Estrogen protects against liver damage in sepsis through inhibiting oxidative stress mediated activation of pyroptosis signaling pathway.

Zihan Xu,Ronghui Fan,Shengzhi Mu,Wujun Wu,Xia Liao,Wenjie Gao,Yaowen Sun,Qingan Jia,Partha Mukhopadhyay

doi:10.1371/journal.pone.0239659

Abstract

Sepsis was characterized by systemic inflammatory response and multisystem organ dysfunction, refering to the activation of inflammatory and oxidative stress pathways. Estrogen has been shown to have anti-inflammatory and antioxidant effects as well as extensive organ protective role. However, whether estrogen alleviates sepsis-induced liver injury and the mechanisms involved remain unknown. Septic mice were constructed by intraperitoneal injection lipopolysaccharide, and the effect of estrogen on liver injury was investigated. Furthermore, the roles of NLRP3 inhibitor MCC950 and mitochondrial ROS specific scavenger Mito-tempo, on the liver injury were explored in septic mice. Female septic mice exhibited liver damage with increased serum AST and ALT level as well as the existence of extensive necrosis, and which was more serious in male septic mice. Moreover, Ovariectomy (OVX) aggravated sepsis-induced liver damage and activation of pyroptosis signaling pathway, which was alleviated by estrogen as evidenced by decreased serum AST, ALT level and number of infiltrating inflammatory cell, as well as protein expression related to pyroptosis. OVX aggravated mitochondrial dysfunction and liver injury in septic mice was also partly reversed by Mito-tempo and MCC950. These results demonstrated that estrogen protected against sepsis-induced liver damage through alteration of mitochondrial function and activation of inflammatory-mediated pyroptosis signaling pathway.

Highlights

Sepsis remains the major cause of mortality in surgical intensive care units (ICU) affecting millions of patients, which is characterized by the systemic inflammatory response and multisystem organ dysfunction [1], such as lung, heart, kidney and liver
We explored the impact of estrogen on sepsis-induced liver injury in mouse model and examined the mitochondrial function and inflammatory- mediated pyroptosis signaling pathway in the liver tissues, in order to determine whether estrogen alleviates sepsis-induced liver injury through alteration of mitochondrial function and inflammatorymediated pyroptosis signaling pathway
Estrogen has been considered as a medical tool to counteract inflammation and clinical symptoms in multiple disorders including acute spinal cord injury [26], multiple sclerosis [27], neurovascular/neuroimmune disease [28], chronic spinal cord injury [29], severe burn injury [30], chronic liver injury [31], inflammatory bowel disease [31], aging [32] and obesity [12]

Summary

Introduction

Sepsis remains the major cause of mortality in surgical intensive care units (ICU) affecting millions of patients, which is characterized by the systemic inflammatory response and multisystem organ dysfunction [1], such as lung, heart, kidney and liver. Mitochondria provided energy support for liver energy metabolism, which are pivotal organelles involved in sepsis liver damage Apart from their effect on producing energy, mitochondrial electron transport was considered as a major source of ROS in hepatocytes. Among many elements affecting cell response to inflammation-associated septic liver injury, more and more researches have stressed the fundamental role of pryoptosis. Pyroptosis was inflammatory response mediated programmed cell death, which was triggered by inflammasome in a caspase-1-dependent manner [8, 9]. Previous study demonstrated that estrogen ameliorated sepsisinduced oxidant liver and intestines injury through regulating the release of inflammatory cytokines and suppressing tissue neutrophil infiltration in rats [16]. Whether estrogen alleviates sepsis-induced liver injury through alteration mitochondrial function and inflammatory-mediated pyroptosis signaling pathway remains unknown. We explored the impact of estrogen on sepsis-induced liver injury in mouse model and examined the mitochondrial function and inflammatory- mediated pyroptosis signaling pathway in the liver tissues, in order to determine whether estrogen alleviates sepsis-induced liver injury through alteration of mitochondrial function and inflammatorymediated pyroptosis signaling pathway

Materials and methods

Results

Discussion