience sample of paediatric patients aged 5-17 years with acute asthma exacerbations who present to an urban, academic, tertiary paediatric emergency department was enrolled. The study protocol and data analysis plan conform to accepted biostatistical and clinical standards for clinical prediction rule development. Modelling of the APR will be performed once the entire sample size of 1500 has accrued. It is anticipated that the APR will improve resource utilisation in the emergency department, aid in standardisation of disease assessment and allow physician and non-physician providers to participate in earlier objective decision making. The objective of this report is to describe the study objectives and detailed methodology of the Acute Asthma Severity Assessment Protocol study.

Asunto(s)

Asma/diagnóstico , Enfermedad Aguda , Adolescente , Asma/fisiopatología , Niño , Preescolar , Protocolos Clínicos , Servicio de Urgencia en Hospital , Femenino , Humanos , Masculino , Modelos Teóricos , Análisis Multivariante , Valor Predictivo de las Pruebas , Estudios Prospectivos , Pruebas de Función Respiratoria , Índice de Severidad de la Enfermedad

RESUMEN

BACKGROUND: In this descriptive case series, 80 soldiers from Fort Campbell, Kentucky, with inhalational exposures during service in Iraq and Afghanistan were evaluated for dyspnea on exertion that prevented them from meeting the U.S. Army's standards for physical fitness. METHODS: The soldiers underwent extensive evaluation of their medical and exposure history, physical examination, pulmonary-function testing, and high-resolution computed tomography (CT). A total of 49 soldiers underwent thoracoscopic lung biopsy after noninvasive evaluation did not provide an explanation for their symptoms. Data on cardiopulmonary-exercise and pulmonary-function testing were compared with data obtained from historical military control subjects. RESULTS: Among the soldiers who were referred for evaluation, a history of inhalational exposure to a 2003 sulfur-mine fire in Iraq was common but not universal. Of the 49 soldiers who underwent lung biopsy, all biopsy samples were abnormal, with 38 soldiers having changes that were diagnostic of constrictive bronchiolitis. In the remaining 11 soldiers, diagnoses other than constrictive bronchiolitis that could explain the presenting dyspnea were established. All soldiers with constrictive bronchiolitis had normal results on chest radiography, but about one quarter were found to have mosaic air trapping or centrilobular nodules on chest CT. The results of pulmonary-function and cardiopulmonary-exercise testing were generally within normal population limits but were inferior to those of the military control subjects. CONCLUSIONS: In 49 previously healthy soldiers with unexplained exertional dyspnea and diminished exercise tolerance after deployment, an analysis of biopsy samples showed diffuse constrictive bronchiolitis, which was possibly associated with inhalational exposure, in 38 soldiers.

Asunto(s)

Bronquiolos/patología , Bronquiolitis Obliterante/fisiopatología , Tolerancia al Ejercicio , Personal Militar , Adulto , Campaña Afgana 2001- , Bronquiolitis Obliterante/diagnóstico por imagen , Bronquiolitis Obliterante/patología , Prueba de Esfuerzo , Estudios de Seguimiento , Humanos , Guerra de Irak 2003-2011 , Pulmón/diagnóstico por imagen , Pulmón/patología , Prevalencia , Pruebas de Función Respiratoria , Tomografía Computarizada por Rayos X , Estados Unidos

