VIRAL-INDUCED T CELL RESPONSES IN COPD EXACERBATION PROTOCOL

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 与烟草有关的肺部疾病，包括伴有和不伴有肺气肿的慢性阻塞性肺疾病(COPD)，是全世界与肺相关的残疾和死亡的主要原因。COPD患者呼吸症状恶化的病因，以及这些需要特殊医疗护理的受试者的表型，可能是不同的，当然也很难理解。在一项纵向队列研究中，我们已经表明，在23个月的时间里，大约一半的重度COPD患者(GOLD阶段III和IV)因呼吸衰竭至少去过一次急救中心和/或住院，而正常对照组或轻度COPD患者(GOLD阶段0-11)不需要紧急医疗护理。然而，令人惊讶的是，我们发现重度COPD患者的年度症状性呼吸道病毒感染率与对照组相似。因此，尽管重度COPD患者有类似的病毒感染记录，但他们仍然比对照组使用更多的医疗资源。一种可能的解释是COPD患者对病毒感染的免疫反应与对照组不同。为了支持这一观点，我们的团队最近表明，患有COPD和肺气肿的稳定前吸烟者的肺特异性免疫表型偏向于T辅助1型(Th1)免疫失调，这在那些没有这种疾病的人中是看不到的。 我们的建议将前瞻性地确定两组患者1)不同阶段的COPD患者，如您手术中对COPD恶化的定义：上呼吸道疾病，定义为鼻炎或咽炎症状，和/或下呼吸道疾病，定义为发热或不发烧时咳嗽、呼吸急促、痰液产生和/或痰颜色变化(体温&GT；37.7度)；其中，恶化的严重程度将根据有效的圣乔治呼吸问卷进行分级；2)住进德克萨斯医疗中心医院的COPD恶化患者。我们还将研究正常对照(吸烟者和不吸烟者)。在这项建议中的一个目标是，我们将确定我们的COPD队列的特征，并前瞻性地确定受试者的表型，以确定是否可以使用一组特定的身体和功能特征来区分有频繁COPD加重的儿童。在我们的研究对象中，将特别强调确定并发肺气肿的作用的研究。充血性心力衰竭和肝肾功能障碍的作用将被调查为经常恶化的受试者的潜在致病因素。在该提案的第二个和第三个目标中，我们将确定病毒和非病毒介导的T细胞反应的机制，这些反应可能导致该队列的频繁恶化和肺功能下降。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tobacco related lung diseases, including chronic obstructive pulmonary disease (COPD) with and without emphysema, are major causes of lung-related disability and death worldwide. The etiology of worsening of respiratory sumptoms in patients with COPD, and the phenotype of these subjects that require special medical attention, are probably heterogeneous and certainly poorly understood. In a longitudinal cohort study, we have shown that approximately one half of subjects with severe COPD (GOLD stage III, and IV), had at least one emergency center visit and/or hospital admission for respiratory failure as compared to no need for urgent medical care in normal controls or subjects with mild COPD (GOLD stage 0-11) in 23 months. Surprisingly however, we found similar annual symptomatic respiratory virus infection rates in severe COPD subjects as compared to controls. Thus, although patients with severe COPD have comparable documented viral infections, they still utilize more medical care resources than controls. One possible explanation is that the immune response to the viral infection in patients with COPD differs fromthat of control groups. In support of this idea, our group has rectntly shown that the lung-specific immune phenotype of stable ex-smokers with COPD and emphysema is biased towards T helper type 1 (Th1) immune dysregulation that is not seen in those without the disease. Our proposal will prospectively identify two cohorts of patients 1) ambulatory patients with various stages of COPD, during stable condition and during COPD exacerbation as defined byour operational definition of COPD exacerbation, as upper respiratory tract illness defined by the presence of symptoms of rhinitis or pharyngitis, and/or lower respiratory tract illness defined by increase cough, shortness of breath, sputum production and/or change in sputum color in the presence or absence of fever (temperature >37.7 degrees); where the severity of exacerbation will be graded based on the validated St George's Respiratory Questionnaire; 2) patients admitted to the Texas Medical Center hospitals with COPD exacerbation. We will also study normal controls (smokers and non-smokers). In aim one of this proposal we will characterize our COPD cohort and will prospectively determine the phenotype of subjects to determine if a specific set of physical and functional characteristics can be used to distinguish sujbects with frequent COPD exacerbation. A special emphasis will be placed on studies that willdefine the role of concurrent emphysema, in our study subjects. The role of congestive heart failure, and liver and kidney dysfunction will be investigated as potential contributing factors in subjects with frequent exacerbation. In the second and third aims of the proposal we will determine the mechanisms for the viral and non-viral mediated T cell responses that may contribute to frequent exacerbation and decline in lung function of this cohort.