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

描述(申请人提供)：辐射诱导的促炎和促纤维化细胞因子的产生会导致对肺的慢性和不可逆转的损害。到目前为止，还没有一种药物表现出足够的安全性，可以作为临床药物用于缓解 暴露在意外或恐怖核事件的辐射中造成的损害。因此，非常需要新的、机械靶向的药物，这些药物可以用来减轻意外暴露后对人类的辐射中毒。许多研究表明鞘磷脂代谢是炎症和纤维化过程的重要介质。辐射产生的炎性和促纤维化细胞因子(如肿瘤坏死因子和转化生长因子)激活鞘磷脂酶和神经酰胺酶来产生鞘氨醇，鞘氨醇激酶(SK1和SK2)将其磷酸化，从而产生鞘氨醇1-磷酸(S1P)。已证实SK的激活和S1P的产生在炎症细胞因子的信号反应中是必不可少的，包括它们通过激活NF？B诱导黏附分子表达的能力。类似地，对转化生长因子的反应中胶原的合成依赖于SKS产生S1P。因此，SKS是减轻损伤性炎症和纤维化药物的合理新靶点。阿波吉生物技术公司已经确定了第一批具有体外和体内活性的口服SK抑制剂。主要的SK2抑制剂，命名为ABC294640，在几个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，对老鼠的治疗 当化合物在暴露前或暴露后给予时，使用ABC294640可保护免受全身或腹部照射的毒性。我们假设ABC294640抑制SK2活性将减轻暴露在电离辐射下的肺纤维化损伤。为了确定将ABC294640用于放射减肥临床试验的合理性，我们将进行以下具体目标：1)确定ABC294640保护培养的人成纤维细胞免受细胞因子诱导的纤维化反应的机制；以及2)表征ABC294640预防胸部照射所致肺纤维化的能力。这些研究将提供必要的实验验证，以证明未来在非人类灵长类动物上进行的验证性研究是合理的，并最终在人类身上进行临床试验。

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.