Quantifying Human Lung Tissue Dose Response Relationship

描述（由申请人提供）：本提案的目的是肺是一个非常辐射敏感的器官。急性和早期的辐射毒性作用让位给慢性晚期影响的进行性组织纤维化和肺炎，这些在放射治疗后3-6个月优先出现，并在整个生命中逐渐升级。我们的分析是一种定量体内正常肺组织的辐射剂量反应关系的方法，该方法基于现成的无创体积计算机断层扫描（CT）成像，因此既适用于人类受试者，也适用于辐射损伤的动物模型。在临床上，我们率先使用高剂量立体定向放射治疗来治疗肺部的小转移性肿瘤；使其能够向目标和邻近组织提供非常高的辐射剂量场（超过50Gy），并在远离目标部位的剂量场中下降。使用这些治疗剂量，实现了很高的局部控制率，使我们能够对患者进行数年的随访。在治疗后6个月对这些患者进行的体积CT扫描显示，在治疗期间高剂量区域对应的病灶纤维化区域，在远端部位未观察到长期损伤。在这些患者中，我们能够应用图像配准技术和每个靶标周围的三维剂量场知识，逐个像素地量化正常肺组织的完整辐射剂量反应关系。我们的观点是，这种方法可以用来量化由于特定药物或干预措施的调节作用而引起的放射生物学反应的变化。我们现在已经在临床上验证了血液中IL-1a循环水平的时间模式与可观察到的肺组织反应的时间过程之间的相关性，这是先前在动物模型中预测的相关性。未来一系列血液炎症分子测量与临床反应标志物之间的对应关系将由我科放射医学对策中心的持续进展指导。我们的假设是，我们的分析将使我们第一次能够根据定量组织反应指标量身定制预防和治疗策略。我们的建议包括在动物模型中进行分级肺照射实验，以验证我们的成像结果并将其与细胞和组织放射生物学的先验知识联系起来。

DESCRIPTION (provided by applicant): The aim of this proposal is lungs are a very radiosensitive organ. Acute and early radiation toxicity effects give way to chronic late-effects of progressive tissue fibrosis and pneumonitis that take precedence 3-6 months post-radiation therapy and appear to escalate throughout life. Our assay is a method for quantifying in-vivo the radiation dose response relationship of normal lung tissue that is based on readily available and non-invasive volumetric computed tomography (CT) imaging and is therefore applicable both to human subjects and in animal models of radiation injury. In the clinic we have pioneered the use of high-dose stereotactic radiation therapy to treat small metastatic tumors of the lung; making it possible to deliver a very high radiation dose field (in excess of 50Gy) to the target and immediately adjacent tissue, and a fall-off in the dose field away from the target site. With these curative doses, a high rate of local control is achieved, allowing us to follow our patients for several years. Volumetric CT scans acquired in these patients six months post-treatment reveal a focal region of fibrosis corresponding to the high-dose region during therapy, and no observable long-term damage in distant sites. In these patients we are able to apply image registration techniques and knowledge of the 3D dose field around each target to quantify, on a pixel-by-pixel basis, the complete radiation dose response relationship of normal lung tissue. Our contention is that this method can be used to quantify changes in the radiobiologic response due to the moderating effects of specific agents or interventions. We have now validated clinically a correlation between temporal patterns of circulating levels of IL-1a in the blood and the time course of observable lung tissue response, a correlation predicted by prior work in animal models Future correspondences between serial blood inflammatory molecule measurements and clinical markers of response will be guided by the continued advances from our department's Center for Medical Countermeasures Against Radiation. Our hypothesis is that our assay will enable us for the first time to tailor preventive and treatment strategies to quantitative tissue reaction metrics. Our proposal includes graded lung irradiation experiments in animal models to validate and link our imaging results to prior knowledge of cellular and tissue radiobiology.