Abstract：
The objective of this study was to explore the effects of antioxidant treatments, specifically N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA), in a mouse model of chlorine (Cl2)-induced lung injury. Additionally, the study aimed to investigate the utility of pig precision-cut lung slices (PCLS) as an ex vivo alternative for studying the short-term effects of Cl2 exposure and evaluating antioxidant treatments. The toxicological responses were analyzed in Cl2-exposed mice (inflammation, airway hyperresponsiveness (AHR)) and PCLS (viability, cytotoxicity, inflammatory mediators). Airways contractions were assessed using a small ventilator for mice and electric-field stimulation (EFS) for PCLS. Antioxidant treatments were administered to evaluate their effects. In Cl2-exposed mice, NAC treatment did not alleviate AHR, but it did reduce the number of neutrophils in bronchoalveolar lavage fluid and inflammatory mediators in lung tissue. In PCLS, exposure to Cl2 resulted in concentration-dependent toxicity, impairing the lung tissue\'s ability to respond to EFS-stimulation. NAC treatment increased viability, mitigated the toxic responses caused by Cl2 exposure, and maintained contractility comparable to unexposed controls. Interestingly, NACA did not provide any additional treatment effect beyond NAC in both models. In conclusion, the establishment of a pig model for Cl2-induced lung damage supports further investigation of NAC as a potential treatment. However, the lack of protective effects on AHR after NAC treatment in mice suggests that NAC alone may not be sufficient as a complete treatment for Cl2 injuries. Optimization of existing medications with a polypharmacy approach may be more successful in addressing the complex sequelae of Cl2-induced lung injury.
摘要：
本研究的目的是探索抗氧化剂治疗的效果，特别是N-乙酰半胱氨酸（NAC）和N-乙酰半胱氨酸酰胺（NACA），在氯（Cl2）诱导的肺损伤的小鼠模型中。此外,该研究旨在研究猪精确切肺切片（PCLS）作为研究Cl2暴露的短期影响和评估抗氧化剂治疗的离体替代方法的实用性。在暴露于Cl2的小鼠中分析了毒理学反应（炎症，气道高反应性(AHR)和PCLS(活力，细胞毒性，炎性介质)。使用小鼠的小型呼吸机和PCLS的电场刺激（EFS）评估气道收缩。施用抗氧化剂治疗以评价其效果。在暴露于Cl2的小鼠中，NAC治疗并未缓解AHR,但它确实减少了支气管肺泡灌洗液中的中性粒细胞和肺组织中的炎症介质的数量。在PCLS中,暴露于Cl2导致浓度依赖性毒性，损害肺组织对EFS刺激的反应能力。NAC处理增加了活力，减轻了Cl2暴露引起的毒性反应，并保持与未暴露对照相当的收缩性。有趣的是,NACA在两种模型中均未提供除NAC以外的任何额外治疗效果。总之,Cl2诱导的肺损伤猪模型的建立支持NAC作为潜在治疗的进一步研究。然而,小鼠NAC治疗后缺乏对AHR的保护作用表明，单独的NAC可能不足以完全治疗Cl2损伤。使用多重用药方法对现有药物进行优化可能会更成功地解决Cl2引起的肺损伤的复杂后遗症。
