Thrombocytopenia is a major complication in hematopoietic-acute radiation syndrome (H-ARS) that increases the risk of mortality from uncontrolled hemorrhage. There is a great demand for new therapies to improve survival and mitigate bleeding in H-ARS. Thrombopoiesis requires interactions between megakaryocytes (MKs) and endothelial cells. 16, 16-dimethyl prostaglandin E₂ (dmPGE₂), a longer-acting analogue of PGE₂, promotes hematopoietic recovery after total-body irradiation (TBI), and various angiotensin-converting enzyme (ACE) inhibitors mitigate endothelial injury after radiation exposure. Here, we tested a combination therapy of dmPGE₂ and lisinopril to mitigate thrombocytopenia in murine models of H-ARS following TBI. After 7.75 Gy TBI, dmPGE₂ and lisinopril each increased survival relative to vehicle controls. Importantly, combined dmPGE₂ and lisinopril therapy enhanced survival greater than either individual agent. Studies performed after 4 Gy TBI revealed reduced numbers of marrow MKs and circulating platelets. In addition, sublethal TBI induced abnormalities both in MK maturation and in in vitro and in vivo platelet function. dmPGE₂, alone and in combination with lisinopril, improved recovery of marrow MKs and peripheral platelets. Finally, sublethal TBI transiently reduced the number of marrow Lin–CD45–CD31⁺Sca-1^– sinusoidal endothelial cells, while combined dmPGE₂ and lisinopril treatment, but not single-agent treatment, accelerated their recovery. Taken together, these data support the concept that combined dmPGE₂ and lisinopril therapy improves thrombocytopenia and survival by promoting recovery of the MK lineage, as well as the MK niche, in the setting of H-ARS.

血小板减少症是造血急性放射综合征 (H-ARS) 的主要并发症，会增加因失控出血而死亡的风险。对提高 H-ARS 患者生存率和减轻出血的新疗法的需求很大。血小板生成需要巨核细胞 (MKs) 和内皮细胞之间的相互作用。16, 16-二甲基前列腺素 E ₂ (dmPGE _{2 ) 是 PGE 2}的长效类似物，可促进全身照射 (TBI) 后的造血功能恢复，各种血管紧张素转换酶 (ACE) 抑制剂可减轻辐射照射后的内皮损伤. 在这里，我们测试了 dmPGE _{2的组合疗法}和赖诺普利可减轻 TBI 后 H-ARS 小鼠模型中的血小板减少症。在 7.75 Gy TBI 后，dmPGE ₂和赖诺普利相对于载体对照均增加了存活率。重要的是，dmPGE ₂和赖诺普利联合治疗比任何一种单独的药物都能提高生存率。4 Gy TBI 后进行的研究显示骨髓 MK 和循环血小板数量减少。此外，亚致死性 TBI 诱导 MK 成熟和体外和体内血小板功能异常。dmPGE ₂单独和与赖诺普利联合使用可改善骨髓 MKs 和外周血小板的恢复。最后，亚致死性 TBI 短暂减少了骨髓 Lin-CD45-CD31 ^+的数量Sca-1 ^–血窦内皮细胞，虽然联合 dmPGE ₂和赖诺普利治疗，但不是单药治疗，加速了它们的恢复。综上所述，这些数据支持了 dmPGE ₂和赖诺普利联合治疗通过促进 MK 谱系以及 MK 生态位在 H-ARS 环境中的恢复来改善血小板减少症和存活率的概念。