Role of Akt in myofibroblast differentiation leading to pulmonary vascular remodeling and idiopathic pulmonary fibrosis
Abdalla, Maha Mahmoud
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Idiopathic pulmonary fibrosis (IPF) is an incurable, chronic and progressive lung disease with severely poor prognosis. The presence of pulmonary hypertension (PH) secondary to IPF is an independent risk factor for increased mortality. Alarmingly, there are no effective pharmacologic treatments for IPF, and lung transplantation remains the only effective option. Therefore, identification of novel therapeutic targets is critical in the hopes of devising new treatments. Persistent myofibroblasts (MFs) differentiation and excess extracellular matrix (ECM) accumulation are hallmark features of IPF. Recently, it has been shown that Akt is upregulated in IPF patients; however whether Akt is necessary for MFs remains unclear. This dissertation sought to 1) identify the role of Akt in MF differentiation leading to IPF, and 2) investigate the safety and efficacy of triciribine (TCBN), a selective Akt inhibitor, as a potential therapeutic option for IPF. The work presented in this thesis has been conducted using a combined approach of pharmacological, genetics, and functional assays. We first identified that Akt is a critical determinant of pathological MF differentiation and ECM expression as evident by loss and gain- of function studies, both in vitro and in vivo. Mechanistically, we found that Akt1 transcriptionally regulates αSMA synthesis, independent of mTOR. Furthermore, TCBN reversed TGFβ (pro-fibrotic cytokine) - and hypoxia-induced pulmonary fibrosis and vascular remodeling, compared to placebo and rapamycin. In contrast, rapamycin, which targets mTOR downstream of Akt, exacerbated fibrosis and vascular remodeling as evident by worsening interstitial fibrosis, micro-hemorrhage, and increased peripheral vascular rarefaction. Collectively, research efforts associated with this thesis 1) identified Akt as a novel target as it is crucial for MFs - central orchestrators of IPF; 2) determined novel anti-fibrotic and anti-remodeling properties of Triciribine; and 3) determined that rapamycin activates Akt via feedback mechanisms, which sheds light on the observed detrimental effects of everolimus, a rapamycin derivative, in IPF patients. In conclusion, our study is the first to determine the crucial role of Akt1 in IPF and associated vascular remodeling. Thus, selective Akt inhibition, not mTOR, may serve as a favorable therapeutic strategy in IPF.