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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

(A–D) Progression of fibrosis in experimentally obtained sections (left column) vs. in ABM simulation (right column); collagen appears blue in Masson’s trichrome stain (left), collagen agents in the model are also blue (right).
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Figure 3: (A–D) Progression of fibrosis in experimentally obtained sections (left column) vs. in ABM simulation (right column); collagen appears blue in Masson’s trichrome stain (left), collagen agents in the model are also blue (right).

Mentions: At baseline, both tissue sections stained with Masson’s trichrome (Figure 3A, left) and the simulation (Figure 3A, right) show a uniform texture across hepatocyte-filled lobules. As hepatocytes died in response to repeated CCL4 administration, persistent damage led to continuous inflammatory activation (Figure 3B), loss of hepatocytes, and the beginnings of collagen deposition – first in the periportal region, then extending across septa to form bridging fibrosis. With continued inflammation, collagen deposits grew and the lobules appeared more deformed, with some regenerative nodules forming as fibrous bands beginning to separate out smaller sections of parenchyma (Figures 3C,D).


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)

(A–D) Progression of fibrosis in experimentally obtained sections (left column) vs. in ABM simulation (right column); collagen appears blue in Masson’s trichrome stain (left), collagen agents in the model are also blue (right).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: (A–D) Progression of fibrosis in experimentally obtained sections (left column) vs. in ABM simulation (right column); collagen appears blue in Masson’s trichrome stain (left), collagen agents in the model are also blue (right).
Mentions: At baseline, both tissue sections stained with Masson’s trichrome (Figure 3A, left) and the simulation (Figure 3A, right) show a uniform texture across hepatocyte-filled lobules. As hepatocytes died in response to repeated CCL4 administration, persistent damage led to continuous inflammatory activation (Figure 3B), loss of hepatocytes, and the beginnings of collagen deposition – first in the periportal region, then extending across septa to form bridging fibrosis. With continued inflammation, collagen deposits grew and the lobules appeared more deformed, with some regenerative nodules forming as fibrous bands beginning to separate out smaller sections of parenchyma (Figures 3C,D).

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