Mitigation of Radiation-Induced Lung Injury in the Dog Model

描述（由申请人提供）：有意或意外暴露于放射源后的放射性肺炎，与肺内皮和上皮细胞的损伤或损失、细胞因子的释放、肺泡腔内炎性细胞的积聚以及随后的肺纤维化有关。这是这项拨款建议的目标，以研究方法，以减轻放射性肺损伤的大型动物模型。本研究选择的药剂将具有不同的减轻电离辐射对肺部影响的推定机制。在目标1中，我们将确定与全身照射联合给药时可预测诱导放射性肺炎的肺局部放射剂量。在目标2中，我们将评价研究药物在目标1中预测诱导肺损伤的辐射剂量下的作用。首先，我们将研究角化细胞生长因子（KGF），也被称为帕利弗明对放射性肺炎的发展的影响。KGF刺激II型肺细胞，并且在啮齿动物中对辐射暴露后的肺和其他肺损伤模型具有保护作用。然后，我们将评估原代骨髓间充质干细胞（BM-MSC）对放射性肺炎发展的影响。据报道，MSC已定向迁移到损伤组织，并减轻了缺血或缺血-再灌注模型中的组织损伤。MSC具有免疫调节作用，也可能有助于受损肺组织的重建。最后，将测试A2 A腺苷受体（AR）激动剂。AR激动剂已显示在组织损伤模型中诱导抗凋亡信号并且是抗炎的。在目标3中，将在增加的肺辐射剂量下测试在目标2中发现最有效的研究药剂。在大型动物模型中开发有效的减轻辐射诱导的肺损伤的临床前策略，将增加成功治疗暴露于核武器或“脏弹”电离辐射的受害者的可能性。

DESCRIPTION (provided by applicant): Radiation pneumonitis after intentional or accidental exposure to a radioactive source, is associated with damage or loss of lung endothelial and epithelial cells, the release of cytokines, an accumulation of inflammatory cells within the alveolar spaces, and later, pulmonary fibrosis. It is the goal of this grant proposal to investigate approaches to mitigate radiation-induced lung injury in a large animal model. The agents selected for the study will have different putative mechanisms for mitigating the effect of the ionizing radiation on the lungs. In aim 1, we will determine the local dose of radiation to the lung which predictably induces radiation pneumonitis when administered in combination with total body irradiation. In aim 2, we will evaluate the effect of the study agents at the dose of radiation predicted to induce lung injury in aim 1. First, we will investigate the effect of keratinocyte growth factor (KGF) otherwise known as palifermin on the development of radiation pneumonitis. KGF stimulates type II pneumocytes and in rodents is protective for the lungs after radiation exposure and in other lung injury models. We will then assess the effect of primary bone marrow-derived mesenchymal stem cells (BM-MSC) on the development of radiation pneumonitis. It has been reported that MSC have directed migration to injured tissue and have mitigated tissue injury in models of ischemia or ischemia-reperfusion. MSC are immunomodulatory and may also contribute to the reconstitution of injured lung tissue. Finally, A2A adenosine receptor (AR) agonists will be tested. AR agonists have been shown to induce anti-apoptotic signals in tissue injury models and are anti-inflammatory. In aim 3, the study agent found to be most effective in aim 2 will be tested at an increased dose of radiation to the lung. Preclinical development of effective strategies for the mitigation of radiation-induced lung injury in a large animal model will increase the probability of successful treatment of victims exposed to ionizing radiation from a nuclear weapon or a 'dirty bomb'.