LncRNA XIST knockdown alleviates LPS-induced acute lung injury by inactivation of XIST/miR-132-3p/MAPK14 pathway: XIST promotes ALI via miR-132-3p/MAPK14 axis

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Abstract

Acute lung injury (ALI) is a fatal inflammatory response syndrome. LncRNA XIST (XIST) is a lung cancer-related gene and participates in pneumonia. However, whether XIST participates in lipopolysaccharides (LPS)-induced ALI remains unclear. LPS-induced inflammation model was constructed in vitro, then cell viability, cytokines, cell apoptosis, protein, and mRNA expressions were individually detected by cell counting kit-8, enzyme-linked immunosorbent assay and flow cytometry, Western blot, and qRT-PCR. A dual-luciferase reporter assay confirmed the relationships among XIST, miR-132-3p, and MAPK14. Furthermore, inflammation and conditions after knockdown of XIST were assessed by hematoxylin and eosin staining, lung wet-to-dry weight ratio, PaO2/FiO2 ratio, and malondialdehyde (MDA) contents using LPS-induced in vivo model. Our findings indicated that the LPS challenge decreased cell viability, increased cell apoptosis, and caused secretions of pro-inflammatory cytokines. Noticeably, LPS significantly upregulated XIST, MAPK14, and downregulated miR-132-3p. Mechanistically, XIST acted as a molecular sponge to suppress miR-132-3p, and MAPK14 was identified as a target of miR-132-3p. Functional analyses demonstrated that XIST silencing remarkably increased cell survival and alleviated cell death and lung injury through decreasing TNF-α, IL-1β, IL-6, accumulation of inflammatory cells, alveolar hemorrhage, MDA release, and increased PaO2/FiO2 ratio, as well as upregulating Bcl-2, and downregulating Bax, MAPK14, and p-extracellular signal-regulated kinases ½. In contrast, inhibition of the miR-132-3p antagonized the effects of XIST silencing. In conclusion, inhibition of XIST exhibited a protective role in LPS-induced ALI through modulating the miR-132-3p/MAPK14 axis.

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Li, C., Liu, J. H., Su, J., Lin, W. J., Zhao, J. Q., Zhang, Z. H., & Wu, Q. (2021). LncRNA XIST knockdown alleviates LPS-induced acute lung injury by inactivation of XIST/miR-132-3p/MAPK14 pathway: XIST promotes ALI via miR-132-3p/MAPK14 axis. Molecular and Cellular Biochemistry, 476(12), 4217–4229. https://doi.org/10.1007/s11010-021-04234-x

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