Genome-wide landscape of mRNAs, microRNAs, lncRNAs, and circRNAs in hemorrhagic shock-induced ALI/ARDS in rats

Abstract

Background: Hemorrhagic shock (HS) can develop into multiple organ dysfunction syndrome, among which acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) usually lead to poor outcomes. The underlying molecular mechanisms of HS-induced ALI/ARDS remain unclear. This study sought to investigate gene expression profiles and predict competing endogenous RNA (ceRNA) regulatory networks in an HS-induced ALI/ARDS preclinical model.

Methods: Sprague Dawley rats were subjected to a fixed volume of hemorrhage (HS, 40% estimated total blood volume) or not (sham) randomly. After 8 hours of observation, left lung tissue was harvested to evaluate lung injury. Right lung was collected for RNA sequencing. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed and the long noncoding RNA (lncRNA)/circular RNA (circRNA)-microRNA (miRNA)-messenger RNA (mRNA) linkages were predicted using the ceRNA theory. Quantitative real-time polymerase chain reaction was used to validate the RNA sequencing findings.

Results: Hemorrhagic shock lungs showed noticeable ALI/ARDS features, and 437 mRNAs, 31 miRNAs, 734 lncRNAs, and 29 circRNAs were differentially expressed. In Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses, the differentially expressed transcripts were enriched in the following terms: the metabolic pathways, signal transduction pathways, necroptosis, DNA damage recognition and repair, inflammatory cell migration and chemotaxis, the NOD-like receptor signaling pathway, the Janus kinase/signal transducer and activator of transcription signaling pathway, the mitogen-activated protein kinase signaling pathway, the phosphatidylinositol-3-kinase/protein kinase B signaling pathway, and so on. Also, this study identified lncRNA-miRNA-mRNA linkages with 12 lncRNAs, 5 miRNAs, 15 mRNAs, and circRNA-miRNA-mRNA linkages with 10 circRNAs, 16 miRNAs, 39 mRNAs. These networks might play important regulatory roles.

Conclusion: This is the first high-throughput analysis of gene expression profiles in HS-induced ALI/ARDS. It shows that metabolism, cell signaling, DNA damage and repair, and necroptosis-related RNAs altered, and inflammatory response-associated RNAs and pathways have pivotal roles in HS-induced ALI/ARDS progression. It also prompts some important RNAs and regulatory networks for future research.

Level of evidence: Basic science article.