Effects of Vitamin A Deficiency on Virus-Infected Airwa*

急性病毒性呼吸道疾病是全世界儿童发病和死亡的主要原因，尤其是在维生素A缺乏症(VAD)普遍存在的地区。这项建议旨在解决VAD可能促进支气管高反应性(BHR)的假设，特别是在上呼吸道感染(URI)期间和之后。这一点在既往哮喘患者中可能会加重。这一假设将通过两个具体目标来解决：(1)确定亚临床VAD是否与患有或不患有哮喘的儿童急性呼吸道疾病后呼吸道反应延长有关。(2)确定VAD是否改变了鼻腔对病毒感染的炎症反应的特征，而病毒感染是支气管高反应性的重要决定因素。现有证据表明，急性上呼吸道疾病后的呼吸道高反应性是病毒侵入下呼吸道、炎症细胞和多肽介质持续存在和/或残留的呼吸道水肿的结果，这可能受VAD的影响。分析呼吸道对组胺的高反应性是一种可行的、可靠的、耐受性良好的方法，可用于连续测量。申请人已经在巴西北卡罗来纳州的纳塔尔进行了一项初步研究，该研究表明，大约30%的儿童存在亚临床维生素A缺乏症，他已经与巴西科学家建立了工作合作关系。儿童研究将在纳塔尔进行，并将在急诊医院就诊期间招募受试者。强迫振荡技术将用于测量2至8岁儿童急性病毒性呼吸道疾病急性期和恢复期的总呼吸阻力。病毒感染将通过使用逆转录酶聚合酶链式反应分析鼻腔灌洗样本来证明。维生素A营养将通过改进的相对剂量反应试验进行评估。呼吸阻力和呼吸道高反应性正常率将在患有或不患有病毒上呼吸道感染的个体中进行比较，这些个体的维生素A储备正常或减少。第二个目标将评估VAD如何改变鼻黏膜上皮对病毒感染的免疫和炎症反应。研究将集中在已知可由VAD和/或病毒感染改变的细胞因子和上皮属性，并被认为影响支气管高反应性。这些研究应该有助于确定VAD是否是病毒性呼吸道疾病后呼吸道病理的重要因素，并阐明可能涉及的一些病理机制。

Acute viral respiratory illnesses are a major cause of morbidity and mortality in children worldwide, but particularly in regions where vitamin A deficiency (VAD) is common. This proposal seeks to address the hypothesis VAD may promote bronchial hyperreactivity (BHR), particularly during and after an upper respiratory infection (URI). This may be accentuated in individuals with pre-existing asthma. The hypothesis will be addressed through two specific aims: (1) To determine whether sub-clinical VAD is associated with prolonged airway reactivity following acute respiratory tract illness in children with or without pre-existing asthma. (2) To establish whether VAD alters the characteristics of the inflammatory response to viral infection in the nasal cavity, which is an important determinant of bronchial hyperreactivity. Prevailing evidence indicates that the airway hyperresponsiveness, that follows acute upper respiratory illness, results from viral invasion of the lower respiratory tract, persistence of inflammatory cells and peptide mediators, and/or residual airway edema, which may be influenced by VAD. The analysis of airway hyperresponsiveness to histamine is a feasible, reliable, well-tolerated approach that can be used for serial measurements. The applicant has conducted a pilot study in Natal, RN, Brazil which indicated that sub- clinical vitamin-A deficiency exists in approximately 30% of the children encountered, and he has established a working collaboration with Brazilian scientists. Studies in children will be conducted in Natal, and subjects will be recruited during visits to the emergency hospital. The forced oscillatory technique will be used to measure total respiratory resistance during the acute and convalescent stages of acute viral respiratory illness in children ages 2 through 8 years. Viral infection will be documented by analysis of nasal lavage specimens using reverse-transcriptase polymerise chain reaction analysis. Vitamin- A nutriture will be assessed through a modified relative dose response test. The rate of normalization of respiratory resistance and airway hyperresponsiveness will be compared in individuals with or without viral upper respiratory tract infections, who have normal or diminished vitamin A stores. The second aim will evaluate how VAD alters the immunologic and inflammatory response of the nasal epithelium to viral infection. Studies will focus on cytokines and epithelial properties that are known to be altered by VAD and/or by viral infection, and are thought to influence bronchial hyperreactivity. These studies should help establish whether VAD is an important contributor to airway pathology following viral respiratory tract illnesses and illuminate some of the pathologic mechanisms that may be involved.