Interstitial lung disease accounts for a group of chronic and progressive disorders associated with severe pulmonary vascular remodeling, peripheral vascular rarefaction and fibrosis, thus limiting lung function. We have previously shown that Akt is necessary for myofibroblast differentiation, a critical event in organ fibrosis. However, the contributory role of the Akt-mTOR pathway in interstitial lung disease and the therapeutic benefits of targeting Akt and mTOR remain unclear.
Herein, we investigated the role of the Akt-mTOR pathway and its downstream molecular mechanisms in chronic hypoxia- and transforming growth factor β (TGFβ)-induced pulmonary vascular pruning and fibrosis in mice. We also determined the therapeutic benefits of the Akt inhibitor triciribine and the mTOR inhibitor rapamycin for the treatment of pulmonary fibrosis in mice.
Our results show that Akt1(-/-) mice are protected from chronic hypoxia-induced peripheral vascular pruning. In contrast, hyperactivation of Akt1 induced focal fibrosis similar to TGFβ-induced fibrosis. Pharmacological inhibition of Akt, but not the Akt substrate mTOR, inhibited hypoxia- and TGFβ-induced pulmonary vascular rarefaction and fibrosis. Mechanistically, we found that Akt1 modulates pulmonary remodeling via regulation of thrombospondin1 (TSP1) expression. Hypoxic Akt1(-/-) mice lungs expressed less TSP1. Moreover, TSP1(-/-) mice were resistant to adMyrAkt1-induced pulmonary fibrosis.
Our study identified Akt1 as a novel target for the treatment of interstitial lung disease and provides pre-clinical data on the potential benefits of the Akt inhibitor triciribine for the treatment of interstitial lung disease.