Amentoflavone prevents sepsis-associated acute lung injury through Nrf2-GCLc-mediated upregulation of glutathione

Abstract

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 CLP-treated rats. AMF ameliorated CLP-induced increase of systemic and lung TNFα and IL-1β and binding activity of p65 NF-κB, 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.

UHPLC‐Q‐TOF MS‐Based Metabolic Analysis for the Therapeutic Efficacy of “Xuebijing Injection” against Sepsis‐Induced Acute Lung Injury

“…Mervyn et al and Novelli et al [ 26 – 28 ] demonstrated that antioxidant depletion such as glutathione (GSH) was one of the most important characteristics in septic patients, which may ultimately lead to severe oxidative stress. Upregulation and activation of GSH could final ameliorate inflammation and histological injury of lung tissues [ 29 ]. In our study, we also observed the same phenomenon that the quantity of GSH was declined significantly, but the quantity of GSH was enhanced after XBJ treatment, indicating that XBJ may be a therapeutic option for sepsis-induced ALI through alleviating oxidative stress.…”

“…Previous studies [ 30 ] found that sphingosine exerted a critical role in signal transduction and participated in the process of growth, senescence, differentiation, and apoptosis. Published articles [ 26 , 27 , 29 ] showed that sphingolipid metabolism also played a critical role in oxidative stress. When sepsis occurs, it is in oxidative status, which causes severe cell membrane damage and sphingolipid loss.…”

Laminarin protects against hydrogen peroxide-induced oxidative damage in MRC-5 cells possibly via regulating NRF2

“…Existed research has indicated that induced NQO1 and HO1 levels were accompanied with the accumulation NRF2 in nucleus, thus protecting cells against oxidative damage ( Zhang et al, 2008 ). In sepsis-induced acute lung injury, up-regulation of the NRF2-GCLC signaling pathway was associated with enhancement of GSH and reduction of oxidative damage ( Zong & Zhang, 2017 ). Consistent with former research, this study found the elevated mRNA and protein levels of NQO1, GCLC and HO1 by NRF2 overexpression, suggesting that NRF2 could promote the expression of NRF2 when it stimulated the cell.…”

Effects of Dapagliflozin on Experimental Sepsis Model in Rats

“…[28,[36][37][38][39][40] In the histopathological evaluation, severe tissue damage was reported. [38] These results are also consistent with the findings we obtained in our sepsis model. It has also been reported that there were increases in the levels of caspase 3 and Bax/BcL 2 in the lungs.…”