How Fibrosis Drugs Work

Researchers at Helmholtz Zentrum München, a partner in the German Center for Lung Research, have discovered a new mechanism of action of two drugs used in the treatment of idiopathic pulmonary fibrosis (IPF). The paper was published in the ‘American Journal of Respiratory Cell and Molecular Biology’.

Increased formation of collagen fibrils (shown here is an electron microscopic picture from cell culture) is characteristic for lung fibrosis. Source: Helmholtz Zentrum München

Pulmonary fibrosis (scarring of lung tissue) is a term used to denote a variety of different lung diseases. All of these are characterized by increased connective tissue formation in the lungs, in particular by increased collagen production. This affects oxygen intake, leads to reduced elasticity, and thus to lung function decline.

“Currently, the drugs Nintedanib and Pirfenidone are widely used in treatment,” said Dr. Claudia Staab-Weijnitz, head of the research project at the Institute of Lung Biology (ILBD) and the Comprehensive Pneumology Center (CPC) at Helmholtz Zentrum München. “Both drugs slow down the progression of the disease, but the mechanisms of action are incompletely understood.”

Investigating the disease in the petri dish

To determine just how the drugs work, the researchers grew petri dish cultures of fibroblasts from IPF patients and healthy donors as controls. “We initially developed a cell culture system that is optimized for the study of collagen biosynthesis and maturation, said first author Larissa Knüppel. Here, the scientists were able to study the effect of the drugs on lung fibroblasts, which were originally derived from IPF patients.

Our analyses showed that both pirfenidone and nintedanib inhibit the formation of collagen fibrils,” said study director Staab-Weijnitz.” Specifically, they reduce the formation of new collagen molecules and, secondly, prevent them from forming into larger assemblies, so-called fibrils.”

Now that these drug effects are understood, the scientists want to pursue this approach further and look for ways to stop collagen fibril assembly more efficiently. The newly established cell culture model will continue to serve them well: “The results show that the optimized human system allows the study of collagen biosynthesis and collagen fibril formation at all regulatory levels. Thus, it is very well suited for use as an initial test system for novel therapeutic strategies for lung fibrosis,” said Staab-Weijnitz, looking to the future.