Warren Pharmaceuticals, Ossining, N.Y., USA.
Blood Purif. 2010;29(2):86-92. doi: 10.1159/000245630. Epub 2010 Jan 8.
Erythropoietin (EPO) is a well-known therapeutic protein employed widely in the treatment of anemia. Over the past decade, abundant evidence has shown that in addition to its systemic role in the regulation of plasma pO(2) by modulating erythrocyte numbers, EPO is also a cytoprotective molecule made locally in response to injury or metabolic stress. Many studies have shown beneficial effects of EPO administration in reducing damage caused by ischemia-reperfusion, trauma, cytotoxicity, infection and inflammation in a variety of organs and tissues. Notably, the receptor mediating the nonerythropoietic effects of EPO differs from the one responsible for hematopoiesis. The tissue-protective receptor exhibits a lower affinity for EPO and is a heteromer consisting of EPO receptor monomers in association with the common receptor that is also employed by granulocyte macrophage colony-stimulating factor, interleukin 3, and interleukin 5. This heteromeric receptor is expressed immediately following injury, whereas EPO production is delayed. Thus, early administration of EPO can dramatically reduce the deleterious components of the local inflammatory cascade. However, a high dose of EPO is required and this also stimulates the bone marrow to produce highly reactive platelets and activates the vascular endothelium into a prothrombotic state. To circumvent these undesirable effects, the EPO molecule has been successfully altered to selectively eliminate erythropoietic and prothrombotic potencies, while preserving tissue-protective activities. Very recently, small peptide mimetics have been developed that recapitulate the tissue-protective activities of EPO. Nonerythropoietic tissue-protective molecules hold high promise in a wide variety of acute and chronic diseases.
促红细胞生成素（EPO）是一种众所周知的治疗性蛋白，广泛用于治疗贫血。在过去的十年中，大量证据表明，除了通过调节红细胞数量来系统地调节血浆 pO2 外，EPO 还是一种局部产生的细胞保护分子，以响应损伤或代谢应激。许多研究表明，EPO 给药可减少缺血再灌注、创伤、细胞毒性、感染和炎症在各种器官和组织中引起的损伤，具有有益作用。值得注意的是，介导 EPO 的非红细胞生成作用的受体与负责造血的受体不同。该组织保护受体对 EPO 的亲和力较低，并且是由 EPO 受体单体与共同受体组成的异源二聚体，共同受体也被粒细胞巨噬细胞集落刺激因子、白细胞介素 3 和白细胞介素 5 采用。这种异源二聚体受体在损伤后立即表达，而 EPO 的产生则延迟。因此，早期给予 EPO 可以显著减少局部炎症级联反应的有害成分。然而，需要高剂量的 EPO，这也会刺激骨髓产生高反应性血小板，并激活血管内皮细胞进入促血栓形成状态。为了避免这些不良影响，EPO 分子已成功改变，以选择性消除其促红细胞生成和促血栓形成作用，同时保留组织保护作用。最近，已经开发出小肽模拟物，可重现 EPO 的组织保护活性。非红细胞生成性组织保护分子在各种急性和慢性疾病中具有很高的应用前景。
