Validating Quantitative Magnetic Resonance Imaging Biomarkers of Idiopathic Pulmonary Fibrosis

肺纤维化导致多种肺部疾病的发病率和死亡率。虽然这可能导致 由于环境暴露或急性损伤，引发肺纤维化的事件通常是未知的。这 特发性肺纤维化（IPF）是间质性肺病的最常见形式，并且其与 诊断后生存期仅为3年。尽管经过数十年的研究，只有两种药物被FDA批准用于治疗 IPF，两者都只是减缓其进展。未能产生逆转或阻止疾病进展的治疗方法 可归因于对IPF病因知之甚少。反过来，理解力差可以归因于 为了检测和量化早期纤维化，并将局部实质重塑与功能，生物力学， 以及引发纤维化的分子过程。消除这一差距将需要大量的科学和技术 发展涉及生物学上真实的疾病模型和敏感和特定的成像技术。 这项研究的长期目标是量化早期肺重塑，并将其与促纤维化机制联系起来。 nisms和紧急病理生理学。我们在本申请中的目标是1）确定生物物理起源 的磁共振成像（MRI）松弛纤维化肺组织，2）量化肺泡通气，3）应用 将这些指标应用于两种真实的转基因小鼠模型，以及4）将定量通气MRI扩展到IPF患者， tients。我们的中心假设是松弛和通气将与纤维化的离体测量相关 (e.g.,局部胶原含量），并提供了定量纤维化进展的灵敏、非侵入性方法 in vivo.我们的基本原理是，一旦在动物模型和IPF患者中得到验证， 用于机制临床前研究和评估IPF进展和治疗疗效。指导 强有力的初步数据和理论工作描述了肺部的MR信号动力学，我们的中心假设 将通过完成以下三个具体目标进行测试：1）验证横向松弛作为 肺纤维化; 2）用多次呼吸HP 129洗脱定量通气受损; 3）证明敏感性， HP 129洗脱MRI对IPF患者通气受损的敏感性在目标1下，我们开发了MRI 序列和重建管道需要完成的工作。在目标2下，我们构建了 验证了超极化气体和MRI兼容的呼吸机，并开发了图像处理工具， 量化局部组织密度。根据目标3，我们率先使用高效的3D螺旋MRI序列 以及基于锁孔的图像重建，以产生高质量的定量人类肺部图像。拟议 研究在生物学和技术上都是创新的，因为它将开发和验证非侵入性的，区域性的， 生物物理组织特性和通气的测量。这些结果意义重大，因为它们将提供 一种检测早期促纤维化事件和非侵入性定量肺纤维化进展的方法。这项工作 将通过评估潜在的肺纤维化治疗产生直接的积极影响，并将促进 这些工具可以转化为临床应用，用于评估疾病进展和治疗反应。

Pulmonary fibrosis contributes to morbidity and mortality in a wide spectrum of lung diseases. While it can result from environmental exposures or acute injuries, the events that initiate lung fibrosis are typically unknown. This Idiopathic Pulmonary Fibrosis (IPF) is the most common form of interstitial lung disease, and it is associated with a post-diagnosis survival of only 3 years. Despite decades of research, only 2 drugs are FDA approved to treat IPF, and both merely slow its progression. Failure to produce treatments to reverse or halt disease progression can be attributed to poorly understood IPF etiology. In turn, poor understanding can be attributed to an inability to detect and quantify early fibrosis and relate regional parenchymal remodeling to the functional, biomechanical, and molecular processes that initiate fibrosis. Eliminating this gap will require significant scientific and technical developments involving both biologically realistic disease models and sensitive and specific imaging technology. The long-term goal of this research is to quantify early pulmonary remodeling and relate it to profibrotic mecha- nisms and emergent pathophysiology. Our objectives in this application are to 1) determine the biophysical origin of magnetic resonance imaging (MRI) relaxation in fibrotic lung tissue, 2) quantify alveolar ventilation, 3) apply these metrics to two realistic, transgenic mouse models, and 4) extend quantitative ventilation MRI to IPF pa- tients. Our central hypothesis is that relaxation and ventilation will correlate with ex vivo measures of fibrosis (e.g., regional collagen content) and provide sensitive, noninvasive methods of quantifying fibrosis progression in vivo. Our rationale is that imaging markers—once validated in animal models and IPF patients—can readily be applied in mechanistic preclinical studies and in assessing IPF progression and therapy efficacy. Guided by strong preliminary data and theoretical work describing MR signal dynamics in the lungs, our central hypothesis will be tested by completing the following three Specific Aims: 1) validate transverse relaxation as a marker of lung fibrosis; 2) quantify impaired ventilation with multi-breath HP 129Xe washout; and 3) demonstrate the sensi- tivity of HP 129Xe washout MRI to impaired ventilation in IPF patients. Under Aim 1, we have developed the MRI sequences and reconstruction pipeline needed to complete the work. Under Aim 2, we have constructed and validated a hyperpolarized gas and MRI-compatible ventilator and developed the image processing tools to quantify regional tissue density. Under Aim 3, we have pioneered the use of efficient 3D spiral MRI sequences and keyhole-based image reconstruction to produce high-quality, quantitative human lung images. The proposed research is innovative both biologically and technically, because it will develop and validate noninvasive, regional measures of biophysical tissue properties and ventilation. These results are significant, because they will provide a means of detecting early pro-fibrotic events and noninvasively quantifying lung fibrosis progression. This work will have an immediate positive impact by allowing potential lung fibrosis therapies to be assessed and will pro- vide tools that can be translated into clinical use for evaluating disease progression and therapy response.