HSPA12B modulates lung injury and neutrophil-related inflammatory responses in LPS-induced acute lung injury: a potential link to the PKC-PAD4 pathway.

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions with high mortality. Excessive neutrophil activation and neutrophil extracellular trap (NET)-related responses, together with pulmonary endothelial barrier impairment, are critical pathological features. Heat shock protein A12B (HSPA12B) has endothelial-protective and anti-inflammatory functions, but its relationship with the PKC-PAD4 pathway and neutrophil-associated lung injury remains unclear. In this study, we combined bioinformatics analysis with an LPS-induced ALI mouse model to examine whether HSPA12B expression is associated with PKC-PAD4 pathway activation and neutrophil-related lung injury. HSPA12B overexpression was associated with reduced pathological lung damage, lower levels of inflammatory cytokines and oxidative stress markers, as well as decreased lung-tissue levels of PKC, PAD4 and neutrophil-associated markers (CitH3, MPO, NE). Conversely, HSPA12B knockdown was accompanied by elevated protein levels of PKC, aggravated lung injury, and further upregulation of these markers; transcriptomic analysis of lungs from HSPA12B-knockdown mice revealed enrichment of the neutrophil extracellular trap formation pathway. These findings indicate that HSPA12B is functionally linked to the PKC-PAD4 cascade and neutrophil-mediated lung injury in LPS-induced ALI. Of note, the PKC-PAD4 link is proposed rather than directly demonstrated, and that isoform-specific and activity-level evidence is still lacking. This study identifies HSPA12B as a potential upstream regulatory node for further mechanistic investigation, providing a basis for future HSPA12B-targeted studies in ALI/ARDS.