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Damage-associated molecular patterns (DAMPs) released in large quantities in trauma are important triggers of post-traumatic immune dysfunction and interest in their potential as therapeutic targets for trauma has increased. Targeting DAMPs such as myoglobin, HMGB1, histones, and nucleic acids have potential for the development of vaccines for trauma. Due to the specific nature of trauma, significant challenges such as the possibility of trauma vaccines causing autoimmune diseases requires further research. The development of trauma vaccines has the potential to establish protection for populations at high risk for trauma and may supplement existing trauma management strategies. Despite advances in medical treatments for severe trauma, it remains a critical condition associated with high mortality. During trauma, the release of endogenous damage-associated molecular patterns (DAMPs) can induce immune dysfunction, leading to sepsis or multiple organ dysfunction syndrome (MODS). Vaccines based on specific pathogen antigens and pathogen-associated molecular patterns (PAMPs) contribute largely to the prevention of communicable diseases through the induction of adaptive immune responses. Vaccines developed based on autologous molecules may also promote recovery from non-communicable diseases (NCDs) by eliciting appropriate immune responses, as recent clinical trials indicate. Developing new vaccines targeting DAMPs may be an effective pre-protective measure for trauma management. We describe the role of DAMPs in post-traumatic immune dysfunction and discuss the potential of harnessing them for trauma vaccine development as well as the risks and challenges. [ABSTRACT FROM AUTHOR]

[Display omitted] • Inhibiting ferroptosis could alleviate acute kidney injury following crush syndrome. • Iron overload produced by myoglobin degradation is a risk factor for ferroptosis. • HMGB1 and souble-stranded DNA trigger ferroptosis via multiple signaling pathways. • Crosstalk between inflammation and ferroptosis. • Inhibition of ferroptosis by alleviating inflammation and anti-lipid peroxidation. Crush syndrome (CS) is a kind of traumatic and ischemic injury that seriously threatens life after prolonged compression. It is characterized by systemic inflammatory reaction, myoglobinuria, hyperkalemia and acute kidney injury (AKI). Especially AKI, it is the leading cause of death from CS. There are various cell death forms in AKI, among which ferroptosis is a typical form of cell death. However, the role of ferroptosis has not been fully revealed in CS-AKI. This review aimed to summarize the evidence of ferroptosis in CS-AKI and its related molecular mechanism, discuss the therapeutic significance of ferroptosis in CS-AKI, and open up new ideas for the treatment of CS-AKI. One of the main pathological manifestations of CS-AKI is renal tubular epithelial cell dysfunction and cell death, which has been attributed to massive deposition of myoglobin. Large amounts of myoglobin released from damaged muscle deposited in the renal tubules, impeding the normal renal tubules function and directly damaging the tubules with oxidative stress and elevated iron levels. Lipid peroxidation damage and iron overload are the distinguishing features of ferroptosis. Moreover, high levels of pro-inflammatory cytokines and damage-associated molecule pattern molecules (HMGB1, double-strand DNA, and macrophage extracellular trap) in renal tissue have been shown to promote ferroptosis. However, how ferroptosis occurs in CS-AKI and whether it can be a therapeutic target remains unclear. In our current work, we systematically reviewed the occurrence and underlying mechanism of ferroptosis in CS-AKI. [ABSTRACT FROM AUTHOR]

Myoglobin (Mb) is the main constituent of vertebrate skeletal muscle and myocardium and plays an essential role in oxygen binding, storage, transport, and earliest disease diagnosis. This study focuses on preparing the novel recombinant rabbit anti-Mb monoclonal antibody and applying it to a diagnosis of Mb deposition in rhabdomyolysis-associated acute kidney injury (RM-AKI). The full-length coding sequence of rat Mb was cloned and expressed, and the high-quality and titer rabbit anti-Mb polyclonal antibodies were produced by the immunogen His-Mb fusion protein. A new hybridoma cell was obtained by hybridoma screening technology. With the help of DNA sequencing and a molecular clonal, anti-Mb monoclonal antibody heavy and light chains expression plasmid was constructed. Finally, the recombinant rabbit anti-Mb monoclonal antibody with extraordinarily high affinity (KD = 1.21 pM) was obtained. Meanwhile, it had broad species reactivity (mouse, rat, human, and horse) and good tissue specificity (skeletal muscle and myocardium). It also had a very good performance in western blotting, immunohistochemistry, and immunofluorescence assay to detect the Mb level in the kidney, myocardium, and skeletal muscle of RM-AKI. This study will be significantly helpful for Mb-associated disease diagnosis, and pathogenesis exploration, and further may act as a neutralizing antibody for disease treatment. [ABSTRACT FROM AUTHOR]

• Ferroptosis in renal tubular epithelial cells (RETCs) was the main cause of CS-AKI. • Mb induced ferroptosis in RETCs. • Rosmarinic acid combined with Deferasirox resisted ferroptosis by activating the Nrf2/KEAP1 pathway. • Rosmarinic acid combined with Deferasirox ameliorated AKI in CS mice. Myoglobin (Mb) induced death of renal tubular epithelial cells (RTECs) is a major pathological factor in crush syndrome-related acute kidney injury (CS-AKI). It is unclear whether ferroptosis is involved and could be a target for treatment. This study aimed to evaluate the potential therapeutic effects of combining the natural small molecule rosemarinic acid (RA) and the iron chelator deferasirox (Dfe) on CS-AKI through inhibition of ferroptosis. Sequencing data were downloaded from the GEO database, and differential expression analysis was performed using the R software limma package. The CS-AKI mouse model was constructed by squeezing the bilateral thighs of mice for 16 h with 1.5 kg weight. TCMK1 and NRK-52E cells were induced with 200 μM Mb and then treated with RA combined with Dfe (Dfe + RA, both were 10 μM). Functional and pathological changes in mouse kidney were evaluated by glomerular filtration rate (GFR) and HE pathology. Immunofluorescence assay was used to detect Mb levels in kidney tissues. The expression levels of ACSL4, GPX4, Keap1, and Nrf2 were analyzed by WB. We found that AKI mice in the GSE44925 cohort highly expressed the ferroptosis markers ACSL4 and PTGS2. CS-AKI mice showed a rapid decrease in GFR, up-regulation of ACSL4 expression in kidney tissue, and down-regulation of GPX4 expression, indicating activation of the ferroptosis pathway. Mb was found to deposit in renal tubules, and it has been proven to cause ferroptosis in TCMK1 and NRK-52E cells in vitro. We found that Dfe had a strong iron ion scavenging effect and inhibited ACSL4 expression. RA could disrupt the interaction between Keap1 andNrf2, stabilize Nrf2, and promote its nuclear translocation, thereby exerting antioxidant effects. The combination of Dfe and RA effectively reversed Mb induced ferroptosis in RTECs. In conclusion, we found that RA combined with Dfe attenuated CS-AKI by inhibiting Mb-induced ferroptosis in RTECs via activating the Nrf2/Keap1 pathway. [Display omitted] [ABSTRACT FROM AUTHOR]