The Emerging Role of Ferroptosis in Sepsis, Opportunity or Challenge?

Sepsis is a syndrome in multi-organ dysfunction triggered by a deleterious immunological reaction of the body to a condition caused by infection, surgery, or trauma. Currently, sepsis is thought to be primarily associated with abnormal immune responses resulting in organ microcirculatory disturbances, cellular mitochondrial dysfunction, and induced cell death, although the exact pathogenesis of sepsis is still inconclusive. In recent years, the role of abnormal metabolism of trace nutrients in the pathogenesis of sepsis has been investigated. Ferroptosis is a type of cell death that relies on iron and is characterized by unique morphological, biochemical, and genetic features. Unlike other forms of cell death, such as autophagy, apoptosis, necrosis, and pyroptosis, ferroptosis is primarily driven by lipid peroxidation. Ferroptosis cells may be immunogenic, amplify inflammatory responses, cause more cell death, and ultimately induce multi-organ failure. An increasing number of studies have indicated the significance of ferroptosis in sepsis and its role in reducing inflammation. The effectiveness of sepsis treatment has been demonstrated by the use of drugs that specifically target molecules associated with the ferroptosis pathway, including ferroptosis inhibitors. Nevertheless, there is a scarcity of studies investigating the multi-organ dysfunction caused by ferroptosis in sepsis. This article presents a summary and evaluation of recent progress in the role of ferroptosis through molecularly regulated mechanisms and its potential mechanisms of action in the multi-organ dysfunction associated with sepsis. It also discusses the current challenges and prospects in understanding the connection between sepsis and ferroptosis, and proposes innovative ideas and strategies for the treatment of sepsis.

[The protective effect of bone marrow mesenchymal stem cells carrying antioxidant gene superoxide dismutase on paraquat lung injury in mice].

OBJECTIVE: To explore the possible mechanism and protective effect of BMSCs (bone mesenchymal stem cells) carrying superoxide dismutase (SOD) gene on mice with paraquat-induced acute lung injury. METHODS: To establish the cell line of BMSCs bringing SOD gene, lentiviral vector bringing SOD gene was built and co-cultured with BMSCs. A total of 100 BALB/c mice were randomly divided into five groups, namely Control group, poisoning group (PQ group) , BMSCs therapy group (BMSC group) , BMSCs-Cherry therapy group (BMSC-Cherry group) , BMSCs-SOD therapy group (BMSC-SOD group) . PQ poisoning model was produced by stomach lavaged once with 1 ml of 25 mg/kg PQ solution, and the equal volume of normal saline (NS) was given to Control group mice instead of PQ. The corresponding BMSCs therapy cell lines were delivered to mice through the tail vein of mice 4h after PQ treatment.Five mice of each group were sacrificed 3 d, 7 d, 14 d and 21 days after corresponding BMSCs therapy cell lines administration, and lung tissues of mice were taken to make sections for histological analysis. The serum levels of glutathione (GSH) , malondialdehyde (MDA) , SOD, and the levels of transforming growth factor-ß (TGF-ß) and tumor necrosis factor-α (TNF-α) in lung tissue were determined. The level of SOD was assayed by Westen-blot. RESULTS: Compared with Control group, the early (3 days) levels of SOD protein in lung tissue of PQ group obviously decreased, and the late (21 days) levels of SOD obviously increased, while in therapy groups, that was higher than that in PQ group, and the BMSCs-SOD group showed most obvious (all P<0.05) . Compared with Control group, the levels of plasma GSH and SOD of PQ group and each therapy group wae significantly lower than those in Control group, while in therapy groups, those were higher than those of PQ group, and the BMSCs-SOD group showed most obvious (all P<0.05) .Compared with Control group, the level of plasma MDA, TNF-α and TGF-ß in PQ group and therapy groups were significantly higher, while in therapy groups, that was lower than that in PQ group, and the BMSCs-SOD group showed most obvious (all P<0.05) . Lung biopsy showed that, the degree of lung tissue damage in each therapy group obviously reduced. CONCLUSION: SOD is the key factor of the removal of reactive oxygen species (ROS) in cells, that can obviously inhibit the oxidative stress damage and the apoptosis induced by PQ, thus significantly increasing alveolar epithelial cell ability to fight outside harmful environment.

SIRT1 exerts protective effects against paraquat-induced injury in mouse type II alveolar epithelial cells by deacetylating NRF2 in vitro.

Silent information regulator 2-related enzyme 1 (SIRT1), a protein deacetylase, is known to strongly protect cells against oxidative stress-induced injury. The nuclear factor E2-related factor 2 (NRF2)-antioxidant response element (ARE) antioxidant pathway plays important regulatory roles in the antioxidant therapy of paraquat (PQ) poisoning. In the present study, we investigated whether the SIRT1/NRF2/ARE signaling pathway plays an important role in lung injury induced by PQ. For this purpose, mouse type II alveolar epithelial cells (AECs­II) were exposed to various concentrations of PQ. The overexpression or silencing of SIRT1 was induced by transfecting the cells with a SIRT1 overexpression vector or shRNA targeting SIRT1, respectively. The protein expression levels of SIRT1 and NRF2 were measured by western blot analysis. The superoxide dismutase (SOD) and catalase (CAT) activities, as well as the glutathione (GSH) and malondialdehyde (MDA) levels were measured using respective kits. Heme oxygenase-1 (HO-1) activity was also determined by ELISA. In addition, cell apoptosis was determined by flow cytometry. The protein stability of NRF2 was analyzed using cycloheximide and its acetylation in the cells was also determined. The following findings were obtained: i) SIRT1 overexpression markedly increased NRF2 protein expression; ii) SIRT1 promoted the transcriptional activity of NRF2 and upregulated the expression of the NRF2 downstream genes, SOD, CAT, GSH and HO-1, thus inhibiting the apoptosis of AECs­II; iii) the inhibition of SIRT1 activity further induced the production of malondialdehyde (MDA), which resulted in increased oxidative damage; iv) SIRT1 promoted the stability of NRF2 by regulating the deacetylation and activation of the NRF2/ARE antioxidant pathway. The findings of this study demonstrate that the protective effects of SIRT1 are associated with the activation of the NRF2/ARE antioxidant pathway in lung injury induced by PQ poisoning.