Mitigation of Radiation-Induced Lung Injury in the Dog Model

描述(申请人提供)：放射性肺炎在故意或意外暴露于放射源后，与肺内皮细胞和上皮细胞的损伤或丢失、细胞因子的释放、肺泡腔内炎症细胞的积聚以及后来的肺纤维化有关。这项拨款提案的目的是研究在大型动物模型中减轻放射性肺损伤的方法。为这项研究选择的药物将有不同的假定机制来减轻电离辐射对肺部的影响。在目标1中，我们将确定当与全身照射联合使用时，可预测地诱发放射性肺炎的肺部局部辐射剂量。在目标2中，我们将评估在目标1中预计会导致肺损伤的辐射剂量的研究试剂的效果。首先，我们将研究角质形成细胞生长因子(KGF)在放射性肺炎发生中的作用。KGF刺激II型肺细胞，在啮齿类动物中，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)在放射性肺炎发展中的作用。有报道称，在缺血或缺血-再灌注模型中，MSC可以定向向损伤组织迁移，减轻组织损伤。间充质干细胞具有免疫调节作用，也可能有助于受损肺组织的重建。最后，将测试A2A腺苷受体(AR)激动剂。AR激动剂已被证明可以在组织损伤模型中诱导抗凋亡信号，并具有抗炎作用。在目标3中，被发现在目标2中最有效的研究试剂将在增加肺部辐射剂量的情况下进行测试。在大型动物模型中开发有效的减轻放射性肺损伤的临床前策略，将增加暴露在核武器或“脏弹”电离辐射下的受害者成功治疗的可能性。

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'.