Researchers at the University Medical Center Mainz and Boston University have discovered a mechanism that promotes the scarring of the lungs and, thus, the development of so-called pulmonary fibrosis. The two DZL scientists, Prof. Dr Andreas Günther and Dr Clemens Ruppert were also involved in the project. They have shown that releasing histone family proteins impairs a signalling pathway that is supposed to prevent lung tissue from proliferating uncontrollably and scarring. Based on this new finding, the research team tested an antibody-based mode of action that can block histones. The preclinical study published in the journal Proceedings of the National Academy of Sciences (PNAS) shows a promising effect of the novel therapeutic approach in the experimental model of pulmonary fibrosis.
Elucidating molecular relationships
Pulmonary fibrosis is a disease that is still incurable and often fatal. Those affected suffer from an uncontrolled proliferation of lung scar tissue triggered by chronic inflammation. As a result, the lungs are less elastic and cannot expand sufficiently when breathing. Patients experience shortness of breath even with slight exertion - in the advanced stages of the disease, even at rest. The exact causes for the development of the disease are still insufficiently understood.
"Our goal is to understand the molecular connections of pulmonary fibrosis more precisely to improve the treatment options. We have identified a previously unknown mechanism that indicates that proteins of the histone family play a crucial role in the disease process when they are released by immune cells. Histones, therefore, form a potential target structure for developing new drugs to treat pulmonary fibrosis," explains Prof. Dr Markus Bosmann, working group leader at the Centre for Thrombosis and Haemostasis (CTH) at the University Medical Center Mainz.
Increased concentration of DNA packaging proteins
Histones are proteins in the cell nucleus that serve to package DNA. If histones are released, for example, by a misdirected defence reaction or cell death, they can intervene in immunological processes. In their preclinical investigations, the Mainz researchers found that samples from patients with pulmonary fibrosis had a significantly higher concentration of histones than healthy volunteers. They showed that the released histones triggered an interplay between messenger substances from the blood platelets and the immune cells. The result: A safety mechanism that is supposed to prevent uncontrolled tissue formation and lung scarring switches off.
Stopping lung scarring
The drugs currently available for treating pulmonary fibrosis inhibit the scarring but cannot completely stop this process. The scientists in
Mainz have tested an innovative substance based on antibodies that can block the released histones. In the experimental model, this showed high efficacy against fibrosis of the lung.
"It is conceivable that an antibody-based agent can be combined with currently used drugs to achieve better treatment results. However, further optimisation and preclinical tests must occur before this innovative active principle can be used clinically. Even though it will take many years, we are confident we are on the right track," says Professor Bosmann.
D.R. Riehl, A. Sharma, J. Roewe, M. Bosmann et al. Externalised histones fuel pulmonary fibrosis via a platelet-macrophage circuit of TGFβ1 and IL-27. PNAS, 2023, 120 (40) e2215421120. DOI: https://doi.org/10.1073/pnas.2215421120