Pulmonary fibrosis is the result of various diseases with no satisfactory treatment approaches. The exosome-mediated transfer of long noncoding RNAs (lncRNAs) has been implicated in the pathological process of lung diseases. Herein, we investigated the therapeutic potential of HOTAIRM1 transferred by alveolar epithelial cell (AEC)-derived exosomes in interstitial pulmonary fibrosis (IPF) and the potential molecular mechanisms. Next-generation sequencing-based gene expression profiling was employed to identify lncRNAs related to IPF. Exosomes were isolated from hypoxia-induced AECs (AEC-exosomes) and identified before use. HOTAIRM1 expression was examined in bleomycin-induced IPF mouse models and the isolated exosomes, and the miRNA downstream of HOTAIRM1 was analyzed. HOTAIRM1 expression was increased in the lung tissues of IPF mice and AEC exosomes. HOTAIRM1 delivered by AEC-exosomes promoted the proliferation and transdifferentiation of lung fibroblasts (LFs). Mechanistically, HOTAIRM1 competitively bound to miR-30d-3p and recruited YY1 to upregulate HSF1 expression. In addition, miR-30d-3p targeted HSF1 by binding to its 3’-UTR and reduced its expression. In vivo assays confirmed the promoting effect of exosomes-HOTAIRM1 on extracellular matrix remodeling by regulating the miR-30d-3p/HSF1/YY1 axis. Overall, HOTAIRM1 loaded by AEC exosomes can accelerate IPF by disrupting miR-30d-3p-mediated inhibition of HSF1 and inducing recruitment of HSF1 by YY1. These results highlight a promising strategy to overcome IPF.
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This work is supported by Project of Sichuan Provincial Department of Science and Technology 2021YFS0373).
The authors declare no competing interests.
Ethics approval/consent to participate
This study was performed with the approval of the Animal Ethics Committee of Sichuan Provincial People’s Hospital (2019047 A) and conformed to the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Extensive efforts were made to minimize animal suffering.
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Chen, L., Yang, Y., Yue, R. et al. Exosomes derived from hypoxia-induced alveolar epithelial cells stimulate interstitial pulmonary fibrosis through a HOTAIRM1-dependent mechanism. Lab Invest 102, 935–944 (2022). https://doi.org/10.1038/s41374-022-00782-y