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Background <p>Idiopathic pulmonary fibrosis (IPF) is a heterogeneous disease caused by an interplay of genetic and environmental factors. Biomarkers that reflect the progression of fibrosis are required for the management of IPF.</p> Methods <p>We extracted serum extracellular vesicles from a discovery cohort (127 IPF patients and 34 controls) and a validation cohort (20 IPF patients and 22 controls). Non-targeted proteomic analysis was performed by a data-independent acquisition method. We investigated the proteomic profiles in relation to multiple clinical parameters associated with IPF. To further evaluate the biological relevance of the identified biomarkers, we analyzed publicly available single-cell RNA sequencing datasets of lung tissue and conducted immunochemical validation using our collected lung samples.</p> Results <p>We obtained 2420 protein profiles in serum extracellular vesicles and identified 19 IPF-associated proteins; their expressions were significantly lung-specific. Protein module analyses revealed that the upstream components of the complement system were increased in IPF. These IPF-associated proteins were involved in various IPF-associated genes and heterogeneously increased in IPF patients. Notably, surfactant protein B (SFTPB) not only showed superior diagnostic performance over the existing marker but was also significantly associated with progressive disease activity, such as the extent of fibrosis and decline in lung function. Furthermore, single-cell RNA-sequencing analysis revealed that SFTPB was associated with the TGF-β/SMAD pathway in <i>SCGB3A2</i> + cells in IPF lungs. SFTPB expression in <i>SCGB3A2</i> + cells was confirmed by immunostaining.</p> Conclusions <p>Serum extracellular vesicles could capture heterogenetic fibrotic profiles in IPF, and SFTPB can be a promising biomarker reflecting the disease activity.</p>

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Serum vesicle biomarkers reflect the disease activity of idiopathic pulmonary fibrosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月15日

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  • Yuya Shirai,
  • Takatoshi Enomoto,
  • Yoshito Takeda,
  • Ryuya Edahiro,
  • Miho Takahashi-Itoh,
  • Yoshimi Noda,
  • Yuichi Adachi,
  • Mana Nakayama,
  • Takahiro Kawasaki,
  • Taro Koba,
  • Yu Futami,
  • Hanako Yoshimura,
  • Saori Amiya,
  • Reina Hara,
  • Makoto Yamamoto,
  • Daisuke Nakatsubo,
  • Yasuhiko Suga,
  • Maiko Naito,
  • Kentaro Masuhiro,
  • Takanori Matsuki,
  • Haruhiko Hirata,
  • Kota Iwahori,
  • Izumi Nagatomo,
  • Kotaro Miyake,
  • Shohei Koyama,
  • Kiyoharu Fukushima,
  • Takayuki Shiroyama,
  • Yujiro Naito,
  • Shinji Futami,
  • Yayoi Natsume-Kitatani,
  • Naoko Ose,
  • Soichiro Funaki,
  • Satoshi Nojima,
  • Shigeyuki Shichino,
  • Masahiro Yanagawa,
  • Yasushi Shintani,
  • Mari Nogami-Itoh,
  • Jun Adachi,
  • Yoshikazu Inoue,
  • Takeshi Tomonaga,
  • Yukinori Okada,
  • Kenji Mizuguchi,
  • Atsushi Kumanogoh

摘要

Background

Idiopathic pulmonary fibrosis (IPF) is a heterogeneous disease caused by an interplay of genetic and environmental factors. Biomarkers that reflect the progression of fibrosis are required for the management of IPF.

Methods

We extracted serum extracellular vesicles from a discovery cohort (127 IPF patients and 34 controls) and a validation cohort (20 IPF patients and 22 controls). Non-targeted proteomic analysis was performed by a data-independent acquisition method. We investigated the proteomic profiles in relation to multiple clinical parameters associated with IPF. To further evaluate the biological relevance of the identified biomarkers, we analyzed publicly available single-cell RNA sequencing datasets of lung tissue and conducted immunochemical validation using our collected lung samples.

Results

We obtained 2420 protein profiles in serum extracellular vesicles and identified 19 IPF-associated proteins; their expressions were significantly lung-specific. Protein module analyses revealed that the upstream components of the complement system were increased in IPF. These IPF-associated proteins were involved in various IPF-associated genes and heterogeneously increased in IPF patients. Notably, surfactant protein B (SFTPB) not only showed superior diagnostic performance over the existing marker but was also significantly associated with progressive disease activity, such as the extent of fibrosis and decline in lung function. Furthermore, single-cell RNA-sequencing analysis revealed that SFTPB was associated with the TGF-β/SMAD pathway in SCGB3A2 + cells in IPF lungs. SFTPB expression in SCGB3A2 + cells was confirmed by immunostaining.

Conclusions

Serum extracellular vesicles could capture heterogenetic fibrotic profiles in IPF, and SFTPB can be a promising biomarker reflecting the disease activity.