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，特别是在维生素A缺乏症常见的地区。该提案旨在解决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。这可能会加剧与预先存在的哮喘的个人。该假设将通过两个特定的目的来解决：（1）确定亚临床VAD是否与有或无既存哮喘的儿童急性呼吸道疾病后的气道反应性延长有关。(2)确定VAD是否改变鼻腔中病毒感染的炎症反应特征，这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气道高反应性是由下呼吸道的病毒入侵、炎性细胞和肽介质的持续存在和/或残余气道水肿引起的，这可能受到VAD的影响。组胺气道高反应性的分析是一种可行的，可靠的，耐受性良好的方法，可用于系列测量。申请人在巴西RN的纳塔尔进行了一项试点研究，该研究表明，约30%的儿童存在亚临床维生素A缺乏症，申请人已与巴西科学家建立了工作合作。儿童研究将在纳塔尔进行，受试者将在急诊医院访视期间招募。强制振荡技术将用于测量2 - 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。将通过使用逆转录酶聚合酶链反应分析鼻灌洗液标本来记录病毒感染。维生素A营养状况将通过改良的相对剂量反应试验进行评估。将在有或没有病毒性上呼吸道感染的个体中比较呼吸阻力和气道高反应性的正常化率，这些个体具有正常或减少的维生素A储存。第二个目标将评估VAD如何改变鼻上皮对病毒感染的免疫和炎症反应。研究将集中在细胞因子和上皮细胞的特性，是已知的VAD和/或病毒感染改变，并认为影响支气管高反应性。这些研究有助于确定VAD是否是病毒性呼吸道疾病后气道病理学的重要贡献者，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.