Viral Induced Asthma Exacerbations

描述(由申请人提供)：病毒性呼吸道感染是哮喘恶化的重要原因。鼻病毒(RV)是在这些患者中检测到的最常见的类型。我们有证据表明，轮状病毒感染下呼吸道，刺激促炎介质的产生，导致中性粒细胞募集，从而导致呼吸道损伤，包括上皮损伤和粘液分泌增加。这些变化导致呼吸道阻塞、高反应性和哮喘症状增加。由于哮喘恶化只发生在患有病毒呼吸道感染的哮喘患者中，宿主易感因素，包括抗病毒因子生成减少或促炎介质释放增加，被怀疑在这些攻击的发病机制中发挥了作用。因此，我们假设病毒诱导的哮喘加重(VIAX)合并RV感染是下呼吸道中性粒细胞募集和激活增强的结果，随后是腔内气道阻塞和气道实质解偶联的结果。我们进一步提出，这种增强的中性粒细胞炎症反应在一组哮喘患者中可以看到，这些患者的抗病毒反应发生了变化，对RV的促炎反应增加。为了验证这一假设，我们将确定VIAX对肺功能的生理学后果，包括管腔内支气管阻塞和呼吸道-实质解偶联。我们还将使用CT扫描、3He-MRI和18FDG PET的放射成像来确定VIAX期间肺功能和结构的变化，并确定这些变化与观察到的肺生理的关系。最后，我们将通过分析痰和支气管灌洗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因素。通过这些观察，我们将能够更好地确定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.