RESUMEN

BACKGROUND: Acute asthma severity scores facilitate assessment and implementation of timely and appropriate therapy for pediatric patients but are complex and challenging for clinicians to use at the bedside. OBJECTIVE: To assess whether a simple, bedside acute asthma severity score comprising 3 standard clinical measures performs as well as more comprehensive asthma scores. METHODS: We prospectively enrolled participants 5 to 17 years of age with acute asthma exacerbations. We recorded 3 asthma scores at baseline and after 2 hours of treatment: the Pediatric Asthma Severity Score (PASS), the Pediatric Respiratory Assessment Measure (PRAM), and the RAD score (Respiratory rate; Accessory muscle use; Decreased breath sounds). We assessed each score for criterion validity in predicting baseline percent forced expiratory volume in 1 second (%FEV(1)) and for responsiveness in predicting change of %FEV(1) after 2 hours of treatment using multiple linear regression models adjusted for age, race, sex, and Global Initiative for Asthma chronic control. RESULTS: Of 536 participants included for analyses, median age was 8.8 years, 60% were male, and 58% were African American. The 3 acute asthma scores demonstrated similar criterion validity to explain variation of baseline %FEV(1) (R(2): 0.434 [PASS]; 0.462 [PRAM]; 0.426 [RAD]), but none demonstrated clinically significant responsiveness to change in %FEV(1) (R(2): 0.109 [PASS]; 0.106 [PRAM]; 0.139 [RAD]). CONCLUSIONS: The RAD score, comprising 3 routinely measured bedside clinical parameters, is a simple and easily used instrument for assessing the severity of an acute asthma exacerbation and has comparable criterion validity and improved responsiveness when compared with 2 more complex acute asthma scores.

Asunto(s)

Asma/fisiopatología , Índice de Severidad de la Enfermedad , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Estudios Prospectivos , Pruebas de Función Respiratoria

Asunto(s)

Asma/fisiopatología , Músculo Esquelético/fisiopatología , Adolescente , Niño , Preescolar , Estudios de Cohortes , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Estudios Prospectivos , Estadísticas no Paramétricas

RESUMEN

Nuclear factor kappa B (NF-kappa B) is a critical transcription factor for the production of many inflammatory cytokines. It is activated in the airway epithelium of human asthmatics and in mice after allergic stimulation. To examine the role of NF-kappa B activation in allergic inflammation, the authors generated transgenic mouse lines that allowed for the inducible stimulation of NF-kappa B in airway epithelial cells. After allergic sensitization with ovalbumin and alum, mice were challenged daily with ovalbumin aerosols and NF-kappa B was activated in airway epithelium by administration of doxycycline. Enhancement of airway epithelial NF-kappa B expression alone did not lead to increased airway responsiveness to methacholine. However, induction of epithelial NF-kappa B during allergic inflammation caused airway hyperresponsiveness, increased airway neutrophilic and lymphocytic inflammation and goblet cell hyperplasia. Accompanying the exaggerated inflammation was an increase in the cytokines granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-15, and KC. Interestingly, the counter regulatory interleukin, IL-10, was suppressed by NF-kappa B activation. The epithelial NF-kappa B dependent modulation of these cytokines provides a plausible explanation for the increased inflammation seen with overexpression of NF-kappa B. Modulation of airway epithelial NF-kappa B activation enhances the airway hyperresponsiveness and mucus secretion found in the mouse lung during allergic inflammation. NF-kappa B represents a potential target for pharmacologic intervention in human asthma.

Asunto(s)

Alérgenos/administración & dosificación , FN-kappa B/biosíntesis , Neumonía/inmunología , Neumonía/metabolismo , Sistema Respiratorio/inmunología , Sistema Respiratorio/metabolismo , Animales , Asma/inmunología , Asma/metabolismo , Líquido del Lavado Bronquioalveolar/citología , Citocinas/metabolismo , Epitelio/inmunología , Epitelio/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Ratones , Ratones Transgénicos , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Neumonía/patología , Sistema Respiratorio/patología , Transducción de Señal

RESUMEN

OBJECTIVE: To determine if African American and European American children with asthma admitted to an intensive care unit (ICU) had different characteristics, we conducted a retrospective chart review of asthma admissions to the region's only pediatric ICU. PATIENTS AND METHODS: A chart review was performed on 125 patients with asthma admitted to the pediatric critical care unit at Vanderbilt Children's Hospital. Descriptive statistics, clinical characteristics, and disparities in care were compared using either Fisher's exact tests or Wilcoxon ranksum tests. RESULTS: Most of the children reported previous admissions to a pediatric ICU (63%) or a hospital (82%) for asthma. Despite this, only 48% of the children were taking inhaled corticosteroids before admission. Only 28% of the children reported being followed by an asthma specialist, but, of these, 97% were taking corticosteroids. There were no racial/ethnic disparities in medication use, treatment, or outcomes. CONCLUSION: We found no racial/ethnic disparities in inpatient/outpatient medication usage, treatment, or outcomes between African American and European American children in our cohort. Recurrent admissions to the ICU among children with severe asthma are common, and inhaled corticosteroids usage is relatively low. Asthmatic children with ICU admissions should be followed and treated aggressively by an asthma specialist.

