Triciribine Therapy Halts Pulmonary Hypertension, Pulmonary Fibrosis Progression
In a recent study entitled “Akt inhibitor, triciribine, ameliorates chronic hypoxia-induced vascular pruning and TGFβ-induced pulmonary fibrosis,” researchers show that triciribine is a potential new treatment for interstitial lung disease, particularly pulmonary fibrosis and pulmonary hypertension. The study was published in the British Journal of Pharmacology.
Pulmonary fibrosis and pulmonary hypertension are two lung diseases characterized by lung tissue scarring and increased blood pressure in lung arteries, and are both associated with high mortality rates.
Previous studies highlighted the role of myofibroblasts (a specialized type of cell) that are associated with organ fibrosis — these cells travel to sites of injury to promote wound healing. Specifically, they contribute to the creation of the extracellular matrix, which is a complex structural entity surrounding and supporting cells that are found in mammalian tissues that are necessary for tissue recovery when it is damaged. However, when hyper activated, myofibroblasts can severely impair organ function by creating an unregulated extracellular matrix — this means that they start to synthesize and deposit excessive amounts of extracellular matrix material, which leads to fibrosis (too much scarring), which is characterized by excessive fibrous supporting tissue. Because of this, myofibroblasts are key players in scar formation and fibrosis in the lungs.
Following their previous results, researchers at University of Georgia showed that the protein Akt1 is involved in myofibroblast differentiation and the synthesis of the extracellular matrix. However, the molecular mechanism of how the pathway regulated by Akt1 actually promotes myofibroblast differentiation remains unknown.
In this new study, the team used mouse models that mimic the human features of the pulmonary hypertension and pulmonary fibrosis to investigate the role of Akt1 in these diseases. The team waited until mice developed the characteristic symptoms of pulmonary fibrosis and hypertension and treated each mouse model with a drug that inhibits Akt1, triciribine, once day for over three weeks. They observed that triciribine-treated mice showed fewer signs of fibrosis and loss of functional blood vessels in the lungs, which allowed lung tissue to recover faster. The team performed further studies and investigated disease development in mice “knocked-out” for Akt1, i.e., mice lacking Akt1 expression. They observed that, as in agreement with their drug-inhibitory effects, Akt1 knock-out mice were protected from disease. This means that the researchers discovered that Akt1 protein is the primary factor leading to the development of pulmonary fibrosis and hypertension. Thus, although preliminary, these results lay the foundation for future studies evaluating the role of triciribine’s efficacy in humans.
Somanath Shenoy, study co-author and associate professor in UGA’s College of Pharmacy commented, “The average life expectancy for people with these diseases is only about five years after diagnosis, and while the drug treatments we currently have may help improve quality of life, they don’t reduce mortality. Our tests show that treatment with triciribine can halt disease progression and may even reverse some of the damage to lung tissue. To our knowledge, this is the first direct evidence that Akt1 causes disease onset and progression of pulmonary fibrosis and pulmonary hypertension. We have also tested this process in human cells taken from diseased lung tissue, and we see very similar results. We still need to identify the downstream effects of Akt1 inhibition to see if there are any negative side effects. But if these tests go well, we hope to begin human trials within the next three to five years.”
Therefore, the team hypothesises that in the future inhibiting the expression of Akt1 protein will prevent or inhibit fibrosis in lung tissue of patients and therefore reduce the mortality associated with the fibrosis tissue buildup in patients’ lungs.