Qualitative rather than quantitative changes are hallmarks of fibroblasts in bleomycin-induced pulmonary fibrosis

Tatsuya Tsukui, Satoshi Ueha, Jun Abe, Shin Ichi Hashimoto, Shigeyuki Shichino, Takeshi Shimaoka, Francis H W Shand, Yasuka Arakawa, Kenshiro Oshima, Masahira Hattori, Yutaka Inagaki, Michio Tomura, Kouji Matsushima

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Pulmonary fibrosis is characterized by accumulation of activated fibroblasts that produce excessive amounts of extracellular matrix components such as collagen type I. However, the dynamics and activation signatures of fibroblasts during fibrogenesis remain poorly understood, especially in vivo. We examined changes in lung tissue cell populations and in the phenotype of activated fibroblasts after acute injury in a model of bleomycin-induced pulmonary fibrosis. Despite clustering of collagen type I-producing fibroblasts in fibrotic regions, flow cytometry-based quantitative analysis of whole lungs revealed that the number of fibroblasts in the lungs remained constant. At the peak of inflammation, fibroblast proliferation and apoptosis were both increased, suggesting that the clustering was not merely a result of proliferation, but also of fibroblast migration from nearby alveolar walls. Parabiosis experiments demonstrated that fibroblasts were not supplied from the circulation. Comprehensive gene expression analysis of freshly isolated fibroblasts revealed a detailed activation signature associated with fibrogenesis, including changes in genes responsible for migration and extracellular matrix construction. The Spp1 gene, which encodes osteopontin, was highly up-regulated and was an identifying characteristic of activated fibroblasts present at the sites of remodeling. Osteopontin may serve as a useful marker of profibrotic fibroblasts. These results provide insights into the cellular and molecular mechanisms underlying pulmonary fibrosis and provide a foundation for development of specific antifibrotic therapies.

Original languageEnglish
Pages (from-to)758-773
Number of pages16
JournalAmerican Journal of Pathology
Volume183
Issue number3
DOIs
Publication statusPublished - 2013 Sep
Externally publishedYes

Fingerprint

Pulmonary Fibrosis
Fibroblasts
Osteopontin
Collagen Type I
Lung
Extracellular Matrix
Cluster Analysis
indium-bleomycin
Parabiosis
Bleomycin
Genes
Flow Cytometry
Apoptosis
Inflammation
Phenotype
Gene Expression

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Tsukui, T., Ueha, S., Abe, J., Hashimoto, S. I., Shichino, S., Shimaoka, T., ... Matsushima, K. (2013). Qualitative rather than quantitative changes are hallmarks of fibroblasts in bleomycin-induced pulmonary fibrosis. American Journal of Pathology, 183(3), 758-773. https://doi.org/10.1016/j.ajpath.2013.06.005

Qualitative rather than quantitative changes are hallmarks of fibroblasts in bleomycin-induced pulmonary fibrosis. / Tsukui, Tatsuya; Ueha, Satoshi; Abe, Jun; Hashimoto, Shin Ichi; Shichino, Shigeyuki; Shimaoka, Takeshi; Shand, Francis H W; Arakawa, Yasuka; Oshima, Kenshiro; Hattori, Masahira; Inagaki, Yutaka; Tomura, Michio; Matsushima, Kouji.

In: American Journal of Pathology, Vol. 183, No. 3, 09.2013, p. 758-773.

Research output: Contribution to journalArticle

Tsukui, T, Ueha, S, Abe, J, Hashimoto, SI, Shichino, S, Shimaoka, T, Shand, FHW, Arakawa, Y, Oshima, K, Hattori, M, Inagaki, Y, Tomura, M & Matsushima, K 2013, 'Qualitative rather than quantitative changes are hallmarks of fibroblasts in bleomycin-induced pulmonary fibrosis', American Journal of Pathology, vol. 183, no. 3, pp. 758-773. https://doi.org/10.1016/j.ajpath.2013.06.005
Tsukui, Tatsuya ; Ueha, Satoshi ; Abe, Jun ; Hashimoto, Shin Ichi ; Shichino, Shigeyuki ; Shimaoka, Takeshi ; Shand, Francis H W ; Arakawa, Yasuka ; Oshima, Kenshiro ; Hattori, Masahira ; Inagaki, Yutaka ; Tomura, Michio ; Matsushima, Kouji. / Qualitative rather than quantitative changes are hallmarks of fibroblasts in bleomycin-induced pulmonary fibrosis. In: American Journal of Pathology. 2013 ; Vol. 183, No. 3. pp. 758-773.
@article{63f86cec699444a8bdfc111bdd41ffd1,
title = "Qualitative rather than quantitative changes are hallmarks of fibroblasts in bleomycin-induced pulmonary fibrosis",
abstract = "Pulmonary fibrosis is characterized by accumulation of activated fibroblasts that produce excessive amounts of extracellular matrix components such as collagen type I. However, the dynamics and activation signatures of fibroblasts during fibrogenesis remain poorly understood, especially in vivo. We examined changes in lung tissue cell populations and in the phenotype of activated fibroblasts after acute injury in a model of bleomycin-induced pulmonary fibrosis. Despite clustering of collagen type I-producing fibroblasts in fibrotic regions, flow cytometry-based quantitative analysis of whole lungs revealed that the number of fibroblasts in the lungs remained constant. At the peak of inflammation, fibroblast proliferation and apoptosis were both increased, suggesting that the clustering was not merely a result of proliferation, but also of fibroblast migration from nearby alveolar walls. Parabiosis experiments demonstrated that fibroblasts were not supplied from the circulation. Comprehensive gene expression analysis of freshly isolated fibroblasts revealed a detailed activation signature associated with fibrogenesis, including changes in genes responsible for migration and extracellular matrix construction. The Spp1 gene, which encodes osteopontin, was highly up-regulated and was an identifying characteristic of activated fibroblasts present at the sites of remodeling. Osteopontin may serve as a useful marker of profibrotic fibroblasts. These results provide insights into the cellular and molecular mechanisms underlying pulmonary fibrosis and provide a foundation for development of specific antifibrotic therapies.",
author = "Tatsuya Tsukui and Satoshi Ueha and Jun Abe and Hashimoto, {Shin Ichi} and Shigeyuki Shichino and Takeshi Shimaoka and Shand, {Francis H W} and Yasuka Arakawa and Kenshiro Oshima and Masahira Hattori and Yutaka Inagaki and Michio Tomura and Kouji Matsushima",
year = "2013",
month = "9",
doi = "10.1016/j.ajpath.2013.06.005",
language = "English",
volume = "183",
pages = "758--773",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - Qualitative rather than quantitative changes are hallmarks of fibroblasts in bleomycin-induced pulmonary fibrosis

