Papadopoulos Konstantinos I, Sutheesophon Warachaya, Manipalviratn Somjate, Aw Tar-Choon
Department of Research and Development, THAI StemLife, Bangkok 10310, Thailand.
Laboratory Department, THAI StemLife, Bangkok 10310, Thailand.
World J Stem Cells. 2021 Oct 26;13(10):1513-1529. doi: 10.4252/wjsc.v13.i10.1513.
Erythropoietin (EPO) is the main mediator of erythropoiesis and an important tissue protective hormone that appears to mediate an ancestral neuroprotective innate immune response mechanism at an early age. When the young brain is threatened-prematurity, neonatal hyperbilirubinemia, malaria- EPO is hyper-secreted disproportionately to any concurrent anemic stimuli. Under eons of severe malarial selection pressure, neuroprotective EPO augmenting genetic determinants such as the various hemoglobinopathies, and the angiotensin converting enzyme (ACE) I/D polymorphism, have been positively selected. When malarial and other cerebral threats abate and the young child survives to adulthood, EPO subsides. Sustained high ACE and angiotensin II (Ang II) levels through the ACE D allele in adulthood may then become detrimental as witnessed by epidemiological studies. The ubiquitous renin angiotensin system (RAS) influences the α-klotho/fibroblast growth factor 23 (FGF23) circuitry, and both are interconnected with EPO. Here we propose that at a young age, EPO augmenting genetic determinants through ACE D allele elevated Ang II levels in some or HbE/beta thalassemia in others would increase EPO levels and shield against coronavirus disease 2019, akin to protection from malaria and dengue fever. Human evolution may use ACE2 as a "bait" for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to gain cellular entry in order to trigger an ACE/ACE2 imbalance and stimulate EPO hypersecretion using tissue RAS, uncoupled from hemoglobin levels. In subjects without EPO augmenting genetic determinants at any age, ACE2 binding and internalization upon SARS-CoV-2 entry would trigger an ACE/ACE2 imbalance, and Ang II oversecretion leading to protective EPO stimulation. In children, low nasal ACE2 Levels would beneficially augment this imbalance, especially for those without protective genetic determinants. On the other hand, in predisposed adults with the ACE D allele, ACE/ACE2 imbalance, may lead to uncontrolled RAS overactivity and an Ang II induced proinflammatory state and immune dysregulation, with interleukin 6 (IL-6), plasminogen activator inhibitor, and FGF23 elevations. IL-6 induced EPO suppression, aggravated through co-morbidities such as hypertension, diabetes, obesity, and RAS pharmacological interventions may potentially lead to acute respiratory distress syndrome, cytokine storm and/or autoimmunity. HbE/beta thalassemia carriers would enjoy protection at any age as their EPO stimulation is uncoupled from the RAS system. The timely use of rhEPO, EPO analogs, acetylsalicylic acid, bioactive lipids, or FGF23 antagonists in genetically predisposed individuals may counteract those detrimental effects.
促红细胞生成素（EPO）是红细胞生成的主要介质，也是一种重要的组织保护激素，似乎在早期介导一种祖传的神经保护先天性免疫反应机制。当幼脑受到威胁时，如早产、新生儿高胆红素血症、疟疾，EPO会过度分泌，与任何并发的贫血刺激不成比例。在长期严重的疟疾选择压力下，增强神经保护作用的EPO相关基因决定因素，如各种血红蛋白病以及血管紧张素转换酶（ACE）I/D多态性，已被正向选择。当疟疾和其他脑部威胁减轻且幼儿存活至成年时，EPO分泌减少。成年期通过ACE D等位基因维持的高ACE和血管紧张素II（Ang II）水平随后可能变得有害，这已被流行病学研究所证实。普遍存在的肾素血管紧张素系统（RAS）影响α-klotho/成纤维细胞生长因子23（FGF23）通路，且两者均与EPO相互关联。在此，我们提出，在幼年时，通过ACE D等位基因增强EPO的基因决定因素会使一些人的Ang II水平升高，而在另一些人（如HbE/β地中海贫血患者）中则会增加EPO水平，从而抵御2019冠状病毒病，类似于抵御疟疾和登革热。人类进化可能利用血管紧张素转换酶2（ACE2）作为严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的“诱饵”以进入细胞，从而引发ACE/ACE2失衡，并利用组织RAS刺激EPO过度分泌，这与血红蛋白水平无关。在任何年龄没有增强EPO基因决定因素的个体中，SARS-CoV-2进入时ACE2的结合和内化会引发ACE/ACE2失衡以及Ang II分泌过多，从而导致保护性EPO刺激。在儿童中，低鼻内ACE2水平将有益地增强这种失衡，特别是对于那些没有保护性基因决定因素的儿童。另一方面，在具有ACE D等位基因的易感成年人中，ACE/ACE2失衡可能导致不受控制的RAS过度活跃以及Ang II诱导的促炎状态和免疫失调，同时伴有白细胞介素6（IL-6）、纤溶酶原激活物抑制剂和FGF23升高。IL-6诱导的EPO抑制，通过高血压、糖尿病、肥胖等合并症以及RAS药物干预而加重，可能潜在地导致急性呼吸窘迫综合征、细胞因子风暴和/或自身免疫。HbE/β地中海贫血携带者在任何年龄都将受到保护，因为他们的EPO刺激与RAS系统无关。在具有遗传易感性的个体中及时使用重组人促红细胞生成素（rhEPO）、EPO类似物、乙酰水杨酸、生物活性脂质或FGF23拮抗剂可能抵消这些有害影响。
