Research groups of the Charité – University Medicine in Berlin and in Heidelberg have succeeded in tracking the development of pulmonary fibrosis in detail. They have been able to demonstrate that the NEDD4-2 protein plays a key role in healthy lungs, and that the absence of this central regulator for various processes is of significance in the development of the disease. The exact development of lung fibrosis and its course can be examined even better now. Based on these findings, new therapeutic approaches can be developed, as de-scribed now in the medical journal Nature Communications* .
Fibrosis of the lung is a severe illness affecting mainly the elderly, and there are hardly any treatment options available. The lung tissue changes progressively and scars. However, the causes of lung fibrosis are largely unknown and the mechanism on a cellular level hardly understood. Using a self-cleaning mechanism called mucociliary clearance, bronchial mucus together with inhaled pathogens and other noxious agents is moved out of the respiratory tract by the lining epithelial cells of the lung mucosa with their cilia. We know that the excessive production or impaired removal of mucus and its components called mucins is associated with a change of these epithelial cells. The NEDD4-2 protein is involved in the breakdown of various other proteins which regulate the function of epithelial cells of the lungs using such processes. This is why NEDD4-2 becomes a key protein in the development of lung fibrosis.
The team of Prof. Dr. Marcus Mall, Director of the Pediatric Clinic, Division of Pneumonology, Immunology and Intensive Care at the Charité and professor of the Berlin Institute of Health (BIH), together with researchers of the German Center for Lung Research (DZL), the Heidelberg University Hospital, and the German Cancer Research Center have succeeded for the first time in developing an animal model which reflects idiopathic pulmonary fibrosis (IPF) in detail. Since NEDD4-2 is indispensable for early development, the coding gene was selectively removed from the lung only in adult animals. The researchers analyzed them at a late point in time, which approximately corresponds to the patient’s diagnosis. Here, measurements of oxygen saturation showed deterioration in lung function which is typical for the disease. Moreover, the structural characteristics of fibrosis such as patchy scarring could be shown by means of tissue sections and imaging of the lungs using computed tomography. The significance of NEDD4-2 in the development of the disease IPF is also evident from the fact that both the amount of transcript and protein in patients’ lung biopsies is significantly reduced. Furthermore, an analysis of the proteome profile, i.e. the entirety of all proteins, by means of mass spectrometry revealed a high degree of conformity in proteins that show a modified expression both in patients with IPF and in animal models. “Our findings may help to further study the development and course of the lung disease and to develop new therapies. For example, substances that may be selected for therapy, can be tried in a preclinical stage, or early detection of the disease may be possible,“ professor Mall suggests.
When studying the underlying disease mechanisms, the researchers found that, due to the absence of NEDD4-2 protein, epithelial cells in the respiratory tract are remodeled: the pro-portion of various cell types has changed and, moreover, the cells produce larger amounts of certain mucins. Together with modified sodium currents in epithelial cells and the resulting reduced volume of liquid film, this leads to impaired removal – the self-cleaning process of the respiratory tract is impaired. Besides, the absence of NEDD4-2 causes increased activity of the profibrotic TGFβ signaling pathway. “This enabled us to establish a direct correlation between the absence of NEDD4-2 and an impaired mucociliary clearance as well as the misregulation of the TGFβ signaling pathway – two disruptions that, according to current findings, play a role in the pathogenesis of IPF,” sums up Dr. Julia Duerr, lead author of the study.
Anti-fibrotic therapies have already been used for several years in the treatment of lung fibrosis. In most cases, they lead to a slowdown in the scarring process, but cannot entirely replace lung transplantation as the final treatment option. “In our model, we have been able to prove such slowdown in disease progression with the use of an already approved anti-fibrotic drug, but not complete healing," professor Mall adds: “In this way, we hope to contribute, through improved preclinical testing, to the faster development of therapeutic ap-proaches.” In subsequent steps, the efficacy of biomarkers for early diagnosis as well as potential new substances for the treatment of lung fibrosis is to be assessed.
Prof. Dr. Marcus A. Mall
Pediatric Clinic, Division of Pneumology, Immunology and Intensive Care
Campus Virchow Clinic
Charité – University Medicine Berlin
and Berlin Institute of Health (BIH)
Telephone: +49 30 450 566 131
E-mail: marcus.mall@charite.de
*Duerr J et al. Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice. Nat Commun (2020), DOI:10.1038/s41467-020-15743-6.
Source: Charité
The Charité – Berlin University of Medicine with its approximately 100 clinics and institutes at 4 campuses and 3,001 beds is one of the largest university hospitals in Europe. In 2018, 152,693 inpatient and day-care cases as well as 692,920 outpatient cases were treated here. At the Charité, research, teaching, and patient care are closely interlinked. The Berlin Uni-versity of Medicine has some 18,000 staff members across the group making the Charité one of the largest employers in Berlin. More than 4,500 of its employees work in patient care and some 4,300 in the scientific area and medical care. In 2018, the Charité reached a total revenue of over 1.8 billion euros. By securing more than 170.9 million euros in external funding, the Charité reached another record. At the Faculty of Medicine, which is one of the largest in Germany, more than 7,500 students are trained in medicine and dentistry. Addi-tionally, there are 619 training positions in 9 healthcare professions. www.charite.de
The Berlin Institute of Health (BIH) is a scientific institution for translational and precision medicine. The BIH pursues new approaches for better prognoses and innovative therapies in progressive diseases in order to give people back their quality of life or maintain it. With translational research and innovation, the BHI paves the way for benefit-oriented, personal-ized healthcare. 90 percent of the funding for the BIH is provided by the Federal Ministry of Education and Research (BMBF) and ten percent by the State of Berlin. The founding insti-tutes Charité – Berlin University of Medicine and Max Delbrueck Center for Molecular Medi¬cine in the Helmholtz Association (MDC) are independent member entities in the BIH. www.bihealth.org
The German Center for Lung Research (DZL e.V.) is an association of 29 leading university and non-university institutions dedicated to the research on diseases of the respiratory tract. The DZL coordinates and conducts fundamental as well as disease- and patient-oriented re-search in the field of lung disease following highest international standards in order to accelerate the translation of findings from fundamental research into new clinical ap-proaches for an improvement in patient care. www.dzl.de
