Amentoflavone prevents sepsis-associated acute lung injury through Nrf2-GCLc-mediated upregulation of glutathione
Amentoflavone prevents sepsis-associated acute lung injury through Nrf2-GCLc-mediated upregulation of glutathione
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DOI：
10.18388/abp.2016_1296
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发表时间：
2017-01-01
影响因子：
1.7
通讯作者：
Zhang, Huali
中科院分区：
文献类型：
--
作者：
Zong, Yuan;Zhang, Huali
脓毒症是一个严重的医学问题，是重症监护病房高死亡率的主要原因之一。50%的严重脓毒症患者会发展为急性肺损伤（ALI）。阿门托黄酮（AMF）是一种多酚类化合物，具有有效的抗炎活性。本研究旨在探讨AMF对盲肠结扎穿刺（CLP）所致脓毒症大鼠ALI的保护作用。结果显示，AMF对脓毒性ALI具有保护作用，其表现为明显改善clpp治疗大鼠肺组织的组织学损伤和减少肺水肿。AMF改善了clp诱导的全身和肺部TNF α和IL-1 β以及p65 NF-kappa B结合活性的升高，表明炎症受到抑制。此外，AMF对clp诱导的氧化应激有一定的抑制作用，表现为clp处理大鼠肺组织耗氧量增加、TBARS含量降低、SOD活性和GSH水平升高。CLP导致Nrf2和GCLc mRNA表达显著降低，AMF抑制了Nrf2和GCLc mRNA表达。慢病毒shrna介导的Nrf2和丁硫氨酸亚砜（BSO）沉默抑制了amf对ALI、炎症和氧化应激的保护作用。BSO是GSH合成抑制剂。AMF增加了clp处理大鼠肺组织中GCLc启动子nrf2结合活性。结果表明，AMF通过上调Nrf2-GCLc信号，增强GSH抗氧化防御，减少氧化应激，最终改善肺炎症和组织学损伤，对脓毒症大鼠ALI具有保护作用。这些数据为脓毒症相关ALI的治疗提供了新的治疗选择。
Sepsis is a serious medical problem and is one of the main causes of high mortality in intensive care units. Fifty percent of patients with severe sepsis will develop acute lung injury (ALI). Amentoflavone (AMF) is a polyphenolic compound possessing potent anti-inflammatory activities. The study aimed to explore the protective effects of AMF against ALI in cecal ligation and puncture (CLP)-induced septic rats. The results showed that AMF administration protected against septic ALI, as reflected by marked amelioration of histological injury of lung tissues and decrease of pulmonary edema in CLPtreated rats. AMF ameliorated CLP-induced increase of systemic and lung TNF alpha and IL-1 beta and binding activity of p65 NF-kappa B, indicating the inhibition of inflammation. Moreover, AMF prevented CLP-induced oxidative stress, as evidenced by increase of oxygen consumption rate, decrease of TBARS content, increase of SOD activity and GSH level in lung tissue of CLP-treated rats. CLP resulted in significant decrease of mRNA expression of Nrf2 and GCLc, which was inhibited by AMF. AMF-induced protective effects on ALI, inflammation, and oxidative stress were inhibited by lentivirus shRNA-mediated silence of Nrf2 and buthionine sulphoximine (BSO), an inhibitor of GSH synthesis. AMF increased Nrf2-binding activity in GCLc promoters in lung tissue of CLP-treated rats. The results suggested that AMF protected against ALI in septic rats through upregulation of Nrf2-GCLc signaling, enhancement of GSH antioxidant defense, reduction of oxidative stress and final amelioration of inflammation and histological injury of lung. The data provide new therapeutic options for the treatment of sepsis-associated ALI.