Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage

Abstract

Uridine metabolism is extensively reported to be involved in combating oxidative stress. Redox-imbalance-mediated ferroptosis plays a pivotal role in sepsis-induced acute lung injury (ALI). This study aims to explore the role of uridine metabolism in sepsis-induced ALI and the regulatory mechanism of uridine in ferroptosis. The Gene Expression Omnibus (GEO) datasets including lung tissues in lipopolysaccharides (LPS) -induced ALI model or human blood sample of sepsis were collected. In vivo and vitro, LPS was injected into mice or administered to THP-1 cells to generate sepsis or inflammatory models. We identified that uridine phosphorylase 1 (UPP1) was upregulated in lung tissues and septic blood samples and uridine significantly alleviated lung injury, inflammation, tissue iron level and lipid peroxidation. Nonetheless, the expression of ferroptosis biomarkers, including SLC7A11, GPX4 and HO-1, were upregulated, while lipid synthesis gene (ACSL4) expression was greatly restricted by uridine supplementation. Moreover, pretreatment of ferroptosis inducer (Erastin or Era) weakened while inhibitor (Ferrostatin-1 or Fer-1) strengthened the protective effects of uridine. Mechanistically, uridine inhibited macrophage ferroptosis by activating Nrf2 signaling pathway. In conclusion, uridine metabolism dysregulation is a novel accelerator for sepsis-induced ALI and uridine supplementation may offer a potential avenue for ameliorating sepsis-induced ALI by suppressing ferroptosis.

Blockage of mechanosensitive Piezo1 channel alleviates the severity of experimental malaria-associated acute lung injury

“…Our data also demonstrated that the level of ferroptosis in CD68 + macrophages (or the number of CD68 + -4-HNE + macrophages/field) was decreased by administration of the Piezo1 inhibitor (GsMTx4), followed by a decline in the number of M1-like macrophages and improved lung injury in experimental MA-ALI mice. Our finding was similar to those of other previous reports, where uridine alleviated sepsis-induced acute lung injury by inhibiting ferroptosis of macrophages [ 52 ]; activated ferroptosis in macrophages contrarily accelerated the occurrence of sepsis [ 53 ]. Moreover, a previous study demonstrated that ferroptosis was triggered by increasing M1-like macrophages in neutrophilic airway inflammation, whereas quercetin decreased the level of ferroptosis in lung tissues by suppressing the pro-inflammatory M1-like macrophages [ 54 ].…”

Uridine and its role in metabolic diseases, tumors, and neurodegenerative diseases

“…It is suggested that uridine-mediated thermoregulation is through its degradation products. Uridine phosphorylase 1 (UPase1), a key enzyme in uridine degradation, is expressed in multiple organs and tissues ( Wang et al, 2020 ; Gonçalves da Silva et al, 2021 ; Lai et al, 2023 ). Inhibition of Upase1 prevents the temperature change by uridine in rabbits and rodents ( Le et al, 2013 ).…”

“…The circadian rhythm of rodents is not consistent with that of humans, but it still has guiding significance for the application of uridine in humans. Another study suggests that daytime uridine supplementation inhibits lipid synthesis, reduces polyunsaturated fatty acid synthesis and increases the proportion of saturated fatty acids by inhibiting the expression of Acyl-CoA synthetase long-chain family member 4 (ACSL4) ( Lai et al, 2023 ), an enzyme is known associated with obesity and fatty liver ( Zhang et al, 2018 ). Thus, it is critical to choose right time for uridine supplementation (such as when uridine phosphorylase activity is low) to achieve better therapeutic outcomes.…”

“…Uridine is a pyrimidine nucleoside found in plasma and cerebrospinal fluid with a concentration higher than the other nucleosides ( Dobolyi et al, 2011 ; Altaweraqi et al, 2020 ). As a simple metabolite, uridine plays a pivotal role in various biological processes, including macromolecule synthesis, circadian rhythms, inflammatory response ( Jeengar et al, 2017 ), antioxidant process ( Lai et al, 2023 ), and aging ( Jiang and Zhao, 2022 ; Zhang et al, 2022 ). Plasma uridine enters cells through nucleoside transporter.…”

Acute respiratory distress syndrome heterogeneity and the septic ARDS subgroup

“…Ferroptosis exists not only in alveolar epithelial cells, but also in alveolar capillary endothelial cells and macrophages (114-117). Researchers are inclined to investigate targeted drugs that can effectively inhibit the process of ferroptosis, thereby potentially impeding the progression of sepsis-induced ARDS (117)(118)(119)(120). In addition, autophagy also plays a role in the process of sepsis-induced lung injury.…”