Fibrin-PET Imaging to Detect Aging Associated Lung Injury in Idiopathic Pulmonary Fibrosis

特发性肺纤维化(IPF)是一种原因不明的严重、慢性、与衰老相关的呼吸系统疾病。 在这种情况下，正常的肺组织逐渐被疤痕(纤维化)取代。这一稳定积累的 疤痕形成会导致肺功能受损，呼吸困难，最终死亡，平均存活时间为 确诊后仅3-5年。目前流行的假说是，IPF的发生是由于异常或 对重复的、微小的肺损伤的过度活跃的伤口愈合反应，由于复杂的 衰老、宿主易感性和环境因素。肺损伤的一个特征是血管外凝血。 并随后在肺泡内沉积纤维蛋白。这个项目的总体假设是，在IPF 1)中 持续的肺损伤，2)衰老与更严重的肺损伤有关，以及3)肺损伤的程度 与疾病活动性和进展速度相关。为了评估IPF患者持续的肺损伤，我们将 使用一种新的分子成像技术，纤维蛋白-PET，测量人类受试者的肺纤维蛋白沉积。 具体而言，我们提出以下建议： 具体目标1：确定是否可以在IPF患者的肺中检测到持续的肺损伤 通过纤维蛋白-PET成像。我们假设IPF患者有持续的肺损伤，并且增加了肺 纤维蛋白沉积是这种损伤的一种表现。为了验证这一假设，我们将进行正电子发射。 使用纤维蛋白特异性探针64Cu-FBP8进行断层扫描(PET)，以比较IPF患者和 健康对照组。 具体目的2：确定增龄是否与IPF肺损伤增加有关。我们 假设衰老与IPF肺损伤程度更大有关。为了检验这一假设，我们将 确定通过纤维蛋白-正电子发射计算机断层扫描确定的肺纤维蛋白沉积范围是否与 IPF年龄增加。 具体目标3：确定肺损伤的程度是否与IPF的疾病活动性相关。 我们假设持续肺损伤的程度与进展速度相关，即疾病活动性， 在IPF中。为了验证这一假设，我们将确定肺纤维蛋白沉积的范围是否由 纤维蛋白-PET成像与IPF中用力肺活量(FVC)下降率相关。

Idiopathic pulmonary fibrosis (IPF) is a severe, chronic, aging-associated respiratory illness of unknown cause in which normal lung tissue is progressively replaced by scarring (fibrosis). This steady accumulation of scarring leads to impaired lung function, difficulty breathing, and eventually death, with an average survival of only 3-5 years after diagnosis. The current prevailing hypothesis is that IPF occurs as a result of aberrant or over-exuberant wound-healing responses to repetitive, microscopic lung injuries, due to a complex interplay of aging, host susceptibility, and environmental factors. One hallmark of lung injury is extravascular coagulation with subsequent intra-alveolar fibrin deposition. The overall hypotheses of this project are that in IPF 1) there is ongoing lung injury, 2) aging is associated with more severe lung injury, and 3) the extent of lung injury correlates with disease activity and pace of progression. To assess ongoing lung injury in IPF patients, we will use a novel molecular imaging technique, fibrin-PET, to measure lung fibrin deposition in human subjects. Specifically, we propose the following: Specific Aim 1: To determine whether ongoing lung injury can be detected in the lungs of IPF patients by fibrin-PET imaging. We hypothesize that IPF patients have ongoing lung injury, and that increased lung fibrin deposition is a manifestation of this injury. To test this hypothesis, we will perform positron emission tomography (PET) with a fibrin-specific probe, 64Cu-FBP8, to compare lung fibrin deposition in IPF patients and healthy controls. Specific Aim 2: To determine whether aging is associated with increased lung injury in IPF. We hypothesize that aging is associated with a greater extent of lung injury in IPF. To test this hypothesis, we will determine whether the extent of lung fibrin deposition, as determined by fibrin-PET imaging, correlates with increasing age in IPF. Specific Aim 3: To determine whether the extent of lung injury correlates with disease activity in IPF. We hypothesize that the extent of ongoing lung injury correlates with pace of progression, i.e. disease activity, in IPF. To test this hypothesis, we will determine whether the extent of lung fibrin deposition, as determined by fibrin-PET imaging, correlates with rate of forced vital capacity (FVC) decline in IPF.