Pathophysiology of Voice Disorders due to Combination Inhaled Corticosteroids in Asthma

项目摘要/摘要 在美国，超过4000万儿童和成年人患有慢性肺部疾病，包括哮喘、慢性 支气管炎和阻塞性肺病。仅哮喘一项就有2500万例， 每十年增长10%。联合吸入皮质类固醇(ICs)是治疗慢性阻塞性肺疾病的首选方法 对呼吸症状的长期管理。令人遗憾的是，ICS也与UP的声音障碍有关 到50%的病例。这些疾病会成为慢性疾病，损害沟通，并具有显著的不良影响。 职业、经济和心理社会后果。考虑到相关的发声障碍的流行率 自2008年禁止使用氯氟化碳推进的吸入器以来，出现了组合IC，临床上令人信服 有证据表明，有必要采取新的研究行动来解决这一对公共卫生的严重威胁。 该研究计划的长期目标是预防和治疗与以下相关的发音障碍 贯穿整个生命周期的组合IC。使用吸入器的儿童面临终身，可能是永久性的 沟通障碍。确定IC相关发音障碍的病理生理学是关键 下一步是开发新的避免发声的哮喘药物。病理生理学的确定是必要的。 治疗、逆转和预防这些声音改变。这 项目在3个假设驱动的目标中实现了这些目标。目标1确定喉部结构 IC使用的生物标志物与儿童和成人的声音障碍相关，其中最常见的两种 哮喘的表型(高TH2过敏和低TH2主要是嗜酸性粒细胞)。目标2量化语音障碍 在活体动物模型中ICS与SHAM的起效和可逆性。《目标3》探讨了黄斑狼疮的发病机制 通过检测与炎症相关的细胞因子(IL-1β、IL-6、肿瘤坏死因子-α)来检测IC相关的嗓音障碍 动物的真声带和人类的假声带。总的来说，这些目标定义了病理生理学 与IC相关的语音障碍相关，为语音障碍的治疗和预防奠定了基础 人口。这一翻译项目将立即产生重大的临床影响，使 在沟通障碍领域产生强大而持久的影响。

PROJECT SUMMARY/ABSTRACT Over 40 million children and adults in the US suffer from chronic pulmonary diseases including asthma, chronic bronchitis and obstructive pulmonary disease. Asthma alone accounts for 25 million cases, with prevalence increasing by 10% each decade. Combination inhaled corticosteroids (ICs) are the treatment of choice for the long-term management of breathing symptoms. Regrettably, ICs are also associated with voice disorders in up to 50% of cases. These disorders become chronic, impair communication, and have significant adverse occupational, financial, and psychosocial consequences. Given the prevalence of voice disorders associated with combination ICs since chlorofluorocarbon-propelled inhalers were banned in 2008, compelling clinical evidence necessitates a new research initiative to address this critical threat to public health. The long-term goal of this research program is to prevent and cure voice disorders associated with combination ICs across the lifespan. Children placed on inhalers face lifelong, possibly permanent communication impairment. Determining the pathophysiology of IC-related voice disorders is the critical next step to developing new voice-sparing asthma drugs. It is essential to determine the pathophysiology of voice disorders associated with combination ICs, to treat, reverse, and prevent these voice changes. This project accomplishes these objectives in 3 hypothesis-driven aims. Aim 1 determines structural laryngeal biomarkers of IC use associated with voice disorders in children and adults with the 2 most common phenotypes of asthma (high TH2 allergic and low TH2 primarily eosinophilic). Aim 2 quantifies voice disorder onset and reversibility for ICs versus sham using an in vivo animal model. Aim 3 examines the pathogenesis of IC-related voice disorders via examination of cytokines associated with inflammation (IL-1β, IL-6, TNF-α) from animal true vocal folds and human false vocal folds. Collectively, these aims define the pathophysiology associated with IC-related voice disorders, laying the foundation for voice disorder cure and prevention in this population. This translational project will have immediate and significant clinical implications, making a powerful and sustained impact in the field of communication disorders.