Quantitative Magnetic Resonance Imaging of Biofilm in Cystic Fibrosis

描述（由申请人提供）：本提案的长期目标是建立一种无创MRI技术，用于测量和监测囊性纤维化（CF）患者的气道分泌物。囊性纤维化（CF）是一种与严重受损的粘膜纤毛清除相关的遗传性疾病，导致慢性多微生物气道生物膜感染、炎症、气道重塑，并最终导致近80%的患者呼吸衰竭。治疗包括气道清除治疗、抗炎治疗以及吸入抗生素、高渗盐水和rhDNase沿着。对患者进行临床、放射学、肺功能研究， 和微生物培养物。目前，CF患者气道的成像评估主要依赖于CT的静态图像，这有助于评估对治疗的反应，但由于需要重复测量和电离辐射剂量的限制，因此受到严重限制。尽管结构MRI已被探索作为CT的替代，但CT和MRI都是半定量的，仅评价肺的静态性质。临床治疗和转化研究迫切需要可以重复使用的过量肺分泌物的定量测量。该补助金的动机是我们最近利用UCSD开发的用于生理研究的快速梯度回波（fGRE）磁共振成像（MRI）序列观察CF患者的肺水密度。这种非侵入性成像序列能够在9秒屏气内获得肺水密度，并且已经被证明对于获得测量健康人类受试者的肺密度是高度可靠的。健康人受试者的肺水密度是来自血液和肺组织的水的量度，但在CF受试者中，肺水密度包括来自过量气道分泌物的水。在16例轻度至重度肺病CF受试者中获得的肺水密度的定量测量结果表明，存在异常高肺水密度的位置，并且这些位置在患者完成2至4次肺活量运动后发生空间移位。在健康受试者中未观察到这两种观察结果。我们怀疑这些高密度区域表明存在过量分泌物。我们广泛的假设是，这些高密度区域将影响局部通气和可能的血流，如定量MRI技术所测量的。我们的基本原理是，CF受试者中过量的气道分泌物将产生血流和通气的异质模式，并且这种模式将随着生物膜移动而随着局部气道的打开和关闭而改变。该项目具有潜在的高回报，因为成功完成这些目标将提供对所观察到的高密度区域的性质和生理意义的基本第一次评估。总之，我们认为所描述的定量密度MRI方法可以满足对CF气道分泌物的客观测量的迫切需要，其可以重复用于评估疾病的严重程度和对治疗的反应。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to establish a non-invasive MRI technique to measure and monitor airway secretions in patients with Cystic Fibrosis (CF). Cystic Fibrosis (CF) is an inherited disease associated with a severely impaired mucociliary clearance that leads to chronic polymicrobial airway biofilm infection, inflammation, airway remodeling and eventually respiratory failure in almost 80% of patients. Therapy includes airway clearance treatments, anti-inflammatory therapy along with inhaled antibiotics, hypertonic saline and rhDNase. Patients are followed clinically, radiographically, with lung function studies, and microbial cultures. Currently, imaging assessment of airways in patients with CF largely relies on static images from CT, which are helpful in assessing response to therapy but are severely limited because of the need for repeated measures and limitations of ionizing radiation dose. Even though structural MRI has been explored as a surrogate for CT, both CT and MRI are semi-quantitative and only evaluate the static nature of the lung. Clinical therapy and translational investigations have a critical need for a quantitative measure of excess lung secretions that could be used repeatedly. This grant is motivated by our recent observations of lung water density in CF patients utilizing a fast gradient echo (fGRE) magnetic resonance imaging (MRI) sequence that has been developed at UCSD for use with physiological studies. This noninvasive imaging sequence is capable of obtaining lung water density within a 9-sec breathhold and has been shown to be highly reliable for obtaining measuring lung density in healthy human subjects. Lung water density in healthy human subjects is a measure of water from blood and lung tissue but in CF subjects, lung water density includes water from excess airway secretions. Quantitative measures of lung water density obtained in 16 CF subjects with mild to severe lung disease have shown there are locations of abnormally high lung water density and these locations shift spatially after patients complete 2 to 4 vital capacity maneuvers. Neither observation is seen in healthy subjects. We suspect that these hyper-dense regions indicate the presence of excess secretions. Our broad hypothesis is that these hyper-dense regions will impact local ventilation and possible blood flow as measured by quantitative MRI techniques. Our rationale is that excess airway secretions in subjects with CF will produce a heterogeneous pattern of blood flow and ventilation and this pattern will change as local airways open and close as biofilm moves. This project has a potentially high reward since successful completion of these aims will provide an essential first assessment of the nature and physiologic significance of the observed high density regions. In summary, we believe the quantitative density MRI method described may fill a critical need for an objective measure of CF airway secretions that can be used repeatedly to assess disease severity and response to therapy.