Lipocalin-2 links spinal cord injury to neurogenic lung injury through MAPK/ERK-ferroptosis signaling: Preliminary evidence for a spinal cord-lung axis.

Abstract

BACKGROUND: Lung injury secondary to acute spinal cord injury (ASCI) is a critical pathological basis for respiratory complications such as pneumonia and respiratory failure, which are major contributors to early mortality and poor outcomes in affected individuals. Despite its clinical relevance, the underlying mechanisms linking ASCI to pulmonary dysfunction remain poorly understood. In this study, we evaluated the role of Lipocalin-2 (LCN2) in ASCI-induced lung injury and investigated the potential involvement of the LCN2/MAPK/ERK signaling axis in this process. METHODS: A mouse model of ASCI-induced lung injury was established. Transcriptomic profiling of lung tissue identified LCN2 as a significantly upregulated gene following ASCI. The role of LCN2 and its downstream signaling pathways was further explored through qRT-PCR, Western blotting, immunofluorescence, and immunohistochemical analyses. RESULTS: LCN2-deficient (LCN2-/-) mice demonstrated markedly improved pulmonary histology and reduced injury markers compared to wild-type controls after ASCI. Downregulation of LCN2 attenuated inflammation, oxidative stress, and apoptosis in lung tissue. Mechanistically, LCN2 promoted ferroptosis via activation of the MAPK/ERK signaling pathway, contributing to pulmonary damage following ASCI. CONCLUSION: This study uncovers a novel mechanistic link between spinal cord injury and neurogenic lung injury via LCN2-mediated ferroptosis. These findings provide insight into the spinal cord-lung axis and highlight the LCN2/MAPK/ERK pathway as a potential early therapeutic target for mitigating secondary pulmonary complications following acute spinal cord injury.