Nonlinear Ultrasound: an Imaging Biomarker of Intestinal Fibrosis in Crohn's Disease

 描述（由申请人提供）：纤维化是许多慢性疾病中导致器官衰竭的最终常见途径，在美国每年导致超过1420亿美元的医疗费用。肠纤维化是克罗恩病（CD）手术干预的主要原因，超过三分之二的患者需要手术干预。尽管CD中纤维化的影响巨大，但我们无法无创检测或测量CD中的肠纤维化。我们最近的初步数据表明，非线性超声刚度成像（USI）的新方法可以准确地检测肠道纤维化。这项研究计划的长期目标是 开发和测试新的克罗恩病肠纤维化测量方法，以确定预后并指导内科和外科治疗。 我们建议评估两种新的超声方法测量CD肠纤维化的准确性。我们的初步数据表明，两种非线性形式的USI（准静态应变成像[QSSI]和剪切波弹性成像[SWEI]）可以准确区分炎症和纤维化肠。该建议的中心假设是，准确测量克罗恩病的肠纤维化将指导治疗，并根据两个观察结果预测未来的临床结果。首先，我们的初步数据表明，非线性QSSI和SWEI方法检测和定量测量啮齿动物肠道纤维化，肠壁应变和剪切波速度，分别作为替代放射学生物标志物。第二，虽然炎症明显地引发纤维化，但是三个观察结果挑战了炎症是使纤维化永久化所必需的范例：公开的数据表明抗炎生物治疗没有改变CD中的手术率;我们的体内研究表明，尽管炎症被根除，纤维化仍自我传播;我们的体外研究表明，在没有炎症的情况下，组织僵硬可以激活纤维形成。我们的研究结果表明，肠壁应变和剪切波速度的测量可以帮助区分狭窄注定需要手术，从那些狭窄可能作出反应 药物治疗，即使有炎症。 本申请旨在：（2）通过将这些USI测量与切除的肠样本的组织病理学进行比较，来测试非线性QSSI和SWEI在横截面人类群组中的准确性;以及（3）通过确定USI测量是否预测CD患者的临床结果，在前瞻性人类纵向队列中测试非线性USI方法的预测准确性。拟议的研究将直接影响整个美国的患者护理，并通过证明新型超声在测量纤维化方面的有效性，刺激超声在其他慢性纤维化疾病状态的临床护理中的进一步创新和应用。

 DESCRIPTION (provided by applicant): Fibrosis is the final common pathway to organ failure in many chronic diseases, and it leads to over $142 billion in annual medical costs in the United States. Intestinal fibrosis is the primary reason for surgical intervention in Crohn's disease (CD) which is required in more than two-thirds of patients. Despite this huge impact of fibrosis in CD, we are unable to noninvasively detect or measure intestinal fibrosis in CD. Our recent preliminary data suggest that novel methods of nonlinear ultrasound stiffness imaging (USI) can accurately detect fibrosis in the intestine. The long-term objective of this research program is to develop and test novel methods of measurement of intestinal fibrosis in Crohn's disease to determine prognosis and guide medical and surgical therapy. We propose to evaluate the accuracy of two novel ultrasound methods for measuring intestinal fibrosis in CD. Our preliminary data show that two nonlinear forms of USI (quasi-static strain imaging [QSSI] and shear wave elasticity imaging [SWEI]) can accurately differentiate inflamed from fibrotic intestine. The central hypothesis of this proposal is that accurate measurement of intestinal fibrosis in Crohn's disease will guide therapy and predict future clinical outcomes based on two observations. First, our preliminary data demonstrate that nonlinear QSSI and SWEI methods detect and quantitatively measure fibrosis of the rodent intestine, with bowel wall strain and shear wave speed, respectively, serving as surrogate radiologic biomarkers. Second, while inflammation clearly initiates fibrosis, three observations have challenged the paradigm that inflammation is required to perpetuate fibrosis: published data demonstrates that anti- inflammatory biologic therapy has not changed surgery rates in CD; our in vivo studies which demonstrate that fibrosis autopropagates despite the eradication of inflammation; and our in vitro studies which demonstrate that tissue stiffness in the absence of inflammation can activate fibrogenesis. Our results suggest that bowel wall strain and shear wave speed measurements can help distinguish strictures destined to require surgery from those strictures likely to respond to medical therapy, even when inflammation is present. This application aims: (1) to test the accuracy of nonlinear QSSI and SWEI in a rat model of intestinal fibrosis used in preclinical therapeutic studies; (2) to test the accuracy of nonlinear QSSI and SWEI in a cross- sectional human cohort by comparing these USI measures to the histopathology of resected bowel specimens; and (3) to test the predictive accuracy of the nonlinear USI methods in a prospective human longitudinal cohort by determining whether USI measurements predict clinical outcomes in patients with CD. The proposed studies will directly impact patient care throughout the United States, and by demonstrating the effectiveness of novel forms of ultrasound in the measurement of fibrosis, spur further innovation and application of ultrasound to clinical care in other chroni, fibrotic disease states.