Redox disturbances and corticosteroid responses in children with severe asthma

描述（由申请方提供）：儿童重度哮喘是一种复杂疾病，其特征为持续气道炎症、持续症状和极端发病率，尽管使用高剂量吸入性皮质类固醇治疗。虽然对严重哮喘的病理生理学知之甚少，但受影响的儿童具有与氧化和还原（“氧化还原”）环境中的紊乱相关的严重气道“氧化应激”。虽然这种氧化应激的临床后果尚不清楚，但这些干扰不可能是良性的。本研究旨在回答一个重要的临床问题，即严重哮喘儿童对皮质类固醇的敏感性是否改变。这项研究将进一步确定气道氧化还原紊乱如何调节重度哮喘儿童对皮质类固醇的反应。假设气道氧化还原紊乱通过糖皮质激素受体的氧化抑制皮质激素敏感性。为了验证这一假设，将对亚特兰大大都市地区的重度哮喘儿童进行肌内皮质类固醇（曲安西龙）给药，这些儿童尽管接受了高剂量的吸入性皮质类固醇治疗，但仍有症状。皮质类固醇不敏感性将被定义为在给予曲安西龙4周后1秒内用力呼气量改善<15%。该项目的具体目的是：1）确定皮质类固醇不敏感的临床模式和患病率; 2）确定气道氧化还原状态改变是否预示皮质类固醇不敏感; 3）确定糖皮质激素受体氧化是否是重度哮喘儿童皮质类固醇不敏感的机制。这里介绍的研究将提供急需的数据，以推动儿童严重哮喘领域的发展。虽然皮质类固醇是哮喘治疗的基石，但很少有证据支持重度哮喘儿童使用大剂量皮质类固醇。从这些目标中获得的新知识将首次证明皮质类固醇不敏感性是否是儿童严重哮喘的真正特征，以及气道氧化还原紊乱是否解释了这一现象。本研究的长期目标是利用这些数据开发新的抗氧化干预措施，以逆转严重哮喘儿童的皮质类固醇不敏感性。因此，这里产生的数据可能会改善这一具有高度挑战性的重度哮喘儿童群体的临床结局，对他们来说，几乎没有其他治疗方法。

DESCRIPTION (provided by applicant): Severe asthma in children is a complex disorder characterized by persistent airway inflammation, ongoing symptoms and extreme morbidity despite treatment with high doses of inhaled corticosteroids. While the pathophysiology of severe asthma is poorly understood, affected children have profound airway "oxidant stress" associated with disturbances in the oxidizing and reducing ("redox") environment. While the clinical ramifications of this oxidant stress are unclear, these disturbances cannot be benign. This study is designed to answer the important clinical question whether corticosteroid sensitivity is altered in children with severe asthma. This study will further determine how airway redox disturbances regulate the response to corticosteroids in children with severe asthma. The hypothesis is that airway redox disturbances inhibit corticosteroid sensitivity through oxidation of the glucocorticoid receptor. To test this hypothesis, the intramuscular corticosteroid, triamcinolone, will be administered to children with severe asthma from the metropolitan Atlanta area who remain symptomatic despite treatment with high doses of inhaled corticosteroids. Corticosteroid insensitivity will be defined as <15% improvement in the forced expiratory volume in one second 4 weeks after triamcinolone administration. The specific aims of this project are: 1) to determine the clinical pattern and prevalence of corticosteroid insensitivity; 2) to determine whether altered airway redox status predicts corticosteroid insensitivity; and 3) to determine whether oxidation of the glucocorticoid receptor is a mechanism of corticosteroid insensitivity in children with severe asthma. The studies presented here will provide critically-needed data to advance the field of severe asthma in children. Although corticosteroids are the cornerstone of asthma treatment, there is very little evidence supporting the use of high doses of corticosteroids in children with severe asthma. New knowledge derived from these aims will demonstrate for the first time whether corticosteroid insensitivity is a true feature of severe asthma in children and whether airway redox disturbances account for this phenomenon. The long-term goal of this research is to utilize these data to develop novel antioxidant interventions to reverse corticosteroid insensitivity in children with severe asthma. The data generated here may therefore improve clinical outcomes in this highly challenging group of children with severe asthma for whom there are very few therapeutic alternatives.