Hesperetin attenuates sepsis-induced intestinal barrier injury by regulating neutrophil extracellular trap formation via the ROS/autophagy signaling pathway

被引:2
|
作者
Chen, Fang [1 ,2 ]
Chu, Chengnan [3 ]
Wang, Xinyu [3 ,4 ]
Yang, Chao [3 ,4 ]
Deng, Yunxuan [3 ,4 ]
Duan, Zehua [3 ,4 ]
Wang, Kai [3 ,4 ]
Liu, Baochen [3 ,4 ]
Ji, Wu [3 ,4 ]
Ding, Weiwei [1 ,2 ,3 ,4 ]
机构
[1] Southeast Univ, Jinling Hosp, Sch Med, Nanjing, Peoples R China
[2] state Key Lab Trauma Burn & Combined Injury, Nanjing, Peoples R China
[3] Nanjing Univ, Jinling Hosp, Affiliated Hosp, Res Inst Gen Surg,Div Trauma,Med Sch, Nanjing 210002, Jiangsu, Peoples R China
[4] Nanjing Univ, Jinling Hosp, Res Inst Gen Surg, Surg Intens Care Unit,Affiliated Hosp,Med Sch, Nanjing 210002, Jiangsu, Peoples R China
基金
中国国家自然科学基金;
关键词
OXIDATIVE STRESS; IN-VIVO; AUTOPHAGY; RAT; DEFINITIONS; DAMAGE; GUT; ROS;
D O I
10.1039/d2fo02707k
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background: Hesperetin (HES), one of the major flavonoids that has various biological activities, such as anti-inflammatory and antioxidant activities, may preserve the intestinal barrier during sepsis. However, the detailed mechanism remains unclear. Our previous studies confirmed that neutrophil extracellular traps (NETs) may jeopardize the intestinal barrier via a reactive oxygen species (ROS)-dependent pathway during sepsis. Therefore, we hypothesized that HES may inhibit NET formation and protect the intestinal barrier function during sepsis. Methods: Mice were pretreated with HES (50 mg kg(-1)) intraperitoneally for one week, and sepsis models were then induced using lipopolysaccharides (LPS) (10 mg kg(-1)). The mice were randomly divided into three groups: (1) sham group; (2) LPS group; and (3) HES + LPS group. Twenty-four hours after LPS injection, the serum and terminal ileum specimens were collected for subsequent studies. To detect ROS production and NET formation in vitro, human neutrophils were collected and incubated with phorbol-12-myristate-13-acetate (PMA) and various concentrations of HES. The level of autophagy was measured by an immunofluorescence assay and western blot analysis. TUNEL staining was utilized to analyze cell apoptosis. Results: The outcomes demonstrated that HES decreased inflammatory cytokine and myeloperoxidase (MPO) levels in serum and attenuated distant organ dysfunction in LPS-induced septic mice. Meanwhile, HES treatment reversed intestinal histopathological damage in septic mice, improving intestinal permeability and enhancing tight junction expression. Moreover, we found that neutrophil infiltration and NET formation in the intestine were suppressed during sepsis after HES pretreatment. In vitro, HES treatment reduced PMA-induced ROS production and NET formation, which were reversed by hydrogen peroxide (H2O2) administration. Notably, HES also inhibited NET formation by reducing the microtubule-associated protein light chain 3 (LC3)-II/LC3-I ratio (an indicator of autophagy) in PMA-induced neutrophils, which was reversed by rapamycin. Moreover, when autophagy was suppressed by chloroquine or induced by rapamycin, apoptosis in cells will be switched with autophagy. Conclusion: Taken together, these findings suggest that HES may inhibit NET formation in a ROS/autophagy-dependent manner and switch neutrophil death from NETosis to apoptosis, which reduced NETs-related intestinal barrier damage, providing a novel protective role in intestinal barrier dysfunction during sepsis.
引用
收藏
页码:4213 / 4227
页数:15
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