The impact of long noncoding RNA LINKA on the GPNMB/HIF-1α signaling pathway in hyperoxic acute lung injury

Objective To investigate the role and mechanism of long noncoding RNA LINKA (LncRNA LINKA) in hyperoxia-induced acute lung injury (HALI), specifically focusing on its impact on the GPNMB (glycoprotein nonmetastatic B protein)/HIF-1α (hypoxia-inducible factor 1-alpha) signaling pathway of apoptosis. Methods An experimental animal study was conducted using specific pathogen-free (SPF) male C57BL/6 mice and GPNMB knockout (KO) mice. Lung injury was assessed by measuring total protein in bronchoalveolar lavage fluid (BALF), lung wet/dry weight (W/D) ratio, serum levels of inflammatory (tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)) and oxidative stress (malondialdehyde (MDA) and superoxide dismutase (SOD)) mediators, histopathological scoring (hematoxylin and eosin staining), apoptosis rate (terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay), and expression levels of GPNMB/HIF-1α pathway proteins (p-GPNMB, phosphorylated leucine-rich repeat kinase 2 (p-LRRK2), p-HIF-1α) and apoptosis regulators (BCL2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2)) via western blotting. Results Overexpression of LncRNA LINKA significantly mitigated HALI in mice, evidenced by: reduced total protein in BALF; decreased lung W/D ratio (indicating attenuated pulmonary edema); lower serum levels of TNF-α, IL-1β, and MDA, and higher SOD; improved lung histopathology with reduced inflammatory cell infiltration and alveolar septal thickening; and decreased apoptosis rate. Conversely, silencing LncRNA LINKA exacerbated HALI. Mechanistically, LncRNA LINKA overexpression increased phosphorylation of GPNMB, LRRK2, and HIF-1α, upregulated antiapoptotic Bcl-2, and downregulated pro-apoptotic Bax. Crucially, these protective effects and pathway activation were abolished in GPNMB KO mice. Conclusions LncRNA LINKA may protect against HALI by activating the GPNMB/HIF-1α signaling pathway, leading to suppressed apoptosis and inflammation. This identifies LncRNA LINKA as a potential therapeutic target for HALI.