Viral Induced Asthma Exacerbations

描述（由申请方提供）：病毒性呼吸道感染是哮喘急性发作的重要原因。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，并刺激促炎介质的产生，导致中性粒细胞的募集，然后引起气道损伤，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。由于哮喘急性发作仅发生在一部分患有病毒性呼吸道感染的哮喘患者中，因此怀疑宿主易感性因素（包括抗病毒因子生成减少或促炎介质释放增加）在这些发作的发病机制中发挥作用。因此，我们假设病毒诱导的哮喘急性发作（VIAX）伴RV感染是下气道中性粒细胞募集和活化增强，随后管腔内气道阻塞和气道实质解偶联的结果。我们进一步提出，这种增强的嗜酸性炎症反应见于抗病毒反应改变和对RV的促炎症反应增加的哮喘患者亚组。为了检验这一假设，我们将确定VIAX对肺功能的生理后果，包括管腔内支气管阻塞和气道-实质解偶联。我们还将使用CT扫描、3 He-MRI和18FDG PET的放射成像来确定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学的关系。 最后，我们将通过分析痰液和支气管灌洗液细胞以及粘膜活检来确定与VIAX相关的下呼吸道炎症的机制，确定这些病毒诱导的效应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性因子。通过这些观察，我们将能够更好地定义VIAX的机制，并希望有助于开发更好的治疗方法。

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.