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A Multiscale Agent-Based in silico Model of Liver Fibrosis Progression.

Dutta-Moscato J, Solovyev A, Mi Q, Nishikawa T, Soto-Gutierrez A, Fox IJ, Vodovotz Y - Front Bioeng Biotechnol (2014)

Bottom Line: The various agents in the simulation are regulated by above-threshold concentrations of pro- and anti-inflammatory cytokines and damage-associated molecular pattern molecules.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

An overview of agent interactions in the model. H, hepatocyte; D, dead hepatocyte; KC, Kupffer cell; HSC, hepatic stellate cell; PF, portal fibroblast; MF, myofibroblast. Diffusible factors TNF-α, tumor necrosis factor alpha; TGF-β1, transforming growth factor beta 1; HMGB1, high mobility group box protein 1. Detailed rules are available in Supplementary Material.
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Figure 2: An overview of agent interactions in the model. H, hepatocyte; D, dead hepatocyte; KC, Kupffer cell; HSC, hepatic stellate cell; PF, portal fibroblast; MF, myofibroblast. Diffusible factors TNF-α, tumor necrosis factor alpha; TGF-β1, transforming growth factor beta 1; HMGB1, high mobility group box protein 1. Detailed rules are available in Supplementary Material.

Mentions: The sequence of events in the LFABM is shown in Figure 2. Administration of CCl4 in animal models causes centrilobular necrosis of hepatocytes (Stachura et al., 1981). In our model, pulses of centrilobular toxicity transform hepatocytes into dead agents. Biologically, Kupffer cells survey the area and phagocytize dead cells and become activated to produce cytokines in the process (Edwards et al., 1993). In the LFABM, upon encountering a dead agent, Kupffer cells phagocytize and become activated to produce TNF-α (a canonical pro-inflammatory cytokine) and TGF-β1 (a canonical anti-inflammatory cytokine) (Martinez et al., 2008). Biologically, inadequate clearance of dead cells can lead to the release of damage-associated molecular pattern (DAMP) molecules such as HMGB1 (Scaffidi et al., 2002; Bell et al., 2006). DAMPs attract monocytes and neutrophils to the liver. Correspondingly, in the LFABM, inadequate clearance of dead agents leads to accumulation of HMGB1, with subsequent recruitment and transformation of monocytes to activated Kupffer cells. All parameters are set with probabilistic ranges.


A Multiscale Agent-Based in silico Model of Liver Fibrosis Progression.

Dutta-Moscato J, Solovyev A, Mi Q, Nishikawa T, Soto-Gutierrez A, Fox IJ, Vodovotz Y - Front Bioeng Biotechnol (2014)

An overview of agent interactions in the model. H, hepatocyte; D, dead hepatocyte; KC, Kupffer cell; HSC, hepatic stellate cell; PF, portal fibroblast; MF, myofibroblast. Diffusible factors TNF-α, tumor necrosis factor alpha; TGF-β1, transforming growth factor beta 1; HMGB1, high mobility group box protein 1. Detailed rules are available in Supplementary Material.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126446&req=5

Figure 2: An overview of agent interactions in the model. H, hepatocyte; D, dead hepatocyte; KC, Kupffer cell; HSC, hepatic stellate cell; PF, portal fibroblast; MF, myofibroblast. Diffusible factors TNF-α, tumor necrosis factor alpha; TGF-β1, transforming growth factor beta 1; HMGB1, high mobility group box protein 1. Detailed rules are available in Supplementary Material.
Mentions: The sequence of events in the LFABM is shown in Figure 2. Administration of CCl4 in animal models causes centrilobular necrosis of hepatocytes (Stachura et al., 1981). In our model, pulses of centrilobular toxicity transform hepatocytes into dead agents. Biologically, Kupffer cells survey the area and phagocytize dead cells and become activated to produce cytokines in the process (Edwards et al., 1993). In the LFABM, upon encountering a dead agent, Kupffer cells phagocytize and become activated to produce TNF-α (a canonical pro-inflammatory cytokine) and TGF-β1 (a canonical anti-inflammatory cytokine) (Martinez et al., 2008). Biologically, inadequate clearance of dead cells can lead to the release of damage-associated molecular pattern (DAMP) molecules such as HMGB1 (Scaffidi et al., 2002; Bell et al., 2006). DAMPs attract monocytes and neutrophils to the liver. Correspondingly, in the LFABM, inadequate clearance of dead agents leads to accumulation of HMGB1, with subsequent recruitment and transformation of monocytes to activated Kupffer cells. All parameters are set with probabilistic ranges.

Bottom Line: The various agents in the simulation are regulated by above-threshold concentrations of pro- and anti-inflammatory cytokines and damage-associated molecular pattern molecules.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus