Mitigation of Radiation-Induced Pulmonary Fibrosis by a Sphingosine Kinase Inhibi

描述（由申请方提供）：辐射诱导的促炎和促纤维化细胞因子的产生导致肺慢性和不可逆损伤。到目前为止，还没有药物表现出足够的安全性特征，可用作临床药物，用于缓解 暴露于意外或恐怖核事件的辐射造成的损害。因此，非常需要新的、机械靶向的药物，其可以用于减轻人类在意外暴露后的辐射中毒。许多研究表明鞘脂代谢是炎症和纤维化过程的关键介质。辐射暴露产生的炎症和促纤维化细胞因子（例如TNF和TGF）激活鞘磷脂酶和神经酰胺酶以产生鞘氨醇，鞘氨醇被鞘氨醇激酶（SK 1和SK 2）磷酸化以产生1-磷酸鞘氨醇（S1 P）。它是建立，SK激活和生产的S1 P是必不可少的炎症细胞因子的信号转导反应，包括他们的能力，通过激活NF？B。类似地，响应于TGF β的胶原蛋白合成依赖于SK产生的S1 P。因此，SK是减轻损伤性炎症和纤维化的药物的合理新靶点。 Apogee生物技术公司已经确定了第一个口服的SK抑制剂在体外和体内的活性。主要的SK2抑制剂，命名为ABC 294640，在几种体内模型中具有抗肿瘤和抗炎活性，同时对动物表现出非常低的毒性。我们的初步研究表明， 与ABC 294640的化合物在暴露前或暴露后给药时，可防止全身或腹部辐射的毒性。 我们假设ABC 294640对SK2活性的抑制将减轻暴露于电离辐射引起的肺纤维化损伤。为了确定将ABC 294640用于放射性激动的临床试验的合理性，我们将进行以下特定目的：1）确定ABC 294640在培养的人成纤维细胞中保护免受苦参碱诱导的纤维化反应的机制;和2）表征ABC 294640保护免受胸部照射引起的肺纤维化的能力。这些研究将提供必要的实验验证，以证明未来在非人灵长类动物中进行的确证性研究以及最终在人类中进行的临床试验的合理性。

DESCRIPTION (provided by applicant): Radiation-induced production of pro-inflammatory and pro-fibrotic cytokines results in chronic and irreversible damage to the lungs. To date, no agent has demonstrated a sufficient safety profile to be utilized as a clinical drug for mitigating damage from exposure to radiation from accidental or terroristic nuclear events. Consequently, there is a great need for new, mechanistically-targeted drugs that can be utilized to mitigate radiation poisoning of humans following unintended exposure. Many studies have implicated sphingolipid metabolism as a critical mediator of inflammatory and fibrotic processes. Inflammatory and pro-fibrotic cytokines produced by radiation exposure (e.g. TNF¿ and TGF¿) activate sphingomyelinases and ceramidases to produce sphingosine, which is phosphorylated by sphingosine kinases (SK1 and SK2) to produce sphingosine 1-phosphate (S1P). It is established that SK activation and production of S1P are essential for signaling responses to inflammatory cytokines, including their ability to induce adhesion molecule expression via activation of NF?B. Similarly, collagen synthesis in response to TGF¿ is dependent on S1P production by SKs. Therefore, SKs are rational new targets for drugs that attenuate damaging inflammation and fibrosis. Apogee Biotechnology Corporation has identified the first orally-available SK inhibitors with activity in vitro and in vivo. The lead SK2 inhibitor, designated as ABC294640, has antitumor and anti-inflammatory activities in several in vivo models, while exhibiting very low toxicity to the animal. Our Preliminary Studies indicate that treatment of mice with ABC294640 protects against toxicity from total body or abdominal irradiation when the compound is given either pre-exposure or post-exposure. We hypothesize that suppression of SK2 activity by ABC294640 will mitigate pulmonary fibrotic damage from exposure to ionizing radiation. To establish justification for moving ABC294640 toward clinical trials for radiomitigation, we will conduct the following Specific Aims: 1) To determine the mechanism for ABC294640 protection against cytokine-induced fibrotic responses in cultured human fibroblasts; and 2) To characterize the ability of ABC294640 to protect against pulmonary fibrosis from thoracic irradiation. These studies will provide the experimental validation needed to justify future confirmatory studies in non- human primates, and ultimately clinical trials in humans.