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 Fe2+ 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 Fe2+ 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.

• Authors: Xiaodong Wang, Chunhua Zhang, Na Zou, Qinghua Chen, Chaojun Wang, Xu Zhou, Li Luo, Haibin Qi, Junhua Li, Zhiyan Liu, Jinghong Yi, Jing Li, Wei Liu
• Journal: Bioengineered (Bioengineered) Vol. 13 Issue 1 Pg. 508-520 (01 2022) ISSN: 2165-5987 [Electronic] United States
• PMID: 34969358 (Publication Type: Journal Article)

Chemical References

• Lipocalin-2
• Lipopolysaccharides
• RNA, Small Interfering
• Lcn2 protein, mouse

Topics

• Animals
• Animals, Newborn
• Disease Models, Animal
• Ferroptosis (drug effects)
• Gene Silencing
• Lipocalin-2 (genetics)
• Lipopolysaccharides (adverse effects)
• MAP Kinase Signaling System
• Mice
• Oxidative Stress (drug effects)
• RNA, Small Interfering (administration & dosage, pharmacology)
• Random Allocation
• Respiratory Distress Syndrome, Newborn (chemically induced, drug therapy, genetics, metabolism)
• Signal Transduction
• Up-Regulation