Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (J.A.M., J.M.L., K.N.V., R.S., C.J., G.L.G., A.J.G., D.L.L.) and Department of Environmental and Occupational Health and Justice, School of Public Health (J.D.L.), Rutgers University, Piscataway, New Jersey.
Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (J.A.M., J.M.L., K.N.V., R.S., C.J., G.L.G., A.J.G., D.L.L.) and Department of Environmental and Occupational Health and Justice, School of Public Health (J.D.L.), Rutgers University, Piscataway, New Jersey
J Pharmacol Exp Ther. 2024 Jan 17;388(2):586-595. doi: 10.1124/jpet.123.001557.
Nitrogen mustard (NM) is a cytotoxic vesicant known to cause pulmonary injury that can progress to fibrosis. NM toxicity is associated with an influx of inflammatory macrophages in the lung. Farnesoid X receptor (FXR) is a nuclear receptor involved in bile acid and lipid homeostasis that has anti-inflammatory activity. In these studies, we analyzed the effects of FXR activation on lung injury, oxidative stress, and fibrosis induced by NM. Male Wistar rats were exposed to phosphate-buffered saline (vehicle control) or NM (0.125 mg/kg) by intratracheal Penncentury-MicroSprayer aerosolization; this was followed by treatment with the FXR synthetic agonist, obeticholic acid (OCA, 15 mg/kg), or vehicle control (0.13-0.18 g peanut butter) 2 hours later and then once per day, 5 days per week thereafter for 28 days. NM caused histopathological changes in the lung, including epithelial thickening, alveolar circularization, and pulmonary edema. Picrosirius red staining and lung hydroxyproline content were increased, indicative of fibrosis; foamy lipid-laden macrophages were also identified in the lung. This was associated with aberrations in pulmonary function, including increases in resistance and hysteresis. Following NM exposure, lung expression of HO-1 and iNOS, and the ratio of nitrates/nitrites in bronchoalveolar lavage fluid (BAL), markers of oxidative stress increased, along with BAL levels of inflammatory proteins, fibrinogen, and sRAGE. Administration of OCA attenuated NM-induced histopathology, oxidative stress, inflammation, and altered lung function. These findings demonstrate that FXR plays a role in limiting NM-induced lung injury and chronic disease, suggesting that activating FXR may represent an effective approach to limiting NM-induced toxicity. SIGNIFICANCE STATEMENT: In this study, the role of farnesoid-X-receptor (FXR) in mustard vesicant-induced pulmonary toxicity was analyzed using nitrogen mustard (NM) as a model. This study's findings that administration of obeticholic acid, an FXR agonist, to rats reduces NM-induced pulmonary injury, oxidative stress, and fibrosis provide novel mechanistic insights into vesicant toxicity, which may be useful in the development of efficacious therapeutics.
氮芥（NM）是一种细胞毒性的水疱剂，已知会导致肺损伤，进而发展为纤维化。NM 毒性与肺中炎症性巨噬细胞的涌入有关。法尼醇 X 受体（FXR）是一种参与胆汁酸和脂质稳态的核受体，具有抗炎活性。在这些研究中，我们分析了 FXR 激活对 NM 诱导的肺损伤、氧化应激和纤维化的影响。雄性 Wistar 大鼠通过气管内 Penncentury-MicroSprayer 雾化吸入磷酸盐缓冲液（载体对照）或 NM（0.125mg/kg）；2 小时后，用 FXR 合成激动剂奥贝胆酸（OCA，15mg/kg）或载体对照（0.13-0.18g 花生酱）处理，然后每天一次，每周 5 天，持续 28 天。NM 导致肺组织病理学改变，包括上皮增厚、肺泡环化和肺水肿。皮罗红染色和肺羟脯氨酸含量增加，提示纤维化；肺中还发现了泡沫状含脂巨噬细胞。这与肺功能异常有关，包括阻力和滞后增加。NM 暴露后，HO-1 和 iNOS 的肺表达以及支气管肺泡灌洗液（BAL）中硝酸盐/亚硝酸盐的比值，氧化应激的标志物增加，同时 BAL 中炎症蛋白、纤维蛋白原和 sRAGE 的水平也增加。OCA 的给药减轻了 NM 诱导的组织病理学改变、氧化应激、炎症和改变的肺功能。这些发现表明，FXR 在限制 NM 诱导的肺损伤和慢性疾病中发挥作用，这表明激活 FXR 可能是限制 NM 诱导的毒性的有效方法。意义声明：在这项研究中，使用氮芥（NM）作为模型分析了法尼醇-X-受体（FXR）在芥子气诱导的肺毒性中的作用。本研究发现，给予 FXR 激动剂奥贝胆酸可减少大鼠 NM 诱导的肺损伤、氧化应激和纤维化，为水疱毒性提供了新的机制见解，这可能有助于开发有效的治疗方法。
