School of Science and Technology, National University of General Martín, Avda Gral Paz 5445, 1650 San Martín, Buenos Aires, Argentina.
Toxicol Appl Pharmacol. 2012 Jun 15;261(3):309-16. doi: 10.1016/j.taap.2012.04.022. Epub 2012 Apr 25.
Uranium compounds are widely used in the nuclear fuel cycle, military and many other diverse industrial processes. Health risks associated with uranium exposure include nephrotoxicity, cancer, respiratory, and immune disorders. Macrophages present in body tissues are the main cell type involved in the internalization of uranium particles. To better understand the pathological effects associated with depleted uranium (DU) inhalation, we examined the metabolic activity, phagocytosis, genotoxicity and inflammation on DU-exposed rat alveolar macrophages (12.5-200 μM). Stability and dissolution of DU could differ depending on the dissolvent and in turn alter its biological action. We dissolved DU in sodium bicarbonate (NaHCO₃ 100 mM) and in what we consider a more physiological vehicle resembling human internal media: sodium chloride (NaCl 0.9%). We demonstrate that uranyl nitrate in NaCl solubilizes, enters the cell, and elicits its cytotoxic effect similarly to when it is diluted in NaHCO₃. We show that irrespective of the dissolvent employed, uranyl nitrate impairs cell metabolism, and at low doses induces both phagocytosis and generation of superoxide anion (O₂⁻). At high doses it provokes the secretion of TNFα and through all the range of doses tested, apoptosis. We herein suggest that at DU low doses O₂⁻ may act as the principal mediator of DNA damage while at higher doses the signaling pathway mediated by O₂⁻ may be blocked, prevailing damage to DNA by the TNFα route. The study of macrophage functions after uranyl nitrate treatment could provide insights into the pathophysiology of uranium-related diseases.
铀化合物被广泛应用于核燃料循环、军事和许多其他不同的工业过程中。与铀接触相关的健康风险包括肾毒性、癌症、呼吸道和免疫系统紊乱。体内组织中的巨噬细胞是参与铀颗粒内化的主要细胞类型。为了更好地了解与贫铀吸入相关的病理效应，我们研究了代谢活性、吞噬作用、遗传毒性和炎症在贫铀暴露的大鼠肺泡巨噬细胞（12.5-200 μM）中的作用。贫铀的稳定性和溶解度可能因溶剂的不同而有所差异，并进而改变其生物学作用。我们将贫铀溶解在碳酸氢钠（NaHCO₃ 100 mM）和我们认为更接近人体内部介质的生理溶剂：氯化钠（NaCl 0.9%）中。我们证明，在 NaCl 溶液中的硝酸铀能够溶解、进入细胞，并产生类似在 NaHCO₃ 中稀释时的细胞毒性作用。我们表明，无论使用哪种溶剂，硝酸铀都会损害细胞代谢，并在低剂量下诱导吞噬作用和生成超氧阴离子（O₂⁻）。在高剂量下，它会引发 TNFα 的分泌，并在测试的所有剂量范围内，引发细胞凋亡。在此，我们建议，在低剂量的 DU 下，O₂⁻可能作为 DNA 损伤的主要介质，而在高剂量下，O₂⁻介导的信号通路可能被阻断，通过 TNFα 途径对 DNA 造成损害。研究硝酸铀处理后的巨噬细胞功能可以深入了解与铀相关疾病的病理生理学。
