Mechanisms of sinusoidal pressure-induced liver fibrosis

• Applicant: Professor Dr. Sebastian Mueller
• Subject Area: Gastroenterology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320419489

All chronic liver diseases frequently lead to scarring of the liver (cirrhosis), which is associated with progressive loss of organ function and a high mortality due to complications such as cancer or portal hypertension. The underlying molecular mechanisms are poorly understood and, except of liver transplantation, no efficient treatment strategies are available. A hallmark of cirrhosis is excess matrix deposition accompanied by elevated liver stiffness (LS). We here introduce the sinusoidal pressure hypothesis (SPH) as novel important mechanistic factor that determines the development of liver cirrhosis. According to SPH, all potential causes of cirrhosis whether of inflammatory or non-inflammatory origin ultimately lead to an elevated sinusoidal pressure (SP). At the cellular level, SP is the actual driving force for the production of extracellular matrix by stretching of perisinusoidal cells e.g. hepatic stellate cells. Elevated LS is the consequence of both elevated SP and increased matrix deposition. According to SPH, fibrosis progression is determined by the degree and time of elevated SP. Arterialization of the fibrotic liver is the final key event ultimately exposing the low-pressure organ liver to pathologically high pressures. We postulate that arterialization defines the point of no return for cirrhosis. The objective of this proposal is to further validate and elucidate SPH at the cellular and systemic level. First, our proposal aims to analyze potential cell types involved in sensing SP and responding to potentially pressure-modulating interventions. In the second aim, the SPH concept will be validated in vivo. The role of pressure, stiffness, arterialization, and cellular as well as intercellular mechanosignaling on fibrosis progression will be studied in mouse models in detail. In the final part, we will validate major findings from aim 1 and 2 in a well-characterized cohort of patients with alcoholic liver disease and different disease stages. As an indirect measure of SP, we will use the dynamic response of LS to alcohol detoxification and we will compare this responsiveness in a selected subcohort over several years. In addition, we will study partial predictors of the SPH such as arterialization.It is expected that the new findings will improve our understanding of mechanosignaling in liver fibrosis, namely the role of SP and a better definition of the so-called point of no return. The new insights could help to identify novel treatment strategies e.g. to lower LS or, second, to better identify patients that are at increased risk to develop fibrosis via mechanosignaling due to SP.

• DFG Programme: Research Grants