Long non-coding RNAs: Promising new targets in pulmonary fibrosis

Abstract

Pulmonary fibrosis is characterized by progressive and irreversible scarring in the lungs with poor prognosis and treatment. It is caused by various factors, including environmental and occupational exposures, and some rheumatic immune diseases. Even the rapid global spread of the COVID-19 pandemic can also cause pulmonary fibrosis with a high probability. Functions attributed to long non-coding RNAs (lncRNAs) make them highly attractive diagnostic and therapeutic targets in fibroproliferative diseases. Therefore, an understanding of the specific mechanisms by which lncRNAs regulate pulmonary fibrotic pathogenesis is urgently needed to identify new possibilities for therapy. In this review, we focus on the molecular mechanisms and implications of lncRNAs targeted protein-coding and non-coding genes during pulmonary fibrogenesis, and systematically analyze the communication of lncRNAs with various types of RNAs, including microRNA, circular RNA and mRNA. Finally, we propose the potential approach of lncRNA-based diagnosis and therapy for pulmonary fibrosis. We hope that understanding these interactions between protein-coding and non-coding genes will contribute to the development of lncRNA-based clinical applications for pulmonary fibrosis.

Keywords: COVID-19; circular RNA; lncRNA; microRNA; pulmonary fibrosis.

FIGURE 1

Molecular mechanisms of lncRNAs and lncRNA‐based clinical applications in pulmonary fibrosis. Aging, environmental exposure or genetic predisposition to alveolar epithelial cell results in the release of pro‐fibrotic factors, such as growth factors, cytokines, chemokines and matrix metalloproteinases, which promote abnormal and persistent fibroblast activation and remodeling, macrophage M1/M2 polarization classification, and endothelial‐mesenchymal transition. Meanwhile, many abnormal organelles, including telomere attrition, endoplasmic reticulum stress and mitochondrial dysfunction, are also involved in fibrogenesis. lncRNAs participate in these abnormal biological processes in the nucleus or cytoplasm via diverse mechanisms and thus regulate numerous signaling pathways in different cell types to control pulmonary fibrogenesis. (1) The images present the various methodologies for lncRNA as the diagnostic marker. (2) lncRNA‐based therapeutic strategies are proposed depending on their different regulatory patterns

FIGURE 2

Regulatory paradigms of lncRNAs in pulmonary fibrosis. (A) lncRNA transcribed from the host gene, which affects the nearby/host genes. (B) lncRNA forms a RNA–protein complex by binding to specific protein to modulate the target gene activity. (C) lncRNA can be processed to yield miRNA or (D) function as a competing miRNA binding. (E) lncRNA cross‐talks with miRNA, circRNA and mRNA