Abstract
Pre-treatment with hsp90 inhibitors reduces the magnitude of LPS-induced ALI in mice. Because the most frequent use of any intervention would be after the onset of ALI/ARDS, we now tested the hypotheses that post-treatment with hsp90 inhibitors would also reduce the magnitude of LPS-induced ALI and would decrease hsp90 activation as reflected in hsp90 Y phosphorylation. 24h after the intratracheal instillation of vehicle or LPS (1.5mg/kg), mice were given either vehicle or the hsp90 inhibitor, AUY-922 ; i.p. 10mg/kg. 48h later, lung tissue was collected. LPS, but neither vehicle nor AUY-922, alone, increased 9-fold hsp90 Y phosphorylation, as detected in immunoprecipitation/immunoblotting experiments; when post-treated with AUY-922, hsp90 phosphorylation was significantly and dramatically reduced to near control levels. Furthermore, LPS produced a profound inflammatory response, characterized by an increase in alveolar septal thickness, hemorrhage and cellular infiltration, reflected in lung sections stained with H&E, as well as by neutrophil accumulation and capillary plugging, revealed immunocytochemically with anti-MPO (myleoperoxidase, an enzyme marker of granulocytes) antibody; inflammation was remarkably reduced in mice post-treated with auyAUY-922. Collectively these data reveal important reparative actions of hsp90 inhibitors when administered after the LPS insult and suggest that prevention of post-translational modifications of hsp90 may be an important therapeutic mechanism. Supported by NHLBI grants HL101902 and HL093460.
- © 2013 ERS