Researchers have found that fibrosis in the lung can be controlled via levels of FOXO3. This dovetails nicely with recent evidence for increased levels of cellular senescence to be a cause of lung fibrosis, as loss of FOXO3 triggers greater senescence in cell populations. This relationship might explain the observed associations of FOXO3 with longevity, though these are not as large as one might expect if it did have a strong effect on senescence. Other FOXO proteins also play a role in the determination of senescence versus self-destruction in cells that are damaged or have reached the end of their replicative life span, as demonstrated by the use of FOXO4-DRI as a senolytic compound that can trigger senescent cell apoptosis. All of this is interesting, but probably somewhat secondary to the goal of destroying senescent cells - it seems likely that FOXO3 is either moderating the bad behavior of senescent cells, preventing their influence from generating fibrosis, or perhaps preventing new cells from becoming senescent without much affecting existing senescent cells.
Idiopathic pulmonary fibrosis is currently an incurable lung disease, in which sufferers lose the ability to absorb adequate oxygen. Although the word 'idiopathic' means that the cause is unknown, the disease primarily affects former and active heavy smokers from the age of 50. An important role in idiopathic pulmonary fibrosis is played by connective tissue cells called fibroblasts. These cells provide structure to the air sacs (alveoli) in the lungs. During development of the disease, characteristic changes to these fibroblasts are observed. "The fibroblasts undergo a kind of personality change. In patients with pulmonary fibrosis, these cells contain increased amounts of contractile proteins, like those involved in muscle cell function." These modified cells, known as myofibroblasts, are responsible for the changes in connective tissue structure. As the disease progresses, the air sacs increasingly degenerate, resulting in damage to the blood vessels in the lungs. This results in shortness of breath.
Researchers decided to look for a factor which might be responsible for the fibroblast changes. Such a factor could hold the key to a possible treatment. The team first compared connective tissue cells from healthy individuals and patients with pulmonary fibrosis. "We noticed a transcription factor called FoxO3. Cells from patients with pulmonary fibrosis contained less of this protein than cells from healthy controls. The results were even clearer once we looked at FoxO3 activity - it was much lower in fibroblasts from patients with pulmonary fibrosis than in cells from healthy people." The researchers then turned their attention to animal research and develped a mouse model of the disease. They found that mice with pulmonary fibrosis also had reduced FoxO3 activity. The effect was much greater in mice which had been genetically modified to lack FoxO3.
Reactivating FoxO3 in patients with pulmonary fibrosis might, therefore, offer a way of treating the disease. This approach proved successful in mice: treating mice with pulmonary fibrosis with UCN-01 resulted in a reduction in symptoms and improved lung function. This effect was not observed in mice that lacked FoxO3. UCN-01 is a substance which activates FoxO3 and is currently undergoing clinical trials as a tumour therapy. Further studies will examine this link more closely, in the hope of eventually being able to start trials on patients.