Depression of lncRNA NEAT1 Antagonizes LPS-Evoked Acute Injury and Inflammatory Response in Alveolar Epithelial Cells via HMGB1-RAGE Signaling.

Hongchao Zhou,Bin Zhang,Xinhui Wang

doi:10.1155/2020/8019467

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.

Highlights

Infection-evoked sepsis is a life-threatening dysfunctional disease that affects the organs, and the lungs are highly susceptible
High Expression of Long noncoding RNAs (lncRNAs) nuclear paraspeckle assembly transcript 1 (NEAT1) Was Observed in a Mouse Model of Acute Lung Injury and in LPS-Injured Alveolar Epithelial Cells
We further simulated Acute lung injury (ALI) in vitro by exposing A549 pulmonary epithelial cells to LPS, and the results corroborated that treatment with 1 μg of LPS dramatically increased NEAT1 expression (Figure 1(c))

Summary

Introduction

Infection-evoked sepsis is a life-threatening dysfunctional disease that affects the organs, and the lungs are highly susceptible. Acute lung injury (ALI) is a common clinical symptom in patients with sepsis. 50% to 55% of patients with ALI will develop severe acute respiratory distress syndrome (ARDS) [1]. ALI/ARDS often occur during clinical complications in intensive care units. The accompanying high-protein pulmonary edema and severe hypoxemic respiratory failure are leading causes of high morbidity and mortality in critically ill patients. Despite progress in understanding the pathogenesis of ALI/ARDS, therapeutic strategies remain unsatisfactory, and mortality remains significant at 35% to 40% [2]

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Results

Conclusion