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Lung Research
20.03.2017

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’.

collagen fibrils

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.

 

Further Information

Background:
The study was developed in cooperation with the Department of Analytical Pathology and several university partners, among others the Shriners Hospital for Children in Portland, Oregon, USA.

Larissa Knüppel is a member of the CPC Research School and participant in the Helmholtz Graduate School Environmental Health (HELENA). In June 2015 the team led by Claudia Staab-Weijnitz discovered a new approach for the treatment of idiopathic pulmonary fibrosis (IPF). The scientists found increased amounts of the protein FKBP10 in the lungs of IPF patients. If the production or activity of this protein could be inhibited, this might result in an additional new approach to therapy.

Original Publication:
Knüppel, L. et al. (2017): A Novel Antifibrotic Mechanism of Nintedanib and Pirfenidone: Inhibition of Collagen Fibril Assembly. American Journal of Respiratory Cell and Molecular Biology, DOI: 10.1165/rcmb.2016-0217OC


The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members.

The Comprehensive Pneumology Center (CPC) is a joint research project of the Helmholtz Zentrum München, the Ludwig-Maximilians-Universität Clinic Complex and the Asklepios Fachkliniken München-Gauting. The CPC's objective is to conduct research on chronic lung diseases in order to develop new diagnosis and therapy strategies. The CPC maintains a focus on experimental pneumology with the investigation of cellular, molecular and immunological mechanisms involved in lung diseases. The CPC is a site of the Deutsches Zentrum für Lungenforschung (DZL). 

The Analytical Pathology Department (AAP) carries out scientific development, as a complement to research units with a clinical and fundamental orientation, of translational research on diseases that occur in tissue. AAP is involved in the translation of (for example) in-vitro models or animal models to application in humans. AAP thus links, in collaboration with the Institute for Pathology (PATH), basic research with diagnostic application, subsequently translating the findings of experimental and molecular pathology into procedures for the classification of diseases and predictive diagnostics dealing with tissue. 

The German Center for Lung Research (DZL) pools German expertise in the field of pulmonology research and clinical pulmonology. The association’s head office is in Giessen. The aim of the DZL is to find answers to open questions in research into lung diseases by adopting an innovative, integrated approach and thus to make a sizeable contribution to improving the prevention, diagnosis and individualized treatment of lung disease and to ensure optimum patient care.