Heat shock protein 70 protects against bleomycin-induced pulmonary fibrosis in mice

Ken Ichiro Tanaka, Yuta Tanaka, Takushi Namba, Arata Azuma, Tohru Mizushima

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Idiopathic pulmonary fibrosis (IPF) involves infiltration of leucocytes, pulmonary injury, fibrosis and resulting pulmonary dysfunction. Myofibroblasts and transforming growth factor (TGF)-β1 have been suggested to play a major role in the pathology and the myofibroblasts are derived from both lung epithelial cells through epithelial-mesenchymal transition (EMT) and activation of lung fibroblasts. Heat shock protein 70 (HSP70) confers protection against various stressors and has the anti-inflammatory activity. In this study, we examined the effect of expression of HSP70 on bleomycin-induced pulmonary fibrosis in mice, a tentative animal model of IPF. Bleomycin-induced pulmonary injury and inflammatory response were ameliorated in transgenic mice overexpressing HSP70 compared to wild-type mice, even though bleomycin-induced pulmonary fibrosis and dysfunction were also suppressed in the transgenic mice. The production of TGF-β1 and expression of pro-inflammatory cytokines was lower in cells from the transgenic mice than wild-type mice after the administration of bleomycin. In vitro, the suppression of HSP70 expression stimulated TGF-β1-induced EMT-like phenotypes of epithelial cells but did not affect the TGF-β1-dependent activation of fibroblasts. Orally administered geranylgeranylacetone (GGA), a clinically used drug with HSP-inducing activity, conferred protection against bleomycin-induced pulmonary injury, as well as against the inflammatory response, fibrosis and dysfunction. These results suggest that HSP70 plays a protective role against bleomycin-induced pulmonary injury, inflammation, fibrosis and dysfunction through cytoprotective effects and by inhibiting the production of TGF-β1, TGF-β1-dependent EMT of epithelial cells and expression of pro-inflammatory cytokines. Results also suggest that HSP70-inducing drugs, such as GGA, could be beneficial in the prophylaxis of IPF.

Original languageEnglish
Pages (from-to)920-931
Number of pages12
JournalBiochemical Pharmacology
Volume80
Issue number6
DOIs
Publication statusPublished - 2010 Sep
Externally publishedYes

Fingerprint

HSP70 Heat-Shock Proteins
Pulmonary Fibrosis
Bleomycin
Transforming Growth Factors
geranylgeranylacetone
Lung Injury
Idiopathic Pulmonary Fibrosis
Epithelial-Mesenchymal Transition
Transgenic Mice
Myofibroblasts
Epithelial Cells
Fibroblasts
Lung
Fibrosis
Chemical activation
Cytokines
Pathology
Infiltration
Pharmaceutical Preparations
Pneumonia

Keywords

  • Bleomycin
  • Epithelial-mesenchymal transition
  • Geranylgeranylacetone
  • Heat shock protein 70
  • Idiopathic pulmonary fibrosis
  • Transforming growth factor-β1

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

Heat shock protein 70 protects against bleomycin-induced pulmonary fibrosis in mice. / Tanaka, Ken Ichiro; Tanaka, Yuta; Namba, Takushi; Azuma, Arata; Mizushima, Tohru.

In: Biochemical Pharmacology, Vol. 80, No. 6, 09.2010, p. 920-931.

Research output: Contribution to journalArticle

Tanaka, Ken Ichiro ; Tanaka, Yuta ; Namba, Takushi ; Azuma, Arata ; Mizushima, Tohru. / Heat shock protein 70 protects against bleomycin-induced pulmonary fibrosis in mice. In: Biochemical Pharmacology. 2010 ; Vol. 80, No. 6. pp. 920-931.
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