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.