Tao Shasha, Rojo de la Vega Montserrat, Quijada Hector, Wondrak Georg T, Wang Ting, Garcia Joe G N, Zhang Donna D
Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA.
Arizona Respiratory Center and Department of Medicine, University of Arizona, Tucson, AZ 85721.
Sci Rep. 2016 Jan 5;6:18760. doi: 10.1038/srep18760.
Mechanical ventilation (MV) is a therapeutic intervention widely used in the clinic to assist patients that have difficulty breathing due to lung edema, trauma, or general anesthesia. However, MV causes ventilator-induced lung injury (VILI), a condition characterized by increased permeability of the alveolar-capillary barrier that results in edema, hemorrhage, and neutrophil infiltration, leading to exacerbated lung inflammation and oxidative stress. This study explored the feasibility of using bixin, a canonical NRF2 inducer identified during the current study, to ameliorate lung damage in a murine VILI model. In vitro, bixin was found to activate the NRF2 signaling pathway through blockage of ubiquitylation and degradation of NRF2 in a KEAP1-C151 dependent manner; intraperitoneal (IP) injection of bixin led to pulmonary upregulation of the NRF2 response in vivo. Remarkably, IP administration of bixin restored normal lung morphology and attenuated inflammatory response and oxidative DNA damage following MV. This observed beneficial effect of bixin derived from induction of the NRF2 cytoprotective response since it was only observed in Nrf2(+/+) but not in Nrf2(-/-) mice. This is the first study providing proof-of-concept that NRF2 activators can be developed into pharmacological agents for clinical use to prevent patients from lung injury during MV treatment.
机械通气（MV）是临床上广泛使用的一种治疗手段，用于辅助因肺水肿、创伤或全身麻醉而呼吸困难的患者。然而，MV会导致呼吸机诱导的肺损伤（VILI），其特征是肺泡-毛细血管屏障通透性增加，导致水肿、出血和中性粒细胞浸润，进而加剧肺部炎症和氧化应激。本研究探讨了使用在本研究中鉴定出的典型NRF2诱导剂β-胡萝卜素改善小鼠VILI模型中肺损伤的可行性。在体外，发现β-胡萝卜素通过以KEAP1-C151依赖的方式阻断NRF2的泛素化和降解来激活NRF2信号通路；腹腔注射β-胡萝卜素导致体内肺组织中NRF2反应上调。值得注意的是，腹腔注射β-胡萝卜素可恢复正常肺形态，并减轻MV后的炎症反应和氧化性DNA损伤。观察到的β-胡萝卜素的这种有益作用源于NRF2细胞保护反应的诱导，因为仅在Nrf2(+/+)小鼠中观察到，而在Nrf2(-/-)小鼠中未观察到。这是第一项提供概念验证的研究，即NRF2激活剂可开发成临床使用的药物制剂，以防止患者在MV治疗期间发生肺损伤。
