Abstract
PurposeWe aimed to identify and verify the key genes and lncRNAs associated with acute lung injury (ALI) and explore the pathogenesis of ALI. Research showed that lower expression of the lncRNA metastasis-associated lung carcinoma transcript 1 (MALAT1) alleviates lung injury induced by lipopolysaccharide (LPS). Nevertheless, the mechanisms of MALAT1 on cellular apoptosis remain unclear in LPS-stimulated ALI. We investigated the mechanism of MALAT1 in modulating the apoptosis of LPS-induced human pulmonary alveolar epithelial cells (HPAEpiC).MethodsDifferentially expressed lncRNAs between the ALI samples and normal controls were identified using gene expression profiles. ALI-related genes were determined by the overlap of differentially expressed genes (DEGs), genes correlated with lung, genes correlated with key lncRNAs, and genes sharing significantly high proportions of microRNA targets with MALAT1. Quantitative real-time PCR (qPCR) was applied to detect the expression of MALAT1, microRNA (miR)-194-5p, and forkhead box P2 (FOXP2) mRNA in 1 μg/ml LPS-treated HPAEpiC. MALAT1 knockdown vectors, miR-194-5p inhibitors, and ov-FOXP2 were constructed and used to transfect HPAEpiC. The influence of MALAT1 knockdown on LPS-induced HPAEpiC proliferation and apoptosis via the miR-194-5p/FOXP2 axis was determined using Cell counting kit-8 (CCK-8) assay, flow cytometry, and Western blotting analysis, respectively. The interactions between MALAT1, miR-194-5p, and FOXP2 were verified using dual-luciferase reporter gene assay.ResultsWe identified a key lncRNA (MALAT1) and three key genes (EYA1, WNT5A, and FOXP2) that are closely correlated with the pathogenesis of ALI. LPS stimulation promoted MALAT1 expression and apoptosis and also inhibited HPAEpiC viability. MALAT1 knockdown significantly improved viability and suppressed the apoptosis of LPS-stimulated HPAEpiC. Moreover, MALAT1 directly targeted miR-194-5p, a downregulated miRNA in LPS-stimulated HPAEpiC, when FOXP2 was overexpressed. MALAT1 knockdown led to the overexpression of miR-194-5p and restrained FOXP2 expression. Furthermore, inhibition of miR-194-5p exerted a rescue effect on MALAT1 knockdown of FOXP2, whereas the overexpression of FOXP2 reversed the effect of MALAT1 knockdown on viability and apoptosis of LPS-stimulated HPAEpiC.ConclusionOur results demonstrated that MALAT1 knockdown alleviated HPAEpiC apoptosis by competitively binding to miR-194-5p and then elevating the inhibitory effect on its target FOXP2. These data provide a novel insight into the role of MALAT1 in the progression of ALI and potential diagnostic and therapeutic strategies for ALI patients.
Highlights
Sepsis is a common condition that can lead to ICU hospitalization and cause damage to multiple organs, among which the lung is the most vulnerable (Kuebler, 2019; Liu et al, 2020b)
We hypothesized a competitive endogenous RNAs (ceRNAs) model in acute lung injury (ALI) that metastasisassociated lung adenocarcinoma transcript 1 (MALAT1) functions as a ceRNA by sponging miR-194-5p to regulate downstream Forkhead box P2 (FOXP2) expression and as a result suppresses apoptosis (Figure 1)
We aimed to demonstrate that the knockdown of Long non-coding RNAs (lncRNAs) MALAT1 alleviates LPS-induced ALI via inhibiting apoptosis by acting as a miR-194-5p sponge to downregulate FOXP2
Summary
Sepsis is a common condition that can lead to ICU hospitalization and cause damage to multiple organs, among which the lung is the most vulnerable (Kuebler, 2019; Liu et al, 2020b). Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are common complications of sepsis that are often lifethreatening (Van Wessem and Leenen, 2018; Forrester et al, 2019). Great progress has been made for the treatment of ALI, the death rate is still as high as 40% (Villar et al, 2014). The pathogenesis of ALI in sepsis is complicated, including the apoptosis of pulmonary cells. There is a disruption of epithelial cell function and increased alveolar epithelial cell apoptosis in sepsis-induced ALI (Gong et al, 2017; Kimura et al, 2017). It is of great interest to improve our understanding of apoptosis in ALI and to formulate effective preventive and treatment strategies
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