Abstract：
Precision-cut lung slices (PCLS) are a suitable model for analyzing the acetylcholinesterase (AChE) activity and subsequent effects after exposure to organophosphorus (OP) compounds. In this study, the AChE activity was determined in intact PCLS for the first time. Since the current standard therapy for OP poisoning (atropine + oxime + benzodiazepine) lacks efficiency, reliable models to study novel therapeutic substances are needed. Models should depict pathophysiological mechanisms and help to evaluate the beneficial effects of new therapeutics. Here PCLS were exposed to three organophosphorus nerve agents (OPNAs): sarin (GB), cyclosarin (GF), and VX. They were then treated with three reactivators: HI-6, obidoxime (OBI), and a non-oxime (NOX-6). The endpoints investigated in this study were the AChE activity and the airway area (AA) change. OPNA exposure led to very low residual AChE activities. Depending on the reactivator properties different AChE reactivation results were measured. GB-inhibited PCLS-AChE was reactivated best, followed by VX and GF. To substantiate these findings and to understand the connection between the molecular and the functional levels in a more profound way the results were correlated to the AA changes. These investigations underline the importance of reactivator use and point to the possibilities for future improvements in the treatment of OPNA-exposed victims.
摘要：
精确切割的肺切片（PCLS）是分析乙酰胆碱酯酶（AChE）活性和暴露于有机磷（OP）化合物后的后续作用的合适模型。在这项研究中,首次在完整的PCLS中测定了AChE活性。由于目前OP中毒的标准疗法（阿托品+肟+苯二氮卓）缺乏疗效，需要可靠的模型来研究新的治疗物质。模型应描述病理生理机制，并有助于评估新疗法的有益效果。在这里，PCLS暴露于三种有机磷神经毒剂（OPNAs）：沙林（GB），环沙林（GF），VX。然后用三种活化剂处理：HI-6，obidoxime（OBI），和非肟(NOX-6)。本研究中研究的终点是AChE活性和气道面积(AA)变化。OPNA暴露导致非常低的残留AChE活性。根据再活化剂的性质,测量不同的AChE再活化结果。GB抑制的PCLS-AChE被最好地重新激活，其次是VX和GF。为了证实这些发现并以更深刻的方式理解分子与功能水平之间的联系，将结果与AA变化相关联。这些调查强调了使用再激活剂的重要性，并指出了未来改善OPNA暴露受害者治疗的可能性。
