A common over-the-counter cough medicine ingredient, dextromethorphan, has shown potential in treating lung fibrosis, a condition affecting hundreds of thousands in Europe alone. Scientists from EMBL Heidelberg, in collaboration with the Translational Lung Research Center (TLRC) Heidelberg and the German Center for Lung Research (DZL), discovered that dextromethorphan can impede collagen formation, reducing lung fibrosis in cellular and animal models. The study, published in Science Translational Medicine, opens new avenues for treating this debilitating condition.
Understanding Lung Fibrosis and the Need for New Treatments
Lung fibrosis is characterized by excessive scarring due to the accumulation of fibrillar collagen in the lung, leading to tissue stiffness, breathing difficulties, and reduced oxygen concentration in the bloodstream. This condition can arise from various factors, including environmental irritants, chemotherapy side effects, and autoimmune diseases. The World Health Organization (WHO) estimates that 761,000 people in its European region suffer from lung fibrosis, resulting in 25,000 deaths and 496,000 healthy years lost since 2019. Currently, there is no cure available, highlighting the urgent need for effective treatments.
Dextromethorphan's Mechanism of Action
Muzamil Majid Khan, EMBL research associate and the paper’s first author, initiated the research with the goal of discovering novel drugs for lung fibrosis. The team screened a library of FDA-approved drugs, including dextromethorphan, using a high-throughput microscopy assay dubbed the ‘scar-in-a-jar’ assay. This in vitro system allowed the scientists to study the complete process of collagen formation and test the efficacy of anti-fibrotic drugs.
Khan explained, “To screen for a potential anti-fibrotic drug, we used first, a high throughput microscopy of an optimized ‘scar-in-a-jar’ assay to identify potential drugs inhibiting collagen trafficking followed by a variety of techniques such as proteomics, transcriptomics, microscopy which allowed us to pin down the mechanisms of action of the drug.”
Preclinical Evidence and Future Clinical Trials
Following the initial screening, dextromethorphan was tested in mouse models of lung fibrosis and live 3D organotypic human lung tissue cultured in the lab. The results indicated that dextromethorphan effectively inhibits collagen and collagen-like cargo secretion, thereby ameliorating lung fibrosis.
Rainer Pepperkok, senior author of the paper and EMBL group leader, noted the collaborative effort facilitated by the DZL consortium, stating, “Being part of a consortium with DZL allowed us to collaborate with a local clinic in Heidelberg – Thoraxclinic – and we are now in the process of planning phase II clinical trials that can investigate if these same findings convey to what works in human patients.”
Next Steps in Research
The scientists plan to further investigate the drug's mechanisms and identify its specific targets in cells within the disease context. This may lead to the development of improved variants of dextromethorphan. Pepperkok emphasized the importance of fundamental research, stating, “It is important to remember that this is still fundamental research and only a very first step in understanding dextromethorphan's impact on lung fibrosis. That said, this fundamental discovery does seem to offer promising therapeutic potential.”
