title: A Multiscale Agent-Based in silico Model of Liver Fibrosis Progression.
abstract: Chronic hepatic inflammation involves a complex interplay of inflammatory and mechanical influences, ultimately manifesting in a characteristic histopathology of liver fibrosis. We created an agent-based model (ABM) of liver tissue in order to computationally examine the consequence of liver inflammation. Our liver fibrosis ABM (LFABM) is comprised of literature-derived rules describing molecular and histopathological aspects of inflammation and fibrosis in a section of chemically injured liver. Hepatocytes are modeled as agents within hexagonal lobules. Injury triggers an inflammatory reaction, which leads to activation of local Kupffer cells and recruitment of monocytes from circulation. Portal fibroblasts and hepatic stellate cells are activated locally by the products of inflammation. The various agents in the simulation are regulated by above-threshold concentrations of pro- and anti-inflammatory cytokines and damage-associated molecular pattern molecules. The simulation progresses from chronic inflammation to collagen deposition, exhibiting periportal fibrosis followed by bridging fibrosis, and culminating in disruption of the regular lobular structure. The ABM exhibited key histopathological features observed in liver sections from rats treated with carbon tetrachloride (CCl4). An in silico "tension test" for the hepatic lobules predicted an overall increase in tissue stiffness, in line with clinical elastography literature and published studies in CCl4-treated rats. Therapy simulations suggested differential anti-fibrotic effects of neutralizing tumor necrosis factor alpha vs. enhancing M2 Kupffer cells. We conclude that a computational model of liver inflammation on a structural skeleton of physical forces can recapitulate key histopathological and macroscopic properties of CCl4-injured liver. This multiscale approach linking molecular and chemomechanical stimuli enables a model that could be used to gain translationally relevant insights into liver fibrosis.
authors.affiliation: Department of Biomedical Informatics, University of Pittsburgh , Pittsburgh, PA , USA ; Department of Surgery, University of Pittsburgh , Pittsburgh, PA , USA ; Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA.
authors.forename: Joyeeta
authors.initials: J
authors.lastname: Dutta-Moscato
authors.affiliation: Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA ; Department of Mathematics, University of Pittsburgh , Pittsburgh, PA , USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Solovyev
authors.affiliation: Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA ; Department of Sports Medicine and Nutrition, University of Pittsburgh , Pittsburgh, PA , USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Mi
authors.affiliation: McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA ; Department of Surgery, Children's Hospital of Pittsburgh , Pittsburgh, PA , USA.
authors.forename: Taichiro
authors.initials: T
authors.lastname: Nishikawa
authors.affiliation: McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA ; Department of Pathology, University of Pittsburgh , Pittsburgh, PA , USA ; Thomas E. Starzl Transplantation Institute, University of Pittsburgh , Pittsburgh, PA , USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Soto-Gutierrez
authors.affiliation: McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA ; Department of Surgery, Children's Hospital of Pittsburgh , Pittsburgh, PA , USA ; Thomas E. Starzl Transplantation Institute, University of Pittsburgh , Pittsburgh, PA , USA.
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Fox
authors.affiliation: Department of Surgery, University of Pittsburgh , Pittsburgh, PA , USA ; Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, PA , USA.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
keywords: cirrhosis; computer simulation; elastography; hepatocyte; inflammation