临床上使用的 PARP 抑制剂奥拉帕利可改善三度烧伤模型鼠的器官功能，抑制炎症反应，加速伤口愈合。
The clinically used PARP inhibitor olaparib improves organ function, suppresses inflammatory responses and accelerates wound healing in a murine model of third-degree burn injury.
机构信息
Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, USA.
Department of Surgery, The University of Texas Medical Branch, Galveston, TX, USA.
出版信息
Br J Pharmacol. 2018 Jan;175(2):232-245. doi: 10.1111/bph.13735. Epub 2017 Mar 5.
BACKGROUND AND PURPOSE
The PARP inhibitor olaparib has recently been approved for human use for the therapy of cancer. Considering the role of PARP in critical illness, we tested the effect of olaparib in a murine model of burn injury, in order to begin exploring the feasibility of repurposing olaparib for the therapy of burn patients.
EXPERIMENTAL APPROACH
Mice were subjected to scald burn injury and randomized into vehicle or olaparib (10 mg·kg ·day i.p.) groups. Outcome variables included indices of organ injury, clinical chemistry parameters, plasma levels of inflammatory mediators (at 24 h, 7 and 21 days) and burn wound size (at 21 days).
KEY RESULTS
Olaparib reduced myeloperoxidase levels in heart and lung homogenates and reduced malondialdehyde levels in all tissues 24 h post-burn. Olaparib also reduced circulating alkaline aminotransferase, amylase and blood urea nitrogen and creatinine levels, indicative of protection against hepatic, pancreatic and renal dysfunction. Pro-inflammatory mediator (TNF-α, IL-1β, IFN-γ, GCSF, GM-CSF, eotaxin, KC, MIP-1-α and IL-3, 6 and 12) levels as well as the levels of several mediators that are generally considered anti-inflammatory (IL-4, 10 and 13) were reduced by olaparib. Plasma troponin-I levels (an indicator of skeletal muscle damage) was also attenuated by olaparib. Finally, olaparib stimulated wound healing.
CONCLUSIONS AND IMPLICATIONS
The clinically approved PARP inhibitor olaparib improves organ function, suppresses inflammatory responses and accelerates wound healing in murine burn injury. The data raise the potential utility of olaparib for severe burn injury.
LINKED ARTICLES
This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.
背景与目的
聚腺苷二磷酸核糖聚合酶（PARP）抑制剂奥拉帕尼最近已被批准用于癌症的治疗。鉴于 PARP 在危重病中的作用，我们在烧伤小鼠模型中测试了奥拉帕尼的作用，以便开始探索将奥拉帕尼重新用于烧伤患者治疗的可行性。
实验方法
将小鼠进行烫伤烧伤损伤，并随机分为载体或奥拉帕尼（10mg·kg·天腹腔注射）组。观察终点包括器官损伤指标、临床化学参数、炎症介质的血浆水平（24 小时、7 天和 21 天）和烧伤创面大小（21 天）。
主要结果
奥拉帕尼降低了烧伤后 24 小时心脏和肺匀浆中的髓过氧化物酶水平，并降低了所有组织中的丙二醛水平。奥拉帕尼还降低了循环碱性氨基转移酶、淀粉酶和血尿素氮和肌酐水平，提示对肝、胰腺和肾功能障碍有保护作用。促炎介质（TNF-α、IL-1β、IFN-γ、GCSF、GM-CSF、嗜酸性粒细胞趋化因子、KC、MIP-1-α 和 IL-3、6 和 12）以及几种通常被认为具有抗炎作用的介质（IL-4、10 和 13）的水平均被奥拉帕尼降低。奥拉帕尼还降低了血浆肌钙蛋白 I 水平（骨骼肌损伤的标志物）。最后，奥拉帕尼刺激了伤口愈合。
结论和意义
临床上已批准的 PARP 抑制剂奥拉帕尼改善了器官功能，抑制了炎症反应，并加速了小鼠烧伤损伤的伤口愈合。这些数据提出了奥拉帕尼在严重烧伤中的潜在应用。
相关文章
本文是一个关于“创新治疗方法，无需从头再来：药物再利用的力量”的专题的一部分。要查看该部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.
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