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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

General trajectory of Kupffer cell activation and cytokine production in simulations (n = 10, mean ± SD). (A) Resident Kupffer cells are at first quiescent (blue), but as inflammation progresses they are activated (red) and drive further recruitment of Kupffer cells; (B) the trajectory of TNF-α (red) and TGF-β1 (blue) as inflammation progresses. Activated Kupffer cells are at first dominated by an M1 phenotype, as demonstrated by the early peak of TNF-α, followed by a later, longer peak of TGF-β1 (transition to a domination of M2 phenotype).
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Figure 4: General trajectory of Kupffer cell activation and cytokine production in simulations (n = 10, mean ± SD). (A) Resident Kupffer cells are at first quiescent (blue), but as inflammation progresses they are activated (red) and drive further recruitment of Kupffer cells; (B) the trajectory of TNF-α (red) and TGF-β1 (blue) as inflammation progresses. Activated Kupffer cells are at first dominated by an M1 phenotype, as demonstrated by the early peak of TNF-α, followed by a later, longer peak of TGF-β1 (transition to a domination of M2 phenotype).

Mentions: To characterize the quantitative rather than qualitative behavior of the ABM, the predicted dynamics of cell populations and cytokine production were assessed. Resident Kupffer cells were activated by the CCL4-induced damage, and a concomitant rise in activated Kupffer cells and concurrent recruitment of further Kupffer cells were observed (Figure 4A). The activation of Kupffer cells slows down as the simulation progresses, but then stabilizes to a steady state after about 300 simulation time steps (Figure S1 in Supplementary Material). The Kupffer cell population was initially dominated by an M1 phenotype, characterized by release of TNF-α (Figure 4B). As Kupffer cells phagocytized dead hepatocytes, their phenotype shifted toward an M2 phenotype, characterized by release of TGF-β1.


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)

General trajectory of Kupffer cell activation and cytokine production in simulations (n = 10, mean ± SD). (A) Resident Kupffer cells are at first quiescent (blue), but as inflammation progresses they are activated (red) and drive further recruitment of Kupffer cells; (B) the trajectory of TNF-α (red) and TGF-β1 (blue) as inflammation progresses. Activated Kupffer cells are at first dominated by an M1 phenotype, as demonstrated by the early peak of TNF-α, followed by a later, longer peak of TGF-β1 (transition to a domination of M2 phenotype).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: General trajectory of Kupffer cell activation and cytokine production in simulations (n = 10, mean ± SD). (A) Resident Kupffer cells are at first quiescent (blue), but as inflammation progresses they are activated (red) and drive further recruitment of Kupffer cells; (B) the trajectory of TNF-α (red) and TGF-β1 (blue) as inflammation progresses. Activated Kupffer cells are at first dominated by an M1 phenotype, as demonstrated by the early peak of TNF-α, followed by a later, longer peak of TGF-β1 (transition to a domination of M2 phenotype).
Mentions: To characterize the quantitative rather than qualitative behavior of the ABM, the predicted dynamics of cell populations and cytokine production were assessed. Resident Kupffer cells were activated by the CCL4-induced damage, and a concomitant rise in activated Kupffer cells and concurrent recruitment of further Kupffer cells were observed (Figure 4A). The activation of Kupffer cells slows down as the simulation progresses, but then stabilizes to a steady state after about 300 simulation time steps (Figure S1 in Supplementary Material). The Kupffer cell population was initially dominated by an M1 phenotype, characterized by release of TNF-α (Figure 4B). As Kupffer cells phagocytized dead hepatocytes, their phenotype shifted toward an M2 phenotype, characterized by release of TGF-β1.

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