Asunto(s)

Asma/etnología , Negro o Afroamericano , Población Blanca , Asma/tratamiento farmacológico , Niño , Cuidados Críticos , Femenino , Disparidades en Atención de Salud , Humanos , Tiempo de Internación , Masculino , Respiración Artificial , Estudios Retrospectivos

RESUMEN

African Americans are disproportionately affected by asthma. Social and economic factors play a role in this disparity, but there is evidence that genetic factors may also influence the development of asthma and response to therapy in African American children. Our hypothesis is that variations in asthma related genes contribute to the observed asthma disparities by influencing the response to asthma-specific therapy. In order to test this hypothesis, we characterized the clinical response to asthma-specific therapy in 107 African American children who presented to the emergency room in status asthmaticus, with a primary outcome indicator of length of time on continuous albuterol. Single locus analysis indicated that genotype variation in glutathione-dependent S-nitrosoglutathione reductase (GSNOR) is associated with a decreased response to asthma treatment in African American children. A post hoc multi-locus analysis revealed that a combination of four single nucleotide polymorphisms (SNPs) within GSNOR, adrenergic receptor beta 2, and carbamoyl phosphate synthetase-1 give a 70% predictive value for lack of response to therapy. This predictive model needs replication in other cohorts of patients with asthma, but suggests gene-gene interactions may have greater significance than that identified with single variants. Our findings also suggest that genetic variants may contribute to the observed population disparities in asthma.

Asunto(s)

Albuterol/uso terapéutico , Aldehído Oxidorreductasas/genética , Asma/genética , Negro o Afroamericano/genética , Broncodilatadores/uso terapéutico , Polimorfismo de Nucleótido Simple/genética , Adolescente , Asma/tratamiento farmacológico , Niño , Preescolar , Resistencia a Medicamentos/genética , Humanos , Desequilibrio de Ligamiento , Farmacogenética , Receptores Adrenérgicos beta 2/genética

RESUMEN

BACKGROUND: Invariant natural killer T (iNKT) cells produce cytokines that can influence the immune response to infection or allergen. Controversy surrounds their role in exacerbations of human atopic asthma. OBJECTIVES: To determine the effect of allergen challenge on iNKT cells' mobilization to the airways and blood and to establish the relationship between airway iNKT cells and bronchial sensitivity to methacholine and allergen in patients with atopic asthma. METHODS: We performed flow cytometry analysis for the iNKT cell receptor Va24 and V311 on bronchoalveolar lavage (BAL) cells at baseline and 24 hours after segmental antigen challenge (SAC) (n = 8) and on peripheral blood mononuclear cells (PBMCs) at baseline and 6 to 7 hours after inhaled allergen (n = 10). Challenges were performed using standardized protein allergens to which the participants were sensitive. RESULTS: The number of BAL eosinophils increased 24 hours after SAC. The low mean (SEM) baseline percentage of iNKT cells in the population of BAL CD4' T cells remained unchanged 24 hours after SAC (0.035% [0.01%] vs 0.049% [0.02%]; n = 8; P = .50). Likewise, the mean (SEM) percentage of iNKT cells in PBMCs was unchanged after inhaled allergen provocation (0.068% [0.033%] vs 0.057% [0.026%]; n = 10; P = .10). No correlation was found between iNKT cells in BAL and the sensitivity to inhaled methacholine or allergen. CONCLUSIONS: The percentages of both BAL and peripheral blood iNKT cells did not increase during allergen provoked asthmatic responses. Determination of iNKT cells in airway biopsy specimens would allow conclusively ruling against mobilization of iNKT cells in allergen-induced asthma exacerbation in humans.

Asunto(s)

Alérgenos/inmunología , Asma/inmunología , Pruebas de Provocación Bronquial , Células T Asesinas Naturales/citología , Células T Asesinas Naturales/inmunología , Adulto , Asma/fisiopatología , Células Sanguíneas/citología , Líquido del Lavado Bronquioalveolar/citología , Eosinófilos/citología , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Volumen Espiratorio Forzado/inmunología , Humanos , Recuento de Linfocitos , Masculino , Cloruro de Metacolina/farmacología , Neutrófilos/citología , Adulto Joven

RESUMEN

The Shanghai Women's Asthma and Allergy Study is the first population-based incidence study designed to assess the associations of dietary antioxidant intake and measures of oxidative stress and antioxidant enzyme activity with development of adult-onset asthma and allergic rhinitis. A total of 65,732 participants in the Shanghai Women's Health Study, an ongoing cohort study in seven districts of Shanghai, People's Republic of China, were recruited to the Shanghai Women's Asthma and Allergy Study from 2003 to 2007. Dietary intake was assessed in the parent study by using a validated and quantitative food frequency questionnaire at baseline recruitment and at the first biennial follow-up survey. Blood and urine samples were collected to measure baseline oxidative stress, antioxidant enzyme activity, and nutrient levels at the baseline survey. Incident asthma and allergic rhinitis were assessed by using a modification of the International Study of Asthma and Allergies in Childhood questionnaire during the biennial in-person survey of the Shanghai Women's Health Study. Diagnosis of asthma was confirmed by either methacholine challenge testing or test of reversibility to beta-agonists. Dietary antioxidant intake, plasma antioxidants, antioxidant enzymes, and urinary isoprostanes, a marker of oxidative stress, were measured prior to disease onset. This paper describes the study objectives, design, population demographics, and recruitment results.

Asunto(s)

Antioxidantes/administración & dosificación , Asma/epidemiología , Hipersensibilidad/epidemiología , Proyectos de Investigación , Salud de la Mujer , Adulto , Edad de Inicio , Anciano , Biomarcadores/sangre , Biomarcadores/orina , Estudios de Casos y Controles , China/epidemiología , Conducta Alimentaria , Femenino , Humanos , Incidencia , Entrevistas como Asunto , Persona de Mediana Edad , Estrés Oxidativo , Estudios Prospectivos , Factores de Riesgo , Encuestas y Cuestionarios

RESUMEN

To investigate changes in oxidant stress during and following acute asthma exacerbations, this study measured 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP (F(2)-IsoP-M), the major urinary metabolite of 15-F(2t)-IsoP, in eight asthmatic adults, during and following an asthma hospitalization. F(2)-IsoP-M concentrations at admission and follow-up were significantly higher than discharge (admission median: 4.12 ng/Cr mg, range 1.89-7.8; follow-up: 2.47 ng/Cr mg (1.56-6.86); discharge: 1.42 ng/Cr mg (0.7-4.44); both p<0.01), but not significantly different between admission and follow-up. F(2)-IsoP-M concentrations at follow-up were higher than a control group with stable asthma (0.68 ng/Cr mg (0.31-1.5), p=0.0008). In conclusion, asthma exacerbations requiring hospitalization are associated with 6-fold higher urinary F(2)-IsoP-M concentrations compared to stable asthmatics. F(2)-IsoP-M concentrations decreased significantly during hospitalization, but significant elevations 3 months following hospitalization suggest ongoing oxidative stress despite clinical improvement. Urinary F(2)-IsoP-M may be a clinically useful, simple non-invasive systemic measure of oxidative stress in asthmatics, providing information not captured by spirometry or symptoms.

