Hydrogen alleviates mitochondrial dysfunction and organ damage via autophagy‑mediated NLRP3 inflammasome inactivation in sepsis

Abstract

Sepsis is a highly heterogeneous syndrome that is caused by a dysregulated host response to infection. The disproportionate inflammatory response to invasive infection is a triggering event inducing sepsis. The activation of inflammasomes in sepsis can amplify inflammatory responses. It has been reported that damaged mitochondria contribute to NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome-related sepsis. Our previous study revealed that hydrogen (H 2 ) exerts anti-inflammatory effects in sepsis but the detailed mechanism remains to be elucidated. In the present study, septic mice induced by cecal ligation and puncture (CLP) and macrophages induced by lipopolysaccha-ride (LPS) were used as models of sepsis in vivo and in vitro , respectively. An inducer and inhibitor of autophagy and the NLRP3 inflammasome were administered to investigate the detailed mechanism of action of H 2 treatment in sepsis. The results demonstrated that LPS and ATP led to NLRP3 inflammasome pathway activation, excessive cytokine release, mitochondrial dysfunction and the activation of autophagy. CLP induced organ injury and NLRP3 pathway activation. H 2 treatment ameliorated vital organ damage, the inflammatory response, mitochondrial dysfunction and NLRP3 pathway activation, and promoted autophagy in macrophages induced by LPS and in CLP mice. However, the inhibitor of autophagy and the inducer of NLRP3 reversed the protective effect of H 2 against organ damage, the inflammatory response and mitochondrial dysfunction in vivo and in vitro . Collectively, the results demonstrated that H 2 alleviated mitochondrial dysfunction and cytokine release via autophagy-mediated NLRP3 inflammasome inactivation.

YiQiFuMai Lyophilized Injection Attenuates Sepsis-Induced Acute Lung Injury via TLR4/Src/VE-cadherin/p120-catenin Signaling Pathway

“…In the progress of sepsis, the intestinal pathogenic microorganisms and their toxins could enter the body circulation after the damage of intestinal barrier, thus causing systemic infections and MODS [38]. Studies have shown that the rst organ to be attacked is lung, and about half of sepsis patients have combined symptoms of ALI [11].…”

Association of Mitochondrial Respiratory Chain Enzymes with the Risk and Mortality of Sepsis Among Chinese Children

“…Currently, the biological implications of mitochondrial dysfunction in sepsis have been widely evaluated [8,21,22]. Mitochondria produce ATP by transferring electrons from substrates sequentially across four respiratory chain complexes (I to IV) and two mobile carriers (coenzyme Q and cytochrome C) to nal electron acceptors [23].…”

“…Mitochondrial dysfunction is deemed as a key cellular event involved in the pathogenesis of multi-organ failure in sepsis, and it is secondary to tissue hypoxia and involves various toxins or mediators of in ammation that impair oxygen utilization (cytopathic hypoxia) [23,24]. There is evidence that damaged mitochondria contribute to NACHT, LRR and PYD domains-containing protein 3 (NLRP3) in ammasome-related sepsis [21]. In addition, hydrogen was found to alleviate mitochondrial dysfunction and cytokine release via autophagy-mediated NLRP3 in ammasome inactivation [11].…”

Potential Therapeutic Applications of Hydrogen in Chronic Inflammatory Diseases: Possible Inhibiting Role on Mitochondrial Stress

“…However, excessive inflammation driven by the inflammasome and IL-1β signaling pathways promotes breast cancer, fibrosarcoma, gastric cancer, and lung metastasis in a context-dependent manner [ 48 ]. Some literature has shown that H 2 can be involved in various models of inflammation based on mechanisms of mitochondrial oxidation inhibition and NLRP3 inflammasome activation ( Table 1 ) [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”

“…that can permeate the cell membrane, only H 2 is able to scavenge ·OH, which is always generated inside of mitochondria [ 13 , 14 ]. It has been shown by literature that H 2 in various animal models of inflammation may be based on mechanisms to inhibit mitochondrial oxidation and NLRP3 inflammasome activation [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. However, the ability for H 2 to inhibit mitochondrial oxidation and NLRP3 inflammasome activation is poorly understood.…”