Coleman Thomas R, Westenfelder Christof, Tögel Florian E, Yang Ying, Hu Zhuma, Swenson Leanne, Leuvenink Henri G D, Ploeg Rutger J, d'Uscio Livius V, Katusic Zvonimir S, Ghezzi Pietro, Zanetti Adriana, Kaushansky Kenneth, Fox Norma E, Cerami Anthony, Brines Michael
The Kenneth S. Warren Institute, Warren Pharmaceuticals, Ossining, NY 10562, USA.
Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5965-70. doi: 10.1073/pnas.0601377103. Epub 2006 Apr 3.
Recombinant human erythropoietin (rhEPO) is receiving increasing attention as a potential therapy for prevention of injury and restoration of function in nonhematopoietic tissues. However, the minimum effective dose required to mimic and augment these normal paracrine functions of erythropoietin (EPO) in some organs (e.g., the brain) is higher than for treatment of anemia. Notably, a dose-dependent risk of adverse effects has been associated with rhEPO administration, especially in high-risk groups, including polycythemia-hyperviscosity syndrome, hypertension, and vascular thrombosis. Of note, several clinical trials employing relatively high dosages of rhEPO in oncology patients were recently halted after an increase in mortality and morbidity, primarily because of thrombotic events. We recently identified a heteromeric EPO receptor complex that mediates tissue protection and is distinct from the homodimeric receptor responsible for the support of erythropoiesis. Moreover, we developed receptor-selective ligands that provide tools to assess which receptor isoform mediates which biological consequence of rhEPO therapy. Here, we demonstrate that rhEPO administration in the rat increases systemic blood pressure, reduces regional renal blood flow, and increases platelet counts and procoagulant activities. In contrast, carbamylated rhEPO, a heteromeric receptor-specific ligand that is fully tissue protective, increases renal blood flow, promotes sodium excretion, reduces injury-induced elevation in procoagulant activity, and does not effect platelet production. These preclinical findings suggest that nonerythropoietic tissue-protective ligands, which appear to elicit fewer adverse effects, may be especially useful in clinical settings for tissue protection.
重组人促红细胞生成素（rhEPO）作为一种预防非造血组织损伤和恢复功能的潜在疗法，正受到越来越多的关注。然而，在某些器官（如大脑）中，模拟和增强促红细胞生成素（EPO）这些正常旁分泌功能所需的最小有效剂量高于治疗贫血所需的剂量。值得注意的是，rhEPO给药存在剂量依赖性不良反应风险，尤其是在高危人群中，包括红细胞增多症-高黏滞综合征、高血压和血管血栓形成。值得注意的是，最近几项在肿瘤患者中使用相对高剂量rhEPO的临床试验在死亡率和发病率增加后被中止，主要原因是血栓事件。我们最近鉴定出一种异源三聚体EPO受体复合物，它介导组织保护，与负责支持红细胞生成的同二聚体受体不同。此外，我们开发了受体选择性配体，为评估哪种受体异构体介导rhEPO治疗的哪种生物学后果提供了工具。在这里，我们证明，在大鼠中给予rhEPO会升高全身血压、减少局部肾血流量，并增加血小板计数和促凝血活性。相比之下，氨甲酰化rhEPO是一种完全具有组织保护作用的异源三聚体受体特异性配体，它能增加肾血流量、促进钠排泄、降低损伤诱导的促凝血活性升高，并且不影响血小板生成。这些临床前研究结果表明，似乎引起较少不良反应的非促红细胞生成的组织保护配体，在临床组织保护环境中可能特别有用。
