title: The Akt inhibitor, triciribine, ameliorates chronic hypoxia-induced vascular pruning and TGFβ-induced pulmonary fibrosis.
abstract: OBJECTIVE
  Interstitial lung disease accounts for a group of chronic and progressive disorders associated with severe pulmonary vascular remodelling, 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.
  
  
  METHODS
  We investigated the role of the Akt-mTOR pathway and its downstream molecular mechanisms in chronic hypoxia- and 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.
  
  
  RESULTS
  Akt1(-) (/) (-) mice were 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 remodelling via regulation of thrombospondin1 (TSP1) expression. Hypoxic Akt1(-) (/) (-) mice lungs expressed less TSP1. Moreover, TSP1(-) (/) (-) mice were resistant to adMyrAkt1-induced pulmonary fibrosis.
  
  
  CONCLUSIONS
  Our study identified Akt1 as a novel target for the treatment of interstitial lung disease and provides preclinical data on the potential benefits of the Akt inhibitor triciribine for the treatment of interstitial lung disease.
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA, USA.|Department of Pharmaceutical Sciences, South College School of Pharmacy, Knoxville, TN, USA.
authors.forename: Maha
authors.initials: M
authors.lastname: Abdalla
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Harika
authors.initials: H
authors.lastname: Sabbineni
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Roshini
authors.initials: R
authors.lastname: Prakash
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA, USA.|Department of Physiology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Adviye
authors.initials: A
authors.lastname: Ergul
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA, USA.|Department of Neurology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Fagan
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA, USA.|Department of Medicine, Georgia Regents University, Augusta, GA, USA.|Vascular Biology Center, Georgia Regents University, Augusta, GA, USA.|Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Payaningal R
authors.initials: PR
authors.lastname: Somanath
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D012263:Ribonucleosides / Q000494:pharmacology* / Q000627:therapeutic use*; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta
chemical_list: D012263:Ribonucleosides; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; C585483:Thbs1 protein, mouse; C023764:triciribine; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt