Assuntos
Doenças Cardiovasculares , Neoplasias , Terapia Nutricional , Humanos , Projetos de Pesquisa , Vitamina DAssuntos
Antiasmáticos/história , Asma/tratamento farmacológico , Asma/história , Administração por Inalação , Antiasmáticos/uso terapêutico , Asma/diagnóstico , Datura stramonium , Quimioterapia Combinada , Dispneia/etiologia , Dispneia/história , Efedrina/história , Efedrina/uso terapêutico , Feminino , História do Século XIX , História do Século XX , Humanos , Fitoterapia/história , Testes de Função Respiratória/história , Rinite Alérgica Sazonal/complicações , Rinite Alérgica Sazonal/história , Simpatomiméticos/história , Simpatomiméticos/uso terapêuticoRESUMO
TBX21 encodes for the transcription factor T-bet (T-box expressed in T cells), which influences naive T lymphocyte development and has been implicated in asthma pathogenesis. Specifically, the T-bet knockout mouse spontaneously develops airway hyperresponsiveness and other changes consistent with asthma. Because airway responsiveness is moderated by the use of inhaled corticosteroids in asthma, it is conceivable that genetic variation in TBX21 may alter asthma phenotypes in a treatment-specific fashion. Here we demonstrate that the nonsynonymous variation in TBX21 coding for replacement of histidine 33 with glutamine is associated with significant improvement in the PC(20) (a measure of airway responsiveness) of asthmatic children in a large clinical trial spanning 4 years. We note that this increase occurs only in the children randomized to inhaled corticosteroids and that it dramatically enhances the overall improvement in PC(20) associated with inhaled corticosteroid usage. The average PC(20) at trial end for subjects on inhaled corticosteroids possessing a variant allele was in the normal range for nonasthmatics. In cellular models, we show that the TBX21 variant increases T helper 1 and decreases T helper 2 cytokine expression comparably with wild type. TBX21 may thus be an important determinant pharmacogenetic response to the therapy of asthma with inhaled corticosteroids.
Assuntos
Corticosteroides/uso terapêutico , Asma/tratamento farmacológico , Asma/genética , Variação Genética , Proteínas com Domínio T/genética , Proteínas com Domínio T/fisiologia , Administração por Inalação , Corticosteroides/metabolismo , Alelos , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Citocinas/metabolismo , DNA Complementar/metabolismo , Dexametasona/farmacologia , Feminino , Genótipo , Glutamina/química , Histidina/química , Humanos , Masculino , Mutagênese Sítio-Dirigida , Fenótipo , Células Th1/citologia , Células Th2/citologia , Fatores de TempoRESUMO
Individuals with asthma have increased levels of nitric oxide in their exhaled air. To explore its role, we have developed a regulatable transgenic mouse capable of overexpressing inducible nitric oxide synthase in a lung-specific fashion. The CC10-rtTA-NOS-2 mouse contains two transgenes, a reverse tetracycline transactivator under the control of the Clara cell protein promoter and the mouse nitric oxide synthase-2 (NOS-2) coding region under control of a tetracycline operator. Addition of doxycycline to the drinking water of CC10-rtTA-NOS-2 mice causes an increase in nitric oxide synthase-2 that is largely confined to the airway epithelium. The fraction of expired nitric oxide increases over the first 24 h from approximately 10 parts per billion to a plateau of approximately 20 parts per billion. There were no obvious differences between CC10-rtTA-NOS-2 mice, with or without doxycycline, and wild-type mice in lung histology, bronchoalveolar protein, total cell count, or count differentials. However, airway resistance was lower in CC10-rtTA-NOS-2 mice with doxycycline than in CC10-rtTA-NOS-2 mice without doxycycline or wild-type mice with doxycycline. Moreover, doxycycline-treated CC10-rtTA-NOS-2 mice were hyporesponsive to methacholine compared with other groups. These data suggest that increased nitric oxide in the airways has no proinflammatory effects per se and may have beneficial effects on pulmonary function.