Abstract
Sepsis-evoked acute lung injury (ALI) and its extreme manifestation, acute respiratory distress syndrome (ARDS), constitute a major cause of mortality in intensive care units. High levels of the long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) have been positively correlated with increased severity and unfavorable prognoses in patients with sepsis. Nevertheless, the function and molecular mechanism of NEAT1 in ALI remain elusive. In the current study, high levels of NEAT1 were confirmed in lipopolysaccharide- (LPS-) induced ALI mice models and in LPS-stimulated cells from the alveolar epithelial A549 cell line. Intriguingly, cessation of NEAT1 led to increased cell viability and decreased lactate dehydrogenase release, apoptosis, and caspase-3/9 activity, which conferred protection against LPS-induced injury in these cells. NEAT1 inhibition also restrained LPS-evoked transcripts and production of inflammatory cytokines IL-6, IL-1β, and TNF-α. A mechanism analysis corroborated the activation of high-mobility group box1 (HMGB1)/receptors for advanced glycation end products (RAGE) and NF-κB signaling in LPS-treated A549 cells. NEAT1 suppression reversed the activation of this pathway. Notably, reactivating HMGB1/RAGE signaling via HMGB1 overexpression blunted the anti-injury and anti-inflammation effects of NEAT1 knockdown. These findings suggest that NEAT1 may aggravate the progression of ALI and ARDS by inducing alveolar epithelial cell injury and inflammation via HMGB1/RAGE signaling, implying a promising treatment target for these conditions.