A novel therapy, using Ghrelin with pegylated G-CSF, inhibits brain hemorrhage from ionizing radiation or combined radiation injury.
A novel therapy, using Ghrelin with pegylated G-CSF, inhibits brain hemorrhage from ionizing radiation or combined radiation injury.
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DOI：
10.15406/ppij.2019.07.00243
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Jiang S
中科院分区：
文献类型：
--
作者：
Kiang JG;Smith JT;Anderson MN;Umali MV;Ho C;Zhai M;Lin B;Jiang S
当由初始急性电离辐射损伤（RI）诱导的继发性反应性代谢和炎症产物或当与后续创伤损伤（CI）组合时引起复杂损伤时，医学治疗变得具有挑战性。由于对许多器官的这种有害影响，CI加剧了原发性损伤的严重程度并降低了存活率。以前，在一项新的研究中，我们报告说，生长激素释放肽治疗显着改善生存后CI。本研究旨在研究由RI和CI诱导的脑出血是否可以通过用聚乙二醇化的G-CSF（即，Neulasta®，FDA批准的药物）。B6 D2 F1雌性小鼠经9.5戈伊~（60）Co-γ射线照射后，造成15%的皮肤表面创伤。在几天内测量了几个终点。RI和CI小鼠脑出血和血小板减少。脑出血严重程度CI小鼠明显高于RI小鼠。用PEG化G-CSF的Ghrelin治疗降低了RI和CI小鼠脑中的严重程度。RI和CI未改变PARP和NF-κB，但显著降低PGC-1α和ghrelin受体;然而，该治疗能够部分恢复ghrelin受体。RI和CI使IL-6、KC、Eotaxin、G-CSF、MIP-2、MCP-1、MIP-1α显著升高，而使IL-2、IL-9、IL-10、IFN-γ、PDGF-bb显著降低; RI和CI显著降低血小板数量、细胞ATP水平、NRF 1/2和AKT磷酸化。该疗法显著减轻了这些CI诱导的变化，并降低了p53-mdm 2介导的caspase-3活化。我们的数据是第一个支持这样的观点，即Ghrelin疗法与聚乙二醇化G-CSF是一种潜在的治疗RI和CI后脑出血的新疗法。
Medical treatment becomes challenging when complicated injuries arise from secondary reactive metabolic and inflammatory products induced by initial acute ionizing radiation injury (RI) or when combined with subsequent trauma insult(s) (CI). With such detrimental effects on many organs, CI exacerbates the severity of primary injuries and decreases survival. Previously, in a novel study, we reported that ghrelin therapy significantly improved survival after CI. This study aimed to investigate whether brain hemorrhage induced by RI and CI could be inhibited by ghrelin therapy with pegylated G-CSF (i.e., Neulasta®, an FDA-approved drug). B6D2F1 female mice were exposed to 9.5 Gy 60Co-γ-radiation followed by 15% total-skin surface wound. Several endpoints were measured at several days. Brain hemorrhage and platelet depletion were observed in RI and CI mice. Brain hemorrhage severity was significantly higher in CI mice than in RI mice. Ghrelin therapy with pegylated G-CSF reduced the severity in brains of both RI and CI mice. RI and CI did not alter PARP and NF-κB but did significantly reduce PGC-1α and ghrelin receptors; the therapy, however, was able to partially recover ghrelin receptors. RI and CI significantly increased IL-6, KC, Eotaxin, G-CSF, MIP-2, MCP-1, MIP-1α, but significantly decreased IL-2, IL-9, IL-10, MIG, IFN-γ, and PDGF-bb; the therapy inhibited these changes. RI and CI significantly reduced platelet numbers, cellular ATP levels, NRF1/2, and AKT phosphorylation. The therapy significantly mitigated these CI-induced changes and reduced p53-mdm2 mediated caspase-3 activation. Our data are the first to support the view that Ghrelin therapy with pegylated G-CSF is potentially a novel therapy for treating brain hemorrhage after RI and CI.