Protective effect of geranylgeranylacetone, an inducer of heat shock protein 70, against drug-induced lung injury/fibrosis in an animal model.
BACKGROUND
To determine whether oral administration of geranylgeranylacetone (GGA), a nontoxic anti-ulcer drug that is an inducer of heat shock protein (HSP) 70, protects against drug-induced lung injury/fibrosis in vivo.


METHODS
We used a bleomycin (BLM)-induced lung fibrosis model in which mice were treated with oral 600 mg/kg of GGA before and after BLM administration. Inflammation and fibrosis were evaluated by histological scoring, hydroxyproline content in the lung and inflammatory cell count, and quantification by ELISA of macrophage inflammatory protein-2 (MIP-2) in bronchoalveolar lavage fluid. Apoptosis was evaluated by the TUNEL method. The induction of HSP70 in the lung was examined with western blot analysis and its localization was determined by immunohistochemistry.


RESULTS
We confirmed the presence of inflammation and fibrosis in the BLM-induced lung injury model and induction of HSP70 by oral administration of GGA. GGA prevented apoptosis of cellular constituents of lung tissue, such as epithelial cells, most likely related to the de novo induction of HSP70 in the lungs. GGA-treated mice also showed less fibrosis of the lungs, associated with the findings of suppression of both production of MIP-2 and inflammatory cell accumulation in the injured lung, compared with vehicle-treated mice.


CONCLUSIONS
GGA had a protective effect on drug-induced lung injury/fibrosis. Disease-modifying antirheumatic drugs such as methotrexate, which are indispensable for the treatment of rheumatoid arthritis, often cause interstitial lung diseases, an adverse event that currently cannot be prevented. Clinical use of GGA for drug-induced pulmonary fibrosis might be considered in the future.
Fujibayashi
Takayoshi
T
Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan. takafuji@med.nagoya-u.ac.jp
Hashimoto
Naozumi
N
Jijiwa
Mayumi
M
Hasegawa
Yoshinori
Y
Kojima
Toshihisa
T
Ishiguro
Naoki
N
D000284:Administration, Oral; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D001761:Bleomycin / Q000009:adverse effects; D001992:Bronchoalveolar Lavage Fluid; D054426:Chemokine CXCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D004224:Diterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006909:Hydroxyproline / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*
D000897:Anti-Ulcer Agents; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D004224:Diterpenes; D018840:HSP70 Heat-Shock Proteins; D001761:Bleomycin; D006909:Hydroxyproline; C031049:geranylgeranylacetone