Asunto(s)

Asma/diagnóstico , Dinoprost/análogos & derivados , Estrés Oxidativo , Adulto , Biomarcadores/orina , Estudios de Casos y Controles , Dinoprost/metabolismo , Dinoprost/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

Although airway epithelial cells provide important barrier and host defense functions, a crucial role for these cells in development of acute lung inflammation and injury has not been elucidated. We investigated whether NF-kappaB pathway signaling in airway epithelium could decisively impact inflammatory phenotypes in the lungs by using a tetracycline-inducible system to achieve selective NF-kappaB activation or inhibition in vivo. In transgenic mice that express a constitutively active form of IkappaB kinase 2 under control of the epithelial-specific CC10 promoter, treatment with doxycycline induced NF-kappaB activation with consequent production of a variety of proinflammatory cytokines, high-protein pulmonary edema, and neutrophilic lung inflammation. Continued treatment with doxycycline caused progressive lung injury and hypoxemia with a high mortality rate. In contrast, inducible expression of a dominant inhibitor of NF-kappaB in airway epithelium prevented lung inflammation and injury resulting from expression of constitutively active form of IkappaB kinase 2 or Escherichia coli LPS delivered directly to the airways or systemically via an osmotic pump implanted in the peritoneal cavity. Our findings indicate that the NF-kappaB pathway in airway epithelial cells is critical for generation of lung inflammation and injury in response to local and systemic stimuli; therefore, targeting inflammatory pathways in airway epithelium could prove to be an effective therapeutic strategy for inflammatory lung diseases.

Asunto(s)

Pulmón/inmunología , Pulmón/patología , FN-kappa B/fisiología , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/patología , Transducción de Señal/inmunología , Enfermedad Aguda , Animales , Células Cultivadas , Femenino , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/prevención & control , Mediadores de Inflamación/metabolismo , Mediadores de Inflamación/fisiología , Lipopolisacáridos/farmacología , Pulmón/metabolismo , Masculino , Ratones , Ratones Transgénicos , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Mucosa Respiratoria/metabolismo , Transducción de Señal/genética , Tráquea/inmunología , Tráquea/metabolismo , Tráquea/patología

RESUMEN

The allergic inflammation occurring in asthma is believed to be accompanied by the production of free radicals. To investigate the role of free radicals and the cells affected we turned to a murine model of allergic inflammation produced by sensitization to ovalbumin with subsequent aerosol challenge. We examined oxidant stress by measuring and localizing the sensitive and specific marker of lipid peroxidation, the F2-isoprostanes. F2-isoprostanes in whole lung increased from 0.30 +/- 0.08 ng/lung at baseline to a peak of 0.061 +/- 0.09 ng/lung on the ninth day of daily aerosol allergen challenge. Increased immunoreactivity to 15-F2t-IsoP (8-iso-PGF2alpha) or to isoketal protein adducts was found in epithelial cells 24 h after the first aerosol challenge and at 5 days in macrophages. Collagen surrounding airways and blood vessels, and airway and vascular smooth muscle, also exhibited increased immunoreactivity after ovalbumin challenge. Dietary vitamin E restriction in conjunction with allergic inflammation led to increased whole lung F2-isoprostanes while supplemental vitamin E suppressed their formation. Similar changes in immunoreactivity to F2-isoprostanes were seen. Airway responsiveness to methacholine was also increased by vitamin E depletion and decreased slightly by supplementation with the antioxidant. Our findings indicate that allergic airway inflammation in mice is associated with an increase in oxidant stress, which is most striking in airway epithelial cells and macrophages. Oxidant stress plays a role in the production of airway responsiveness.

Asunto(s)

Asma/fisiopatología , F2-Isoprostanos/fisiología , Estrés Oxidativo , Animales , Asma/inmunología , Líquido del Lavado Bronquioalveolar/química , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Peroxidación de Lípido/efectos de los fármacos , Pulmón/inmunología , Pulmón/fisiología , Macrófagos Alveolares/química , Cloruro de Metacolina , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ovalbúmina/inmunología , Organismos Libres de Patógenos Específicos , Espectrometría de Masa por Ionización de Electrospray , Vitamina E/administración & dosificación , Vitamina E/sangre , Deficiencia de Vitamina E/fisiopatología

