Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Exosomes derived from hypoxia-induced alveolar epithelial cells stimulate interstitial pulmonary fibrosis through a HOTAIRM1-dependent mechanism


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.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: HOTAIRM1 is increased in lung tissues of IPF mice and initiates IPF.
Fig. 2: Exos-HOTAIRM1 stimulates the proliferation and transdifferentiation of LFs.
Fig. 3: HOTAIRM1 upregulates HSF1 by recruiting YY1.
Fig. 4: HOTAIRM1 binds to miR-30d-3p and consequently increases the expression of the miR-30d-3p target HSF1.
Fig. 5: HOTAIRM1 enhances the proliferation and transdifferentiation of LFs through the miR-30d-3p/YY1/HSF1 axis.
Fig. 6: Exos-HOTAIRM1 contributes to extracellular matrix remodeling in IPF mice through the miR-30d-3p/YY1/HSF1 axis.
Fig. 7: Schematic diagram of the mechanism by which HOTAIRM1 delivered by AEC-Exos affects the extracellular matrix remodeling of IPF.

Data availability

The data and materials of the study can be obtained from the corresponding author upon request.


  1. Antoniou, K. M., Margaritopoulos, G. A., Tomassetti, S., Bonella, F., Costabel, U. & Poletti, V. Interstitial lung disease. Eur. Respir. Rev. 23, 40–54 (2014).

    Article  Google Scholar 

  2. Meyer, K. C. Pulmonary fibrosis, part I: epidemiology, pathogenesis, and diagnosis. Expert Rev. Respir. Med. 11, 343–359 (2017).

    CAS  PubMed  Google Scholar 

  3. Sgalla, G., Kulkarni, T., Antin-Ozerkis, D., Thannickal, V. J. & Richeldi, L. Update in Pulmonary Fibrosis 2018. Am. J. Respir. Crit. Care Med. 200, 292–300 (2019).

    CAS  Article  Google Scholar 

  4. Chioma, O. S. & Drake, W. P. Role of microbial agents in pulmonary fibrosis. Yale J. Biol. Med. 90, 219–227 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Mathai, S. K. & Schwartz, D. A. Translational research in pulmonary fibrosis. Transl. Res. 209, 1–13 (2019).

    Article  Google Scholar 

  6. Pegtel, D. M. & Gould, S. J. Exosomes. Annu. Rev. Biochem. 88, 487–514 (2019).

    CAS  Article  Google Scholar 

  7. Poulet C, Njock MS, Moermans C, Louis E, Louis R, Malaise M, et al. Exosomal long non-coding RNAs in lung diseases. Int. J. Mol. Sci. 21, 3580–3635 (2020).

    Article  Google Scholar 

  8. Cao, G., Zhang, J., Wang, M., Song, X., Liu, W. & Mao, C. et al. Differential expression of long non-coding RNAs in bleomycin-induced lung fibrosis. Int. J. Mol. Med. 32, 355–364 (2013).

    CAS  Article  Google Scholar 

  9. Bhan, A., Soleimani, M. & Mandal, S. S. Long noncoding RNA and cancer: a new paradigm. Cancer Res 77, 3965–3981 (2017).

    CAS  Article  Google Scholar 

  10. Xiong, F., Yin, H., Zhang, H., Zhu, C., Zhang, B. & Chen, S. et al. Clinicopathologic features and the prognostic implications of long noncoding RNA HOTAIRM1 in non-small cell lung cancer. Genet. Test Mol. Biomarkers 24, 47–53 (2020).

    CAS  Article  Google Scholar 

  11. Tanwar, V. S., Zhang, X., Jagannathan, L., Jose, C. C. & Cuddapah, S. Cadmium exposure upregulates SNAIL through miR-30 repression in human lung epithelial cells. Toxicol Appl. Pharmacol. 373, 1–9 (2019).

    CAS  Article  Google Scholar 

  12. Yang, C., Zhang, J. J., Peng, Y. P., Zhu, Y., Yin, L. D. & Wei, J. S. et al. A Yin-Yang 1/miR-30a regulatory circuit modulates autophagy in pancreatic cancer cells. J. Transl. Med. 15, 211 (2017).

    Article  Google Scholar 

  13. Zhang, C., Zhu, X., Hua, Y., Zhao, Q., Wang, K. & Zhen, L. et al. YY1 mediates TGF-beta1-induced EMT and pro-fibrogenesis in alveolar epithelial cells. Respir Res. 20, 249 (2019).

    Article  Google Scholar 

  14. Yang, W., Feng, B., Meng, Y., Wang, J., Geng, B. & Cui, Q. et al. FAM3C-YY1 axis is essential for TGFbeta-promoted proliferation and migration of human breast cancer MDA-MB-231 cells via the activation of HSF1. J. Cell Mol. Med. 23, 3464–3475 (2019).

    CAS  Article  Google Scholar 

  15. Chen, L., Yang, Y., Peng, X., Yan, H., Zhang, X. & Yin, L. et al. Transcription factor YY1 inhibits the expression of THY1 to promote interstitial pulmonary fibrosis by activating the HSF1/miR-214 axis. Aging 12, 8339–8351 (2020).

