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Deficiency of HtrA3 Attenuates Bleomycin-Induced Pulmonary Fibrosis Via TGF-β1/Smad Signaling Pathway

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Abstract

Purpose

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by excessive extracellular matrix deposition. No effective treatments are currently available for IPF. High-temperature requirement A3 (HtrA3) suppresses tumor development by antagonizing transforming growth factor β (TGF-β) signaling; however, little is known about the role of HtrA3 in IPF. This study investigated the role of HtrA3 in IPF and underlying mechanisms.

Methods

Lung tissues were collected from patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis, and HtrA3 expression was measured in tissue samples. Then, HtrA3 gene knockout mice were treated with BLM to induce pulmonary fibrosis and explore the effects and underlying mechanism of HtrA3 on pulmonary fibrosis.

Results

HtrA3 was up-regulated in the lung tissues of patients with IPF and the pulmonary fibrotic mouse model compared to corresponding control groups. HtrA3 knockout decreased pulmonary fibrosis-related protein expression, alleviated the symptoms of pulmonary fibrosis, and inhibited epithelial-mesenchymal transition (EMT) in BLM-induced lung tissue compared with BLM-induced wild-type mice. The TGF-β1/Smad signaling pathway was activated in fibrotic lung tissue, whereas HtrA3 knockout inhibited this pathway.

Conclusion

The expression level of HtrA3 is increased in fibrotic lungs. HtrA3 knockout alleviates the symptoms of pulmonary fibrosis probably via the TGF-β1/Smad signaling pathway. Therefore, HtrA3 inhibition is a potential therapeutic target for pulmonary fibrosis.

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Data Availability

The analyzed data sets generated during the present study are available from the corresponding author on reasonable request.

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Funding

This present study was supported by the Natural Science Foundation of Jiangsu Province (No. BK20190150), the National Natural Science Foundation of China (No.82070059).

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Authors and Affiliations

  1. Wuxi Laboratory of Organ Transplantation, The Affiliated Wuxi People’s Hospital of Nan**g Medical University, No. 299 QingYang Road, Wuxi, 214023, Jiangsu, People’s Republic of China

    Guirong Li, Chenyou Shen, Xusheng Yang, Cheng Jiang, Jianxin Tan & **gyu Chen

  2. Center of Clinical Research, The Affiliated Wuxi People’s Hospital of Nan**g Medical University, No. 299 QingYang Road, Wuxi, 214023, Jiangsu, People’s Republic of China

    Guirong Li & Jian Zou

  3. Wuxi Lung Transplantation Center, The Affiliated Wuxi People’s Hospital of Nan**g Medical University, No. 299 QingYang Road, Wuxi, 214023, Jiangsu, People’s Republic of China

    Dong Wei, **ucheng Yang & **gyu Chen

  4. Department of Cardiothoracic Surgery, The Affiliated Wuxi People’s Hospital of Nan**g Medical University, No. 299 QingYang Road, Wuxi, 214023, Jiangsu, People’s Republic of China

    Wenjun Mao

Authors
  1. Guirong Li
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  3. Dong Wei
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  10. **gyu Chen
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Contributions

GL: designed the study, analyzed the data and wrote the manuscript. GL, DW and CS: acquired and analyzed data. DW, XCY and WM: collected clinical samples and performed clinical experiments. XSY, CJ and JT: performed animal experiments. JZ: analyzed the data and helped to write the paper. GL and JC: provided the financial support for this work. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Guirong Li or **gyu Chen.

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Competing interests

The authors declare no competing interests.

Ethical Approval

The study was approved by the Ethics Committee for the Use of Human Samples of Nan**g Medical University in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. All participants gave written informed consent.

Research Involving Human and Animal Participants

All animal experiments were approved by the Institutional Animal Care and Use Committee of Nan**g Medical University.

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Li, G., Shen, C., Wei, D. et al. Deficiency of HtrA3 Attenuates Bleomycin-Induced Pulmonary Fibrosis Via TGF-β1/Smad Signaling Pathway. Lung 201, 235–242 (2023). https://doi.org/10.1007/s00408-023-00608-8

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