Abstract
Neutrophils release chromatin and antimicrobial proteins to trap and kill microbes, which is termed as neutrophil extracellular trap (NET) formation. NETs play a pivotal role in host defense against infection. However, emerging evidence indicated that NETs also contribute to an exaggerated inflammatory response and organic injuries in sepsis. Zingerone, a natural compound extracted from Zingiber officinale, exerts antioxidant, anti-inflammatory, and antioncogenic properties. In this study, we found that treatment with zingerone reduced organ injury and improved the outcome in a cecal ligation puncture- (CLP-) induced polymicrobial sepsis model. Administration of zingerone also alleviates reactive oxygen species (ROS) accumulation and systematic inflammation in septic mice and inhibits neutrophil extracellular traps (NETs) formation in vivo and in vitro. Furthermore, inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2) with its specific antagonist significantly counteracted the suppressive effects of zingerone on ROS and NETs and retarded the protective role of zingerone against sepsis-associated organ injury. In addition, exposure to zingerone does not affect phagocytic activity of neutrophils in vitro and bacterial dissemination in vivo. Above all, our results indicate that zingerone treatment obviously attenuates NET formation and inflammatory response via Nrf2-mediated ROS inhibition, thus providing a novel therapeutic strategy against sepsis-induced injury.
Highlights
Sepsis is a life-threatening syndrome characterized by excessive inflammatory responses from the host that causes multiple organ dysfunction [1]
The results showed that ZIN pretreatment significantly suppressed neutrophil extracellular trap (NET) release compared to neutrophils stimulated only with Phorbol 12-myristate 13-acetate (PMA) (Figure 4(d))
We previously reported that ZIN treatment ameliorates airway inflammation and protects the OVA-induced oxidative stress in asthma by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 signaling pathways [24]
Summary
Sepsis is a life-threatening syndrome characterized by excessive inflammatory responses from the host that causes multiple organ dysfunction [1]. Antibiotics play a key role in the therapy of severe sepsis. Their serious side effects, such as antibiotic resistance, dysbacteriosis, and acute kidney injury, impelled us to seek new treatment strategies and medications [4, 5]. Polymorphonuclear neutrophil (PMN) granulocytes play an essential role in the innate immune response to infection. Prior studies have demonstrated that neutrophils eliminate infectious organisms by a combination of phagocytosis, degranulation, and release of NETs [6]. NETs can cause liver damage in sepsis caused by methicillin-
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