FOXF1 protein suppresses pulmonary fibrosis
The FOXF1 gene suppresses pulmonary fibrosis (scarring of the lungs), according to a study by researchers from the Perinatal Institute of Cincinnati Children's Hospital Research Foundation. Therefore, FOXF1 and related pathways could be targeted to combat idiopathic pulmonary fibrosis (IPF), the most common and lethal interstitial lung disease.
IPF is characterized by aberrant accumulation of collagen-secreting myofibroblasts resulting in a progressive and irreversible decline in lung function. The molecular mechanisms regulating myofibroblast expansion has not been fully understood, hindering the development of effective therapies. Any disease that is of uncertain or unknown origin may be termed idiopathic. What causes IPF remains unknown and the clinical course of the disease can be unpredictable. Patients with IPF may experience shortness of breath, a dry cough, tiredness, and more severe complications such as pulmonary hypertension, heart failure, pneumonia, and pulmonary embolism. The median survival rate is only about 3 years after diagnosis. Thus, novel therapeutic approaches are much needed.
The FOXF1 gene codes for the forkhead box F1 (FOXF1) protein
, which is a transcription factor that controls the activity of many other genes. FOXF1 is involved in the development of pulmonary mesenchyme. Although previous studies establish FOXF1 as a crucial regulator during organ development and acute injury, the role of FOXF1 in lung diseases still remains a mystery. This is in part due to the lack of suitable mouse models.
In this work, the researchers analyzed human IPF genomics data, human IPF and normal lung tissues, and transgenic mice with myofibroblast-specific deletion of FOXF1. They found that FOXF1 inhibits pulmonary fibrosis. FOXF1 expression was decreased in human IPF lung fibroblasts and in mouse fibroblasts during bleomycin-induced pulmonary fibrosis. Mouse experiments revealed that loss of FOXF1 exacerbated bleomycin-induced pulmonary fibrosis, collagen deposition, invasion of lung myofibroblasts, and pulmonary inflammation. Mechanically, FOXF1 directly binds to CDH2 and CDH11 promoters and differentially regulates transcription of these genes. In vitro experiments showed that re-expression of CDH2 or inhibition of CDH11 in FOXF1-deficient cells reduces myofibroblast invasion.
These data suggest FOXF1 as an anti-fibrotic factor that regulates key myofibroblast functions driving fibrogenesis. So boosting FOXF1 in IPF might have therapeutic effects. The researchers have published their findings in a paper titled "FOXF1 Inhibits Pulmonary Fibrosis by Preventing CDH2-CDH11 Cadherin Switch in Myofibroblasts" in the April 10, 2018 issue of the journal Cell Reports.
According to senior author of the study Dr. Tanya Kalin, they'll conduct further experiments to assess the effect of increasing FOXF1 expression in lung tissues.
Globally, there are about five million people living with pulmonary fibrosis. The incidence of IPF increases significantly after the age of fifty. Since what causes IPF remains unknown, current treatment for the disease is not effective enough and patient prognosis is quite poor. The new study suggests targeting FOXF1 as a therapeutic strategy to combat IPF, although it requires many experiments before the strategy can be moved to clinical trials.