Molecular immunology · 2026
GOLPH3 promotes alveolar epithelial glycocalyx shedding and barrier disruption in lipopolysaccharide-induced acute lung injury via the ERK/MMP2/9 axis.
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Wang Yanru, Wang Xinye, Liu Suxiao
Аннотация
BACKGROUND: Acute lung injury (ALI) is a life-threatening syndrome with high mortality, characterized by alveolar epithelial barrier disruption and excessive inflammatory injury. The epithelial glycocalyx, a layer critical for barrier integrity, undergoes shedding during ALI. However, the underlying regulatory mechanisms remain poorly understood. This study investigates the role of Golgi phosphoprotein 3 (GOLPH3) in glycocalyx-mediated barrier dysfunction in ALI.
METHODS: A Lipopolysaccharide (LPS)-induced ALI model was established in MLE-12 cells and C57BL/6 mice. Bioinformatics analysis of the GSE18341 dataset was performed to identify differentially expressed genes and enriched pathways. GOLPH3 was silenced or overexpressed to determine its function, and the MEK inhibitor U0126 was used for rescue experiments. Glycocalyx integrity, tight junction proteins, and ERK/MMP pathway mediators were analyzed by western blotting, immunofluorescence, transmission electron microscopy, and ELISA.
RESULTS: LPS markedly reduced MLE-12 cell viability, disrupted tight junction protein expression, and induced glycocalyx damage. Bioinformatic analysis identified GOLPH3 as a potential regulator of LPS-induced ALI. GOLPH3 expression positively correlated with MAPK/ERK pathway and MMP2/9-associated biological processes and was elevated in both LPS-treated cells and mouse lung tissues. GOLPH3 knockdown attenuated LPS-induced ERK activation, MMP2/9 upregulation, inflammatory cytokine release, glycocalyx shedding, and barrier disruption. Conversely, GOLPH3 overexpression exacerbated these effects, which were reversed by U0126.
CONCLUSION: GOLPH3 is a critical mediator of LPS-induced ALI. GOLPH3 promotes alveolar epithelial glycocalyx shedding and barrier disruption by activating the ERK-MMP2/9 axis, highlighting GOLPH3 as a potential therapeutic target for ALI that warrants further in vivo validation.
METHODS: A Lipopolysaccharide (LPS)-induced ALI model was established in MLE-12 cells and C57BL/6 mice. Bioinformatics analysis of the GSE18341 dataset was performed to identify differentially expressed genes and enriched pathways. GOLPH3 was silenced or overexpressed to determine its function, and the MEK inhibitor U0126 was used for rescue experiments. Glycocalyx integrity, tight junction proteins, and ERK/MMP pathway mediators were analyzed by western blotting, immunofluorescence, transmission electron microscopy, and ELISA.
RESULTS: LPS markedly reduced MLE-12 cell viability, disrupted tight junction protein expression, and induced glycocalyx damage. Bioinformatic analysis identified GOLPH3 as a potential regulator of LPS-induced ALI. GOLPH3 expression positively correlated with MAPK/ERK pathway and MMP2/9-associated biological processes and was elevated in both LPS-treated cells and mouse lung tissues. GOLPH3 knockdown attenuated LPS-induced ERK activation, MMP2/9 upregulation, inflammatory cytokine release, glycocalyx shedding, and barrier disruption. Conversely, GOLPH3 overexpression exacerbated these effects, which were reversed by U0126.
CONCLUSION: GOLPH3 is a critical mediator of LPS-induced ALI. GOLPH3 promotes alveolar epithelial glycocalyx shedding and barrier disruption by activating the ERK-MMP2/9 axis, highlighting GOLPH3 as a potential therapeutic target for ALI that warrants further in vivo validation.