Abstract

Background Bone morphogenetic protein-7 (BMP-7) antagonises transforming growth factor-β (TGF-β). This study investigated the ability of a prodrug BMP-7, designed as micelle nanoparticles for nasal inhalation, to ameliorate pulmonary fibrosis in a bleomycin (BLM)-induced murine model.

Materials and Methods Fluorescently labelled BMP-7 was delivered to murine lungs via nasal inhalation. Thirty-eight C57BL/6J mice were divided into three groups: control, BLM and BLM with prodrug BMP-7. We then administered the prodrug BMP-7 and vehicle nasally every 72 hours for 21 days. Single-cell RNA sequencing was performed on bronchoalveolar lavage fluid (BALF) from 18 mice, divided into four groups: control, prodrug BMP-7 alone, BLM and BLM with prodrug BMP-7, to assess effects on alveolar macrophages (AM). The expression of ApoE+ AM was compared between normal and idiopathic pulmonary fibrosis (IPF) patients.

Results The prodrug BMP-7 group showed reduced BALF inflammatory cells and significant fibrosis reduction compared to the BLM group. Western blot showed decreased levels of collagen I, α-SMA and fibronectin in the prodrug BMP-7 group, along with downregulation of TGF-β/SMAD signalling. ELISA indicated decreased levels of chemokines CXCL10 and CXCL2 in tissue and BALF. Single-cell RNA sequencing revealed a significant increase in bone marrow-derived ApoE+ AM in the BLM group, which was reduced with prodrug BMP-7. Additionally, ApoE+ expression was higher in IPF patients compared to controls.

Conclusions Prodrug BMP-7 shows potential as a therapeutic agent for pulmonary fibrosis by modulating ApoE+ AM.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This work was supported by grants from the National Research Foundation of Korea (NRF-2021R1A2C3003496, NRF-2022R1A2C3004609, NFR-2022M3A9G8016257) funded by the Korean government (MSIP).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Institutional Review Board of Severance Hospital gave ethical approval for this work.

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Footnotes

↵* Nam Eun Kim, Sue Bean cho, and Mi Hwa Shin are co-first authors.

Take home message: Novel micellised nanoparticle prodrug BMP-7, targeting alveolar macrophages, shows promising results in attenuating pulmonary fibrosis, signifying a potential breakthrough in regulating ApoE alveolar macrophage.

Data Availability

All data produced in the present study are available upon reasonable request to the authors

AbbreviationIPFidiopathic pulmonary fibrosisscRNA-seqsingle-cell RNA sequencingAECalveolar epithelial cellEMTepithelial mesenchymal transitionTGF-βtransforming growth factor βAMalveolar macrophagesIMinterstitial macrophagesApoEapolipoprotein EPTDprotein transduction domainICGindocyanine greenBMPbone morphogenic proteinsrhBMP-7recombinant BMP-7prodrug BMP-7micellised protein transduction domain bone morphogenic protein-7BLMbleomycinBALFbronchoalveolar lavage fluidBMMbone marrow-derived macrophagesResMresident macrophages