Viral Induced Asthma Exacerbations

描述（由申请人提供）：病毒性呼吸道感染是哮喘加重的重要原因。鼻病毒（RV）是这些患者中最常见的类型。我们有证据表明RV感染下气道，刺激促炎介质的产生，导致中性粒细胞的募集，从而导致气道损伤，包括上皮损伤和粘液分泌增加。这些变化导致气道阻塞、高反应性和哮喘症状增加。由于哮喘恶化只发生在一部分患有病毒性呼吸道感染的哮喘患者中，宿主易感因素，包括抗病毒因子的产生减少或促炎介质的释放增加，被怀疑在这些发作的发病机制中起作用。因此，我们假设病毒诱导的哮喘加重（VIAX）伴RV感染是下气道中性粒细胞募集和激活增强的结果，随后出现腔内气道阻塞和气道实质解偶联。我们进一步提出，这种增强的嗜中性粒细胞炎症反应出现在哮喘患者的一个亚群中，这些患者的抗病毒反应改变，对RV的促炎反应增加。为了验证这一假设，我们将确定VIAX对肺功能的生理影响，包括腔内支气管阻塞和气道-实质解耦。我们还将使用CT扫描、3He-MRI和18FDG PET等放射学成像来确定VIAX期间肺的功能和结构变化，并确定这些变化与观察到的肺生理的关系。最后，我们将通过分析痰液和支气管灌洗细胞以及粘膜活检来确定与VIAX相关的下气道炎症的机制，确定这些病毒诱导的影响与气流阻塞和肺结构的关系，并开始确定可能调节这些过程的遗传宿主易感因素。从这些观察结果中，我们将能够更好地定义VIAX的机制，并有望帮助开发改进的治疗方法。

DESCRIPTION (provided by applicant): Viral respiratory tract infections are an important cause of asthma exacerbations. Rhinoviruses (RV) are the most common type detected in these patients. We have evidence that RV infect the lower airway, and stimulate the generation of proinflammatory mediators leading to recruitment of neutrophils which then cause airway injury including epithelial damage and increased mucus secretion. These changes result in airway obstruction, hyper-responsiveness and increased asthma symptoms. Since asthma exacerbations develop only in a subset of asthma patients who suffer a viral respiratory tract infection, host susceptibility factors including decreased generation of antiviral factors or increased release of proinflammatory mediators have been suspected to play a role in the pathogenesis of these attacks. We therefore, hypothesize that virus-induced asthma exacerbation (VIAX) with RV infections are the result of enhanced neutrophil recruitment and activation in the lower airway with subsequent intraluminal airway obstruction and airway parenchymal uncoupling. We further propose that this enhanced neutrophilic inflammatory response is seen in a subset of asthma patients with altered antiviral responses and increased generation of proinflammatory responses to RV. To test this hypothesis we will determine the physiological consequences of VIAX on lung function including intraluminal bronchial obstruction and airway-parenchymal uncoupling. We will also use radiological imaging with CT scans, 3He-MRI, and 18FDG PET to determine the functional and structural changes in the lung during VIAX and to determine the relationship of these changes to observed pulmonary physiology. Finally we will determine the mechanisms of lower airway inflammation associated with the VIAX by analysis of sputum and bronchial lavage cells and mucosal biopsies, determine the relationship of these virus-induced effects to airflow obstruction and lung structure, and begin to determine the genetic host susceptibility factors that may regulate these processes. From these observations, we will be able to better define the mechanisms of VIAX and hopefully help develop improved treatment.