AU - Tsukui, Tatsuya

AU - Ueha, Satoshi

AU - Abe, Jun

AU - Hashimoto, Shin Ichi

AU - Shichino, Shigeyuki

AU - Shimaoka, Takeshi

AU - Shand, Francis H W

AU - Arakawa, Yasuka

AU - Oshima, Kenshiro

AU - Hattori, Masahira

AU - Inagaki, Yutaka

AU - Tomura, Michio

AU - Matsushima, Kouji

PY - 2013/9

Y1 - 2013/9

N2 - Pulmonary fibrosis is characterized by accumulation of activated fibroblasts that produce excessive amounts of extracellular matrix components such as collagen type I. However, the dynamics and activation signatures of fibroblasts during fibrogenesis remain poorly understood, especially in vivo. We examined changes in lung tissue cell populations and in the phenotype of activated fibroblasts after acute injury in a model of bleomycin-induced pulmonary fibrosis. Despite clustering of collagen type I-producing fibroblasts in fibrotic regions, flow cytometry-based quantitative analysis of whole lungs revealed that the number of fibroblasts in the lungs remained constant. At the peak of inflammation, fibroblast proliferation and apoptosis were both increased, suggesting that the clustering was not merely a result of proliferation, but also of fibroblast migration from nearby alveolar walls. Parabiosis experiments demonstrated that fibroblasts were not supplied from the circulation. Comprehensive gene expression analysis of freshly isolated fibroblasts revealed a detailed activation signature associated with fibrogenesis, including changes in genes responsible for migration and extracellular matrix construction. The Spp1 gene, which encodes osteopontin, was highly up-regulated and was an identifying characteristic of activated fibroblasts present at the sites of remodeling. Osteopontin may serve as a useful marker of profibrotic fibroblasts. These results provide insights into the cellular and molecular mechanisms underlying pulmonary fibrosis and provide a foundation for development of specific antifibrotic therapies.

AB - Pulmonary fibrosis is characterized by accumulation of activated fibroblasts that produce excessive amounts of extracellular matrix components such as collagen type I. However, the dynamics and activation signatures of fibroblasts during fibrogenesis remain poorly understood, especially in vivo. We examined changes in lung tissue cell populations and in the phenotype of activated fibroblasts after acute injury in a model of bleomycin-induced pulmonary fibrosis. Despite clustering of collagen type I-producing fibroblasts in fibrotic regions, flow cytometry-based quantitative analysis of whole lungs revealed that the number of fibroblasts in the lungs remained constant. At the peak of inflammation, fibroblast proliferation and apoptosis were both increased, suggesting that the clustering was not merely a result of proliferation, but also of fibroblast migration from nearby alveolar walls. Parabiosis experiments demonstrated that fibroblasts were not supplied from the circulation. Comprehensive gene expression analysis of freshly isolated fibroblasts revealed a detailed activation signature associated with fibrogenesis, including changes in genes responsible for migration and extracellular matrix construction. The Spp1 gene, which encodes osteopontin, was highly up-regulated and was an identifying characteristic of activated fibroblasts present at the sites of remodeling. Osteopontin may serve as a useful marker of profibrotic fibroblasts. These results provide insights into the cellular and molecular mechanisms underlying pulmonary fibrosis and provide a foundation for development of specific antifibrotic therapies.

UR - http://www.scopus.com/inward/record.url?scp=84883155635&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84883155635&partnerID=8YFLogxK

U2 - 10.1016/j.ajpath.2013.06.005

DO - 10.1016/j.ajpath.2013.06.005

M3 - Article

C2 - 23886891

AN - SCOPUS:84883155635

VL - 183

SP - 758

EP - 773

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 3

ER -