RESUMEN

F2-isoprostanes are produced in vivo by nonenzymatic peroxidation of arachidonic acid esterified in phospholipids. Increased urinary and plasma F2-isoprostane levels are associated with a number of human diseases. These metabolites are regarded as excellent markers of oxidant stress in vivo. Isoprostanes are initially generated in situ, i.e. when the arachidonate precursor is esterified in phospholipids, and they are subsequently released in free form. Although the mechanism(s) responsible for the release of free isoprostanes after in situ generation in membrane phospholipids is, for the most part, unknown, this process is likely mediated by phospholipase A2 activity(ies). Here we reported that human plasma contains an enzymatic activity that catalyzes this reaction. The activity associates with high density and low density lipoprotein and comigrates with platelet-activating factor (PAF) acetylhydrolase on KBr density gradients. Plasma samples from subjects deficient in PAF acetylhydrolase do not release F2-isoprostanes from esterified precursors. The intracellular PAF acetylhydrolase II, which shares homology to the plasma enzyme, also catalyzes this reaction. We found that both the intracellular and plasma PAF acetylhydrolases have high affinity for esterified F2-isoprostanes. However, the rate of esterified F2-isoprostane hydrolysis is much slower compared with the rate of hydrolysis of other substrates utilized by these enzymes. Studies using PAF acetylhydrolase transgenic mice indicated that these animals have a higher capacity to release F2-isoprostanes compared with nontransgenic littermates. Our results suggested that PAF acetylhydrolases play key roles in the hydrolysis of F2-isoprostanes esterified on phospholipids in vivo.

Asunto(s)

1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , F2-Isoprostanos/química , Fosfolípidos/química , 1-Alquil-2-acetilglicerofosfocolina Esterasa/química , Acetatos/química , Aldehídos/química , Animales , Bromuros/química , Catálisis , ADN Complementario/metabolismo , Humanos , Hidrólisis , Isoprostanos/química , Cinética , Lipoproteínas/química , Ratones , Ratones Transgénicos , Ovalbúmina/metabolismo , Oxidantes/química , Estrés Oxidativo , Fosfatidilcolinas/química , Fosfolipasas A2 , Éteres Fosfolípidos/química , Compuestos de Potasio/química , Proteínas Recombinantes/química , Tráquea/metabolismo

RESUMEN

Cyclooxygenase (COX) inhibition during allergic sensitization and allergen airway challenge results in augmented allergic inflammation. We hypothesized that this increase in allergic inflammation was dependent on increased generation of leukotrienes that results from COX inhibition, as leukotrienes are important proinflammatory mediators of allergic disease. To test this hypothesis, we allergically sensitized and challenged mice deficient in 5-lipoxygenase (5-LO). We found that 5-LO knockout mice that were treated with a COX inhibitor during allergic sensitization and challenge had significantly increased airway hyperresponsiveness (AHR) (p < 0.01) and airway eosinophilia (p < 0.01) compared with 5-LO knockout mice that were treated with vehicle. The proinflammatory cytokines have also been hypothesized to be critical regulators of airway inflammation and AHR. We found that the increase in airway eosinophilia seen with COX inhibition is dependent on IL-5, whereas the increase in AHR is not dependent on this cytokine. In contrast, the COX inhibition-mediated increase in AHR is dependent on IL-13, but airway eosinophilia is not. These results elucidate the pathways by which COX inhibition exerts a critical effect of the pulmonary allergen-induced inflammatory response and confirm that COX products are important regulators of allergic inflammation.

Asunto(s)

Alérgenos/inmunología , Inhibidores de la Ciclooxigenasa/farmacología , Interleucina-13/inmunología , Hipersensibilidad Respiratoria/inmunología , Animales , Araquidonato 5-Lipooxigenasa/deficiencia , Araquidonato 5-Lipooxigenasa/inmunología , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/patología , Eosinofilia/inmunología , Femenino , Inflamación/enzimología , Inflamación/inmunología , Interleucina-5/inmunología , Ratones , Ratones Noqueados , Hipersensibilidad Respiratoria/patología

