Noel John G, Ramser Benjamin J, Cancelas Jose A, McCormack Francis X, Gardner Jason C
Department of Research, Shriners Hospitals for Children, Cincinnati, Ohio.
Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio.
Exp Hematol. 2017 Dec;56:16-30. doi: 10.1016/j.exphem.2017.08.005. Epub 2017 Sep 1.
Inflammation-mediated impairment of erythropoiesis plays a central role in the development of the anemia of critical illness (ACI). ACI develops despite elevation of endogenous erythropoietin (EPO), does not respond to exogenous erythropoietin (EPO) supplementation, and contributes significantly to transfusion requirements in burned patients. We have reported previously that the reduction of red blood cell mass in the bone marrow of a burn-injured ACI mouse model is granulocyte colony-stimulating factor (G-CSF) dependent. Given that elevated G-CSF levels also have been associated with lower hemoglobin levels and increased transfusion requirements in trauma victims, we postulated that G-CSF mediates postburn EPO resistance. In ACI mice, we found that bone marrow erythroid differentiation, viability, and proliferation are impaired after thermal injury of the skin. These changes in the marrow were associated with attenuated phosphorylation of known EPO-responsive signaling nodes, signal transducer and activator of transcription 5 (STAT5) Y694 and STAT3 S727, in bone marrow erythroid cells and developed despite highly elevated levels of endogenous EPO. Severely blunted STAT5 Y694 phosphorylation in bone marrow erythroid cells after exogenous EPO supplementation confirmed that EPO signaling was impaired in ACI mice. Importantly, parenteral administration of anti-G-CSF largely rescued postburn bone marrow erythroid differentiation arrest and EPO signaling in erythroid cells. Together, these data provide strong evidence for a role for G-CSF in the development of ACI after burn injury through suppression of EPO signaling in bone marrow erythroid cells.
炎症介导的红细胞生成受损在危重症贫血（ACI）的发生发展中起核心作用。尽管内源性促红细胞生成素（EPO）升高，ACI仍会发生，对外源性促红细胞生成素（EPO）补充无反应，并且在烧伤患者的输血需求中起重要作用。我们之前报道过，烧伤损伤的ACI小鼠模型骨髓中红细胞数量的减少是粒细胞集落刺激因子（G-CSF）依赖性的。鉴于创伤患者中G-CSF水平升高也与较低的血红蛋白水平和增加的输血需求相关，我们推测G-CSF介导烧伤后EPO抵抗。在ACI小鼠中，我们发现皮肤热损伤后骨髓红系分化、活力和增殖受损。骨髓中的这些变化与骨髓红系细胞中已知的EPO反应信号节点、信号转导和转录激活因子5（STAT5）Y694和STAT3 S727的磷酸化减弱有关，尽管内源性EPO水平大幅升高，但这些变化仍会出现。外源性补充EPO后，骨髓红系细胞中STAT5 Y694磷酸化严重减弱，证实ACI小鼠中EPO信号受损。重要的是，胃肠外给予抗G-CSF在很大程度上挽救了烧伤后骨髓红系分化停滞和红系细胞中的EPO信号。总之，这些数据为G-CSF通过抑制骨髓红系细胞中的EPO信号在烧伤后ACI发生发展中的作用提供了有力证据。
