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

Abstract：

:Idiopathic pulmonary fibrosis (IPF) involves infiltration of leucocytes, pulmonary injury, fibrosis and resulting pulmonary dysfunction. Myofibroblasts and transforming growth factor (TGF)-beta1 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-beta1 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-beta1-induced EMT-like phenotypes of epithelial cells but did not affect the TGF-beta1-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-beta1, TGF-beta1-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.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Tanaka K,Tanaka Y,Namba T,Azuma A,Mizushima T

doi

10.1016/j.bcp.2010.05.025

subject

Has Abstract

pub_date

2010-09-15 00:00:00

pages

920-31

issue

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(10)00389-8

journal_volume

pub_type

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