In a recent study published in the American Journal of Respiratory and Critical Care Medicine, a team of researchers from the Helmholtz Zentrum München was able to identify a novel mechanism that contributes to the development of idiopathic pulmonary fibrosis (IPF). In their study titled “Regulation of 26S Proteasome Activity in Pulmonary Fibrosis,” the researchers demonstrate that an increase in protein turnover by the central protein degradation machinery of the cell — the proteasome, — is associated with changes in lung tissue.

Idiopathic pulmonary fibrosis occurs when lung tissue becomes damaged and scarred. This thickened, stiff tissue makes it more difficult for the lungs to work properly. As pulmonary fibrosis worsens, patients become progressively more short of breath. The scarring associated with pulmonary fibrosis can be caused by a multitude of factors. But in most cases, clinicians cannot pinpoint what is causing the problem. When a cause cannot be found, the condition is termed idiopathic pulmonary fibrosis.

Myofibroblasts are cells responsible for the production of the connective tissue. In the study, the researchers discovered that the activation of myofibroblasts in the lung is dependent on an increase in protein turnover by the 26S proteasome. Using both in vitro and in vivo models of pulmonary fibrosis, the researchers determined that an activation of the 26S proteasome during the transformation of normal fibroblasts into myofibroblasts. In the fibrotic lung tissue of patients with IPF, the researchers also detected an increased protein turnover.

“Conversely, 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,” said Silke Meiners.

“Understanding the mechanisms that lead to a disease such as IPF helps us identify innovative approaches that allow therapeutic intervention,” commented Professor Oliver Eickelberg, director of the Institute of Lung Biology and scientific director of the CPC.

The researchers will continue their efforts in studying the potential use of drugs able to inhibit the 26S proteasome, but that do not affect other cell proteasome complexes. Lung experts speculate that activation of the 26S proteasome may occur in fibrotic conditions including kidney and heart fibrosis, because the differentiation of fibroblasts into myofibroblasts is a mechanism implicated in the pathological alteration that occur in these conditions.

In eukaryotic cells, most proteins in the cytosol and nucleus are degraded via the ubiquitin-proteasome pathway. The 26S proteasome is a 2.5-MDa molecular machine built from approximately 31 different subunits, which catalyzes protein degradation. It contains a barrel-shaped proteolytic core complex (the 20S proteasome), capped at one or both ends by 19S regulatory complexes, which recognize ubiquitinated proteins.

In the study, the researchers used siRNA, a subunit of the 19S regulator, which inhibited the 26S proteasome and suppressed a differentiation of fibroblasts into pathological myofibroblasts. This strategy is more precise than the use of catalytic proteasome inhibitors, which inhibit all active proteasomes, specifically the 26S and 20S proteasome complexes, in a non-targeted manner. The use of proteasome inhibitors is controversial because of its toxic effects. The specific 26S proteasome inhibition strategy in this study represents a new and specific method that could reduce side effects, since only specific cells are attacked.

The researchers will continue to work on the examination of substances that interfere specifically with 26S proteasome activity. The researchers are also planning a compound screening for new substances that induce a specific 26S proteasome inhibition.