RESUMEN

BACKGROUND: Respiratory syncytial virus (RSV) is the leading infectious cause of respiratory failure and wheezing in infants and young children. Prematurity is the greatest risk factor for severe RSV-induced disease, and recent studies suggest that premature children have lower levels of the type I IFNs (alpha/beta), for which signal transducer and activator of transcription (STAT) 1 is a critical intracellular signaling molecule. OBJECTIVE: We hypothesized that RSV infection in STAT 1 knockout (STAT 1 KO) mice would result in both increased airway resistance and airway hyperresponsiveness. METHODS: Wild-type (WT) and STAT 1 KO mice on a BALB/c background were either RSV or mock infected. Phenotypic response to infection was assessed by means of plethysmography, immunohistochemistry, and lung cytokine measurement. RESULTS: We found that STAT 1 KO mice infected with RSV (STAT 1 KO-RSV) had greater baseline lung resistance (P=.05) and airway responsiveness (P<.001) than mock-infected STAT 1 KO (STAT 1 KO-MOCK), RSV-infected wild type (WT-RSV), and mock-infected wild type (WT-MOCK) mice. In addition, the STAT 1 KO-RSV mice showed induction of mucus production and expression of gob-5 and Muc5ac, conditions not present in any of the other 3 groups. IL-17, a cytokine that regulates Muc5ac expression, was expressed in the lungs of the STAT 1 KO-RSV mice, whereas lung levels of IL-17 were undetectable in the remaining groups. Expression of the IL-23-specific p19 subunit was also increased in the STAT 1 KO-RSV mice but not in the WT-RSV mice. CONCLUSION: These results show that STAT 1 has an important regulatory role in RSV-induced alteration of airway function.

Asunto(s)

Proteínas de Unión al ADN/deficiencia , Interleucina-17/biosíntesis , Pulmón/virología , Moco/metabolismo , Infecciones por Virus Sincitial Respiratorio/fisiopatología , Transactivadores/deficiencia , Animales , Western Blotting , Hiperreactividad Bronquial/etiología , Líquido del Lavado Bronquioalveolar/citología , Canales de Cloruro/biosíntesis , Eosinofilia/etiología , Femenino , Inmunohistoquímica , Pulmón/fisiopatología , Masculino , Ratones , Ratones Noqueados , Mucina 5AC , Mucinas/biosíntesis , Mucoproteínas/biosíntesis , Pruebas de Función Respiratoria , Virus Sincitial Respiratorio Humano , Factor de Transcripción STAT1

RESUMEN

Two postulated intrinsic anti-inflammatory mechanisms in asthma include the low affinity IgE receptor, or CD23, and interleukin 1 receptor antagonist (IL-1ra). We investigated the role these mediators play in the asthmatic response by measuring local levels in human asthmatics before and after segmental allergen challenge and examined the effect of inhaled corticosteroids on soluble CD23 and IL-1ra levels. Ten subjects underwent bronchoscopy at baseline and 24 hours after antigen challenge. Prior to challenge and every 12 hours afterward subjects received beclomethasone 252 microg or placebo. Fluid was analyzed for sCD23 and IL-1ra using ELISA immunoassays. Eosinophil percentages significantly increased at 24 hours following antigen challenge. sCD23 levels were generally undetectable at baseline and increased significantly following antigen challenge. IL-1ra levels increased 28-fold in the late-phase response. Beclomethasone significantly reduced the late-phase eosinophil percentage at 24 hours compared with placebo but did not attenuate late-phase sCD23 or IL-1ra levels. Our data showed a significant rise in the levels of two mediators thought to play an important role in the attenuation of the asthmatic response. The finding that steroid treatment did not enhance these levels suggests that this may be an independent approach to asthma therapy that should be investigated.

Asunto(s)

Asma/inmunología , Receptores de IgE/biosíntesis , Receptores de Interleucina-1/antagonistas & inhibidores , Adolescente , Adulto , Antiinflamatorios/farmacología , Asma/diagnóstico , Beclometasona/farmacología , Pruebas de Provocación Bronquial , Estudios Cruzados , Método Doble Ciego , Ensayo de Inmunoadsorción Enzimática , Eosinófilos/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores de Interleucina-1/biosíntesis