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. ? ? ?
