Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
Toxicol Sci. 2011 Jul;122(1):177-84. doi: 10.1093/toxsci/kfr079. Epub 2011 Apr 11.
Anemia is probably one of the most well-known toxic effects of lead. Previously, lead-induced anemia was considered to be from the inhibition of δ-aminolevulinic acid dehydratase participating in the heme biosynthesis. However, little is known whether lead could affect the destruction of erythrocyte, another important factor for anemia. In the present study, we demonstrated that lead could accelerate the splenic sequestration of erythrocytes through phosphatidylserine (PS) exposure and subsequently increased erythrophagocytosis. In freshly isolated human erythrocytes, Pb(2+)- induced PS exposure at relatively low concentrations (∼0.1 μM) by inhibiting flippase, a key aminophospholipid translocase for the maintenance of PS asymmetry and adenosine triphosphate depletion appeared to underlie this phenomenon. Abnormal shape changes of erythrocytes and microvesicle generation and other triggers for the erythrophagocytosis were also observed in the Pb(2+)-exposed erythrocytes. In vitro data showed that human macrophage indeed recognized and phagocytosis PS-exposed erythrocytes. In good accordance with these in vitro results, the oral administration of Pb(2+) increased PS exposure on erythrocytes in rat in vivo. In addition, reduction of hematocrit and hemoglobin and increased spleen weight were observed along with enhanced splenic sequestration of erythrocytes in the rats exposed to Pb(2+) subchronically for 4 weeks through drinking water. In conclusion, these results suggest that Pb(2+)-induced anemia may be explained at least in part by increased PS exposure on erythrocytes, erythrophagocytosis, and splenic sequestration.
贫血可能是铅中毒最广为人知的毒性作用之一。以前，铅诱导的贫血被认为是由于δ-氨基-γ-酮戊酸脱水酶（一种参与血红素生物合成的酶）受到抑制所致。然而，目前尚不清楚铅是否会影响红细胞的破坏，这是导致贫血的另一个重要因素。在本研究中，我们发现铅可以通过暴露磷脂酰丝氨酸（PS）来加速脾脏对红细胞的扣押，从而增加红细胞的吞噬作用。在新分离的人红细胞中，Pb(2+)通过抑制翻转酶（一种维持 PS 不对称性和三磷酸腺苷耗竭的关键氨基磷脂转运体）在相对较低的浓度（约 0.1 μM）下诱导 PS 暴露，似乎是这种现象的基础。在 Pb(2+)暴露的红细胞中，还观察到红细胞的异常形状变化、微囊泡生成和其他触发红细胞吞噬的因素。体外数据表明，人巨噬细胞确实识别并吞噬 PS 暴露的红细胞。与这些体外结果非常一致的是，通过饮用水给大鼠口服 Pb(2+)会增加其体内红细胞上的 PS 暴露。此外，在 Pb(2+)亚慢性暴露 4 周的大鼠中，还观察到红细胞比容和血红蛋白降低，脾脏重量增加，以及脾脏对红细胞的扣押增加。综上所述，这些结果表明，Pb(2+)诱导的贫血至少部分可以通过红细胞上 PS 暴露增加、红细胞吞噬作用和脾脏扣押来解释。
