Advanced physical methods in hepatotoxicity studies

Drug-induced idiosyncratic liver damage (DILI) is an acute hepatic adverse reaction that occurs in a small number of drug users. DILI and is a major problem for clinical practice, the pharmaceutical industry and regulatory authorities around the world. The main goal of the Prospective European Drug-Induced Liver Injury Network (PRO-EURO-DILI-NET) COST event is to create a unique, collaborative, interdisciplinary network of stakeholders in the field of DILI, including clinical practice (primary hepatologists, clinical pharmacologists, epidemiologists, pathologists), academics and basic research scientists (molecular biologists, physicists, biochemists, chemists, bioinformatics), the pharmaceutical industry, excellent SMEs and regulatory authorities. Our group has the knowledge and methodology that is indispensable for PRO-EURO-DILI-NET COST events. The involvement of our team in the PRO-EURO-DILI-NET COST event will subsequently contribute to the improvement of regulatory decisions regarding DILI. The following project, which we propose within the COST action, will anchor advanced physical methods in hepatotoxicity research. Recent studies have confirmed the association of the mechanical forces and geometric constraints acting on cells of the innate immune system with the molecular inflammatory processes that take place in these cells. These studies, however, do not explain the specific mechanism of action of external forces on inflammatory processes. The lack of a link between the action of external force and the resulting influence of the inflammatory process in the form of a detailed understanding of the whole interaction at the cellular and molecular level is crucial for further development, not only to expand basic knowledge of mechanical factors affecting processes controlling cellular behavior and functionality. fundamental meaning. In recent years, mechanical action has been shown to play a key role in the inflammatory response through activation of the inflammasome. Activation of the inflamasome plays a major role in hepatocyte damage, immune cell activation, and the progression of hepatitis. Because mechanical forces play a very important role in the liver during pathological conditions, a link between cellular mechanics and the inflammatory process can be expected in liver cells. Therefore, we propose to study the basic sub-cellular processes operating in liver cells and cells of the non-specific immune system due to the mechanical action created by the specific environment. We expect results and new knowledge about the possibilities of controlling cellular functions using mechanical forces. The contribution of our expertise to this project will be, in particular, an understanding of current and potential in vitro models of hepatotoxicity, including dynamic 3-D culture systems, as well as a critical evaluation of their strengths, limitations and applications in preclinical evaluation.