Corsetti Giovanni, Romano Claudia, Stacchiotti Alessandra, Pasini Evasio, Dioguardi Francesco S
Department of Clinical and Experimental Sciences, Division of Anatomy and Physiopathology, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
"S. Maugeri Foundation", IRCCS, Cardiology Division, Lumezzane Medical Centre, Brescia, Italy.
Biol Trace Elem Res. 2017 Jul;178(1):86-97. doi: 10.1007/s12011-016-0912-z. Epub 2016 Dec 24.
Lead (Pb) is an environmental oncogenic metal that induces immunotoxicity and anaemia. Emerging evidence has linked Pb toxicity with endoplasmic reticulum-driven apoptosis and autophagy. Glucose-regulated protein of 78 kDa (Grp78 or binding immunoglobulin protein (BiP)), a master endoplasmic reticulum chaperone, drives macrophage activation and regulates protein folding and calcium flux in response to heavy metals. The spleen may be involved in Pb poisoning due to its crucial role in erythrocatheresis and immune response, although there are no data to support this theory. Here, we found haematic and histopathological changes in the spleen of mice exposed to medium doses of Pb acetate (200 ppm-1 mM) in drinking water for 45 days. Pb deposition was also detected in organs such as the liver, kidney, brain, bone, blood and faeces, indicating an accumulation of this metal despite relatively short exposure time. Blood Pb content (BBL) reached 21.6 μg/dL; echinocytes and poikilocytes were found in Pb smears of treated group. Inside the spleen, higher Fe(II) and Fe(III) deposits inside macrophages were observed. Grp78 immunostaining, weakly expressed in spleen cells of control mice, after Pb exposure was specifically restricted to macrophages and megakaryocytes of the marginal zone of red pulp. Furthermore, Pb exposure induced superoxide dismutase 1 (SOD1) expression, cleaved caspase-3 and p62/SQSTM1, consistent with oxidative stress, apoptosis and dysregulated autophagy in spleen compartments. We suggest that even at a middle dose, oral Pb intake induces oxidant iron deposition in the spleen and that this may trigger sustained Grp78 redistribution to cells, thus leading to oxidative and autophagy dysfunction as early local reactions to this dangerous metal.
铅（Pb）是一种环境致癌金属，可诱发免疫毒性和贫血。新出现的证据已将铅毒性与内质网驱动的细胞凋亡和自噬联系起来。78 kDa的葡萄糖调节蛋白（Grp78或结合免疫球蛋白蛋白（BiP））是一种主要的内质网伴侣蛋白，可驱动巨噬细胞活化，并响应重金属调节蛋白质折叠和钙通量。脾脏可能参与铅中毒，因为它在红细胞清除和免疫反应中起关键作用，尽管尚无数据支持这一理论。在这里，我们发现，给小鼠饮用含中等剂量醋酸铅（200 ppm - 1 mM）的水45天后，其脾脏出现血液学和组织病理学变化。在肝脏、肾脏、大脑、骨骼、血液和粪便等器官中也检测到铅沉积，这表明尽管接触时间相对较短，但这种金属仍会蓄积。血铅含量（BBL）达到21.6 μg/dL；在治疗组的铅涂片上发现了棘红细胞和异形红细胞。在脾脏内部，观察到巨噬细胞内有更高的亚铁（Fe(II)）和铁（Fe(III)）沉积。Grp78免疫染色在对照小鼠的脾细胞中弱表达，铅暴露后特异性局限于红髓边缘区的巨噬细胞和巨核细胞。此外，铅暴露诱导超氧化物歧化酶1（SOD1）表达、半胱天冬酶-3（caspase-3）裂解和p62/SQSTM1表达，这与脾脏区室中的氧化应激、细胞凋亡和自噬失调一致。我们认为，即使是中等剂量，经口摄入铅也会在脾脏中诱导氧化性铁沉积，这可能会触发Grp78持续重新分布到细胞中，从而导致氧化和自噬功能障碍，作为对这种危险金属的早期局部反应。
