Growth of Normal Tissues: Radiobiological Implications

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Normal tissue toxicity is a dose-limitation for cancer radiotherapy. The long-term goal of this work is to understand the cellular perturbations that result from irradiation and the underlying dynamics that lead to failure of dose-limiting tissues whose dynamics are largely unknown. Fundamental questions, which this proposal addresses, are: "Why does the organ not fail until many months after the initial damage has been both inflicted and recognized? How does homeostatic control of the tissue breakdown? What are the characteristics of the population dynamic parameters which modulate the final outcome?" Normal tissues have become conventionally categorized as either acute- or late- responding depending on the latent periods after which they functionally express their damage following irradiation. This proposal focuses on lung (typically considered a late-responding normal tissue). The specific aims will establish the normal homeostatic mechanisms of the lung, the effects of these mechanisms in the restoration of normal tissue function after X- irradiation and the modulation of homeostasis by treatment with keratinocyte growth factor (KGF). Growth factors offer a novel means of mitigating normal tissue radiotoxicity. Their rational use, however, requires a better understanding of the population dynamics of tissues in order to define strategies for radioprotection. We will detail the proliferative, differentiation, and apoptotic status of defined subpopulations of cells and determine the specific kinetic mechanisms by which irradiation and KGF perturb the population dynamics of the alveolar epithelium. The experiments will determine the cellular mechanisms by which KGF protects the lung from radiation damage. Measurement of these parameters at the time of irradiation and periodically thereafter, will determine the population dynamic mechanisms that contribute to the dose- and time-responses we have quantitated after either radiation alone or following KGF pretreatment. Firstly, we will test the hypothesis that KGF will protect the lung when given in a fractionated irradiation regime, as is the clinical norm. Secondly, we hypothesize that KGF will be useful for salvage of radiation damage. We will test this by treating with KGF post- irradiation of the lung. Thirdly, we will test our hypothesis that KGF will not stimulate proliferation of small amounts of residual tumor or micrometastases. This is important if KGF is to be useful when given post-treatment when small amounts of tumor might remain. This work uses a new analytical framework to relate proliferative and apoptotic quantities of normal tissues.