SS-31 ameliorates hepatic injury in rats subjected to severe burns plus delayed resuscitation via inhibiting the mtDNA/STING pathway in Kupffer cells
Introduction
The incidence of burns has been reported to vary from 5 to 10 per 1000 individuals. Patients with severe burns (Total Body Surface Area (TBSA) > 30%) have high rates of disability and mortality [1]. Although there has been great improvement in the treatment of burns, multiple organ dysfunction syndrome (MODS) represents the main cause of death. Hepatic injury is common in patients with severe burns (morbidity ranges from 25% to 60%), which leads to an increased mortality rate [2].
Severe burns lead to increased microvascular permeability and organ hypoperfusion. Fluid resuscitation immediately after burns can ameliorate organ injury. However, severe burns plus delayed resuscitation (B + DR), which involves resuscitation more than 6 h after the burns, are common in restricted environments [3]. Persistent hypoperfusion leads to tissue hypoxia, calcium overload, cell injury and hypoxanthine accumulation. During delayed resuscitation, hypoxanthine transforms to xanthine and uric acid, leading to the production of high levels of ROS [4].
The hepatocytes located between the sinusoids are consistently exposed to a hyperoxic environment, which makes them vulnerable to oxidative stress [5]. Hepatocytes are rich in mitochondria. Mitochondria are intracellular organelles with double-membrane structures. ROS is mainly produced in mitochondria. ROS also damages mitochondrial membranes, leading to the release of mitochondrial contents (including mtDNA) to the hepatocyte cytosol [6]. In addition, mitochondrial dysfunction leads to further production of ROS. ROS can directly attack cell components and trigger apoptosis [7]. Therefore, we hypothesized that mtDNA derived from hepatocytes is released into the extracellular space under oxidative stress.
KCs (hepatic macrophages) are one of the most abundant immune cells in the liver. STING is mainly expressed in KCs, which can be activated by aberrant DNA species in the cytosol. Activation of the STING pathway leads to the production of type I interferons (IFN I), tumor necrosis factor–α (TNF–α), and interleukin-6 (IL-6) [8]. Functional polarization of macrophages into M1 or M2 cells have been investigated recently. M1 cells produce multiple proinflammatory cytokines, while M2 cells are critical to the resolution of inflammation [9]. We hypothesized that the mtDNA/STING pathway-mediated cytokine storm and KCs polarization are involved in the development of hepatic injury.
Identification of factors that activate KCs is important. Mitochondria evolved from bacteria, and mtDNA is similar to bacterial DNA in structure, acting as a damage-associated molecular pattern (DAMP) [10]. Accordingly, we posited that mtDNA could trigger sterile inflammation by activating KCs during B + DR. Although previous studies demonstrated that mtDNA is a toxic mediator that amplifies organ injury [11], the role of mtDNA/STING in activating KCs during B + DR remains to be explored.
The hepatic injury induced by B + DR creates challenges for clinical treatment. SS-31 (D-Arg-2′,6′-dimethylTyr-Lys-Phe-NH2), which belongs to the Szeto-Schiller (SS) family, has strong antioxidant activity. SS-31 specifically accumulates in the inner mitochondrial membrane, which makes it more effective than traditional antioxidants [12]. This study aimed to determine whether SS-31 could ameliorate B + DR-induced hepatic injury.
Section snippets
Methods
Our study was performed according to guidelines of the Animal Investigation Ethics Committee of Nanjing First Hospital.
SS-31 prevents hepatic injury and oxidative stress
Compared to the sham group, rats subjected to B + DR showed a prominent elevation in serum levels of ALT, AST and total bilirubin. The rats treated with SS-31 exhibited reduction in these markers. Compared to those of the sham rats, rats from the B + DR group had significantly increased hepatic levels of MDA, but decreased levels of Mn-SOD and GSH-Px. We indicated that SS-31 alleviates oxidative stress in the liver (Supplementary Fig. 1).
Mitochondrial measurement
The damage to hepatocyte mitochondria was characterized
Discussion
In this study, we found that B + DR caused severe hepatic injury. The hepatic levels of antioxidants were reduced, whereas levels of oxidants were elevated after B + DR. A large amount of ROS has been considered to be the main cause of hepatic injury.
First, excessive ROS caused hepatic injury by damaging hepatocyte mitochondria.
After H/R, hepatocyte mitochondrial dysfunction was characterized by mitochondrial swelling, the loss of mitochondrial cristae and loss of MMP. Mitochondria are not only
Declaration of competing interest
None of the authors had a conflict of interest regarding the study.
None of the authors have anything to disclose.
Acknowledgements
This work was supported by Scientific and Technological Development Fund of Nanjing Medical University (NMUB2019135).
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