A Multiscale Agent-Based in silico Model of Liver Fibrosis Progression
نویسندگان
چکیده
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.
منابع مشابه
Determining the progression stages of liver fibrosis in patients with chronic hepatitis B
Introduction: Chronic hepatitis B (CHB) leads to liver fibrosis, its failure, and death in the long term. The stage of fibrosis in CHB patients can also be detected based on the biochemical markers. The aim of this study was to predict the state of liver fibrosis in CHB patients and determine the possibility of patients shifting from a given state to another one. Materials and Methods: This stu...
متن کاملThymoquinone restores liver fibrosis and improves oxidative stress status in a lipopolysaccharide-induced inflammation model in rats
Objective: Liver fibrosis is the primary sign of chronic liver injury induced by various causes. Thymoquinone (TQ) is the major ingredient of Nigella sativa with several beneficial effects on the body. In the present study, we aimed to investigate the effect of TQ on liver fibrosis in a lipopolysaccharide (LPS)-induced inflammation in male rats. Materials and methods: Fifty male Wistar rats wer...
متن کاملMechanistic agent-based damage and repair models as hypotheses for patterns of necrosis caused by drug induced liver injury
Increasing model reuse and facilitating repurposing is expected to expand simulation use for better understanding biological phenomena. We demonstrate doing so in the context of liver diseases caused by toxic exposure to xenobiotics. A clinical goal is improved mechanistic explanations of how damage is generated, which can lead to new strategies to block and/or reverse injury. A goal for this w...
متن کاملMelatonin Pretreatment Enhances the Homing of Bone Marrow-derived Mesenchymal Stem Cells Following Transplantation in a Rat Model of Liver Fibrosis
Background: Bone marrow-derived mesenchymal stem cells (BMMSCs) transplantation has been considered as a promising milestone in liver fibrosis treatment. However, low amounts of homing are a major obstacle. We aimed to investigate the role of melatonin pretreatment in BMMSC homing into experimental liver fibrosis. Methods: BMMSCs were obtained, grown, propagated and preconditioned with 5 µ...
متن کاملBackground: Hepatic steatosis is commonly observed in patients with chronic hepatitis C (CHC). Many studies indicate a relationship between steatosis and fibrosis progression. The aim of this study was to analyze the prevalence of hepatic steatosis and related factors in Iranian CHC patients. Methods: One hundred and fifteen consecutive patients with CHC were enrolled which were treat...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 2 شماره
صفحات -
تاریخ انتشار 2014