Swedish Defence Research Agency, CBRN Defence and Security, Umeå, Sweden.
Swedish Defence Research Agency, CBRN Defence and Security, Umeå, Sweden.
Chem Biol Interact. 2024 Nov 1;403:111225. doi: 10.1016/j.cbi.2024.111225. Epub 2024 Sep 3.
Following inhalation exposure to organophosphorus nerve agents, symptoms rapidly develop and severe respiratory symptoms, such as bronchorrhea and bronchoconstriction are the leading causes of lethality. Nerve agent-induced lung injury is little investigated and the standard treatment for symptomatic relief targets the enzyme acetylcholinesterase and muscarinic acetylcholine and GABAergic receptors. In the present study, cellular responses in lung tissue during the acute (40 min) and extended phase (24 h) following severe exposure to the nerve agent VX have been investigated using an ex vivo rat precision-cut lung slice model including electrostimulation to induce a cholinergic response. Changes in protein amount, cell viability, together with, inflammatory and oxidative stress markers have been determined in both the lung tissue and incubation medium. During the acute phase, VX caused significantly increased airway contraction and decreased airway relaxation. Five micromolar of VX did not affect the sample protein levels and cell viability in lung tissue. Among seven markers of cellular responses investigated in the lung tissue, increased levels of heme oxygenase-1 and matrix metalloproteinase-9 together with decreased levels of glutathione in the incubation medium were observed in the acute phase following VX-exposure compared to electrostimulation only. No difference in cellular response was observed following VX-exposure for 24 h compared to the air control. In comparison, LPS-exposure resulted in time-dependent changes in all markers of inflammation and oxidative response. In conclusion, the present study demonstrated VX-specific patterns of oxidative responses in the lung, as well as, signs of inflammatory response and remodelling of extracellular matrix. These potential mechanisms of tissue injury should be further investigated for their potential as additional therapeutic targets during the acute phase of intoxication.
在吸入有机磷神经毒剂后，症状迅速发展，严重的呼吸道症状，如支气管分泌物和支气管收缩，是导致死亡的主要原因。神经毒剂引起的肺损伤研究甚少，症状缓解的标准治疗针对的是酶乙酰胆碱酯酶和毒蕈碱乙酰胆碱和 GABA 能受体。在本研究中，使用离体大鼠精密切割肺切片模型（包括电刺激以诱导胆碱能反应）研究了严重暴露于神经毒剂 VX 后的急性（40 分钟）和扩展期（24 小时）肺组织中的细胞反应。在肺组织和孵育培养基中测定了蛋白质含量、细胞活力以及炎症和氧化应激标志物的变化。在急性期，VX 导致气道收缩显著增加，气道松弛减少。5 微摩尔 VX 不会影响肺组织样本的蛋白水平和细胞活力。在肺组织中研究的七种细胞反应标志物中，与仅电刺激相比，VX 暴露后的急性期观察到血红素加氧酶-1和基质金属蛋白酶-9的水平升高，以及孵育培养基中谷胱甘肽的水平降低。与空气对照相比，VX 暴露 24 小时后，细胞反应没有差异。相比之下，LPS 暴露导致所有炎症和氧化反应标志物的时间依赖性变化。总之，本研究表明 VX 对肺的氧化反应具有特异性模式，以及炎症反应和细胞外基质重塑的迹象。这些潜在的组织损伤机制应在中毒的急性期进一步研究，作为额外的治疗靶点。
