Lipocalin-2 silencing suppresses inflammation and oxidative stress of acute respiratory distress syndrome by ferroptosis via inhibition of MAPK/ERK pathway in neonatal mice

Abstract

Neonatal acute respiratory distress syndrome (ARDS) has high morbidity and mortality rates worldwide, but there is a lack of pharmacologic treatment and clinical targeted therapies. In this study, we aimed to explore the effects of Lipocalin-2 (LCN2) on ferroptosis-mediated inflammation and oxidative stress in neonatal ARDS and the potential mechanism. In this study, we established an in vivo ARDS mouse model and an in vitro ARDS cell model by LPS (Lipopolysaccharide) stimulation. Lung tissue injury was evaluated by wet/dry ratios and histopathological examination. LCN2 expression was detected by qRT-PCR and Western blot. Inflammatory factors, oxidative stress and apoptosis were also detected. Ferroptosis was identified by detection of Fe 2+ level and ferroptosis-associated protein expressions. Mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinase (ERK) pathway signaling was examined by Western blot analysis. The data revealed that LCN2 expression was significantly upregulated in neonatal mice with ARDS. Interference with LCN2 protected LPS-induced lung in neonatal mouse by reducing the radio of wet/dry and alleviating pathological damages. In addition, LCN2 silencing repressed LPS-induced inflammation, oxidative stress in vivo and in vitro, as well as apoptosis. Meanwhile, decreased level of Fe 2+ and transferrin while increased levels of ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4) were observed. The expression MAPK/ERK pathway was inhibited by depletion of LCN2. The present results suggest that LCN2 knockdown protected LPS-induced ARDS model via inhibition of ferroptosis-related inflammation and oxidative stress by inhibiting the MAPK/ERK pathway, thereby presenting a novel target for the treatment of ARDS.

Network Pharmacology Identifies Therapeutic Targets and the Mechanisms of Glutathione Action in Ferroptosis Occurring in Oral Cancer

“…Activation of MAPK signaling induced ferroptosis in human pancreatic islet-cell clusters ( Li and Leung 2020 ). In contrast, inhibition of MAPK signaling suppressed inflammation and oxidative stress of acute respiratory distress syndrome caused by ferroptosis ( Wang et al, 2022 ). In other studies, MAPK signaling was found to control ferroptosis in various cancers including nasopharyngeal carcinoma, hepatocellular carcinoma, osteosarcoma, and non-small cell lung cancer through redox balance ( Poursaitidis et al, 2017 ; Lv et al, 2020 ; Chang et al, 2021 ; He et al, 2021 ).…”

L-F001, a Multifunctional Fasudil-Lipoic Acid Dimer Prevents RSL3-Induced Ferroptosis via Maintaining Iron Homeostasis and Inhibiting JNK in HT22 Cells

“…As for the other two MAPKs signaling (ERK and P38), they can all be activated by the same stimulation factors such as cytokines, neurotransmitters, hormones, cellular stress, and so on, and undergo the same changes. Many articles related to ferroptosis only detect one of them to characterize the change of ERK and P38 (Yang et al, 2021 ; Wang et al, 2022 ). In this study, we focused on the protective effects of L-F001 on ferroptosis and tentatively evaluated the JNK pathway.…”

Effects of microRNA-101-3p on predicting pediatric acute respiratory distress syndrome and its role in human alveolar epithelial cell

“…In idiopathic pulmonary fibrosis, Sox9 participates in the migration and survival of fibroblasts [ 44 ]. Several studies reveal the underlying mechanism of ARDS by conducting in vivo mouse model and an in vitro cell model [ 45 , 46 ]. Compared to these publications, we examined not only the effects of miR-338-3p in A549 cells caused by LPS, but also the diagnostic role of miR-338-3p for PARDS patients.…”