Long noncoding RNAs (lncRNAs) act as essential regulators of various diseases. However, the functions of lncRNAs in sepsis-induced acute lung injury (SALI) remain unclear. Here, we found that lipopolysaccharide could upregulate lncRNA-p21 expression in mesenchymal stem cells (MSCs) in a time- and dose-dependent manner and that lncRNA-p21 was packaged into exosomes. Furthermore, we demonstrated that treatment with exosomal lncRNA-p21 could increase the expression of sirtuin 1 (SIRT1) to protect MLE-12 cells from apoptosis during sepsis. Moreover, we identified SIRT1 as a direct target of miR-181 and found that the level of SIRT1 was negatively correlated with the level of miR-181. The luciferase reporter assay also confirmed the negative correlation between the levels of miR-181 and lncRNA-p21. Our results showed that the lncRNA-p21-induced downregulation of miR-181 might suppress epithelial cell apoptosis and alleviate lung tissue injury by upregulating SIRT1 expression, suggesting the potential therapeutic effects of lncRNA-p21 on SALI. In conclusion, we found that the novel lncRNA-p21/miR-181/SIRT1 pathway may play an important role in the progression of SALI, and MSC-derived exosomes may be a new therapeutic strategy for this disease.
Background
Bone marrow-derived endothelial progenitor cells (EPCs) are shown to attenuate lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in animal models. However, the molecular mechanism is largely unknown.
Materials and methods
The animal model of ALI was induced by intratracheal instillation of purified LPS with 2.5 mg/ml/kg. The expression of microRNAs and ADAM15 in lung tissues and LPS-induced mouse pulmonary microvascular endothelial cells (MPMVECs) was determined by quantitative real-time PCR and western blot analysis. The target relationship between miR-10a/b-5p and ADAM15 was confirmed by luciferase reporter assay and RNA interference. The effect of EPCs on MPMVEC proliferation was detected by MTT assay.
Results
EPCs increased the expression of miR-10a/b-5p and reduced ADAM15 protein level in LPS-induced ALI lung tissues and MPMVECs (
p
< 0.05), and promoted LPS-induced MPMVEC proliferation (
p
< 0.05). ADAM15 was confirmed to be a downstream target of miR-10a/b-5p. Additionally, EPCs promoted LPS-induced MPMVEC proliferation and exerted the therapeutic effect of ALI via regulating miR-10a/b-5p/ADAM15 axis.
Conclusion
EPC transplantation exerted its therapeutic effect of ALI via increasing miR-10a/b-5p and reducing ADAM15, thus providing a novel insight into the molecular mechanism of EPC transplantation in treating ALI.
Electronic supplementary material
The online version of this article (10.1186/s12944-019-1079-3) contains supplementary material, which is available to authorized users.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.