A new study led by researchers at the Comprehensive Pneumology Center (CPC) at Helmholtz Zentrum Munich in Germany recently revealed a new mechanism that contributes to the development of idiopathic pulmonary fibrosis (IPF). The study is entitled “Regulation of 26S Proteasome Activity in Pulmonary Fibrosis” and was published in the American Journal of Respiratory and Critical Care Medicine.
IPF is an aggressive and fatal lung disease of unknown origin in which the alveoli and the lung tissue are damaged, becoming thick and scarred (fibrosis), leading to severe breathing difficulties and a compromised oxygen transfer between the lungs and the bloodstream. The disorder is characterized by a shortness of breath that gradually worsens, with respiratory failure being the main cause of death. There is no cure for IPF and it is estimated that almost 130,000 individuals in the United States and 5 million worldwide suffer from the disease. IPF has a particularly poor prognosis and around two-thirds of the patients die within five years after being diagnosed.
A massive accumulation of connective and scar tissue can be observed in the lungs of IPF patients. The connective tissue is primarily produced by cells called myofibroblasts, which are involved in tissue repair. Upon pathological tissue remodeling, as is the case on IPF, the cell and protein homeostasis can be altered. One important system for the maintenance of protein homeostasis is the proteasome, a protein complex responsible for the degradation and turnover of proteins that are old, no longer needed or defective, in a tightly regulated manner.
In the study, researchers hypothesized that the proteasome is dysregulated upon fibrotic lung remodeling contributing to IPF pathogenesis. To test their hypothesis, the team treated lung fibroblasts with TGF-beta to induce myofibroblast differentiation and investigated proteasome activity. Apart from lung cells, researchers also tested mouse models of lung fibrosis and human IPF.
Researchers found that myofibroblast differentiation is accompanied by the activation of the cytosolic 26S proteasome, the most exclusive system present in mammals which is dependent on the regulatory subunit Rpn6. Myofibroblasts in the lungs of IPF patients were reported to over-express Rpn6. Researchers depleted Rpn6 in human lung fibroblasts and found that it inhibited the activity of the 26S proteasome and suppressed fibroblasts differentiation into pathological myofibroblasts.
The study’s senior author Dr. Silke Meiners explained the team’s findings in a news release, “we were able to show that targeted inhibition of the 26S proteasome prevents the differentiation of primary human lung fibroblasts into myofibroblasts, confirming the essential role of enhanced proteasomal protein degradation for this pathological process,”
The research team concluded that myofibroblast differentiation in lung tissue both in vitro and in vivo is linked to the activation of the 26S proteasome and subsequent increase in protein degradation. The team suggests that the proteasome most likely plays an important role in IPF pathogenesis, and that the specific inhibition of the 26S proteasome might represent a novel therapeutic approach for IPF and potentially also to other fibrotic disorders, like heart and kidney fibrosis.
“Understanding the mechanisms that lead to a disease such as IPF helps us identify innovative approaches that allow therapeutic intervention,” concluded the study’s co-author and Scientific Director of the CPC, Dr. Oliver Eickelberg. The team’s next goal is to test the therapeutic value of specific 26S proteasome inhibitors.