    CAS  Article  Google Scholar 

  16. Liu, X., Yang, L., Kwak, D., Hou, L., Shang, R. & Meyer, C. et al. Profound increase of lung airway resistance in heart failure: a potential important contributor for dyspnea. J. Cardiovasc. Transl. Res. 12, 271–279 (2019).

    Article  Google Scholar 

  17. Chen, D., Li, Y., Wang, Y. & Xu, J. LncRNA HOTAIRM1 knockdown inhibits cell glycolysis metabolism and tumor progression by miR-498/ABCE1 axis in non-small cell lung cancer. Genes Genom 43, 183–194 (2021).

    CAS  Article  Google Scholar 

  18. Liang, L., Gu, W., Li, M., Gao, R., Zhang, X. & Guo, C. et al. The long noncoding RNA HOTAIRM1 controlled by AML1 enhances glucocorticoid resistance by activating RHOA/ROCK1 pathway through suppressing ARHGAP18. Cell Death Dis. 12, 702 (2021).

    CAS  Article  Google Scholar 

  19. Ren, Y., Zhang, K., Wang, J., Meng, X., Du, X. & Shi, Z. et al. HOTAIRM1 promotes osteogenic differentiation and alleviates osteoclast differentiation by inactivating the NF-kappaB pathway. Acta Bioch Bioph Sin 53, 201–211 (2021).

    CAS  Article  Google Scholar 

  20. Alkhateeb T, Bah I, Kumbhare A, Youssef D, Yao ZQ, McCall CE, et al. Long non-coding RNA hotairm1 promotes S100A9 support of MDSC expansion during sepsis. J. Clin. Cell Immunol, 11, 600 (2020).

    PubMed  PubMed Central  Google Scholar 

  21. Sakai, N. & Tager, A. M. Fibrosis of two: Epithelial cell-fibroblast interactions in pulmonary fibrosis. Biochim. Biophys. Acta 1832, 911–921 (2013).

    CAS  Article  Google Scholar 

  22. Guan, H., Peng, R., Mao, L., Fang, F., Xu, B. & Chen, M. Injured tubular epithelial cells activate fibroblasts to promote kidney fibrosis through miR-150-containing exosomes. Exp Cell Res. 392, 112007 (2020).

    CAS  Article  Google Scholar 

  23. Wang, W., Han, Y., Jo, H. A., Lee, J. & Song, Y. S. Non-coding RNAs shuttled via exosomes reshape the hypoxic tumor microenvironment. J. Hematol. Oncol. 13, 67 (2020).

    Article  Google Scholar 

  24. Han, X., Jiang, H., Qi, J., Li, J., Yang, J. & Tian, Y. et al. Novel lncRNA UPLA1 mediates tumorigenesis and prognosis in lung adenocarcinoma. Cell Death Dis. 11, 999 (2020).

    CAS  Article  Google Scholar 

  25. Song, S., Wang, Z., Li, Y., Ma, L., Jin, J. & Scott, A. W. et al. PPARdelta interacts with the hippo coactivator YAP1 to promote SOX9 expression and gastric cancer progression. Mol. Cancer Res. 18, 390–402 (2020).

    CAS  Article  Google Scholar 

  26. Li, D., Chai, L., Yu, X., Song, Y., Zhu, X. & Fan, S. et al. The HOTAIRM1/miR-107/TDG axis regulates papillary thyroid cancer cell proliferation and invasion. Cell Death Dis. 11, 227 (2020).

    CAS  Article  Google Scholar 

  27. Chao, H., Zhang, M., Hou, H., Zhang, Z. & Li, N. HOTAIRM1 suppresses cell proliferation and invasion in ovarian cancer through facilitating ARHGAP24 expression by sponging miR-106a-5p. Life Sci. 243, 117296 (2020).

    CAS  Article  Google Scholar 

  28. Ali Syeda Z, Langden SSS, Munkhzul C, Lee M, Song SJ. Regulatory mechanism of MicroRNA expression in cancer. Int. J. Mol. Sci. 21, 1723 (2020).

    Article  Google Scholar 

  29. Zhao, S., Xiao, X., Sun, S., Li, D., Wang, W. & Fu, Y. et al. MicroRNA-30d/JAG1 axis modulates pulmonary fibrosis through Notch signaling pathway. Pathol Res. Pract. 214, 1315–1323 (2018).

    CAS  Article  Google Scholar 

  30. Deng, Z., Fear, M. W., Suk Choi, Y., Wood, F. M., Allahham, A. & Mutsaers, S. E. et al. The extracellular matrix and mechanotransduction in pulmonary fibrosis. Int. J. Biochem. Cell Biol. 126, 105802 (2020).

    CAS  Article  Google Scholar 

  31. Kolahian, S., Fernandez, I. E., Eickelberg, O. & Hartl, D. Immune mechanisms in pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 55, 309–322 (2016).

    CAS  Article  Google Scholar 

Download references


This work is supported by Project of Sichuan Provincial Department of Science and Technology 2021YFS0373).

Author information

Authors and Affiliations



L.C., Y.Y., and R.Y. designed the study. X.P., H.Y., and X.H. collated the data, carried out data analyses and produced the initial draft of the manuscript. L.C. and Y.Y. contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

Corresponding author

Correspondence to XiaoBo Huang.

Ethics declarations

Competing interests

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links