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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

Effect of anti-TNF treatment or M2 enhancement of Kupffer cells in the simulations (n = 10, mean ± SD). (A) TGF-β1 levels in the model with anti-TNF treatment (red), and in the model with enhanced M2 behavior (blue), compared to TGF-β1 levels in the baseline model (black); (B) TNF-α levels in the model with anti-TNF treatment (red), and in the model with enhanced M2 behavior (blue), compared to TNF-α levels in the baseline model (black); (C) growth of collagen in the anti-TNF-treated model (red), and in the model with enhanced M2 behavior (blue), compared to growth of collagen in the baseline model (black).
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Figure 6: Effect of anti-TNF treatment or M2 enhancement of Kupffer cells in the simulations (n = 10, mean ± SD). (A) TGF-β1 levels in the model with anti-TNF treatment (red), and in the model with enhanced M2 behavior (blue), compared to TGF-β1 levels in the baseline model (black); (B) TNF-α levels in the model with anti-TNF treatment (red), and in the model with enhanced M2 behavior (blue), compared to TNF-α levels in the baseline model (black); (C) growth of collagen in the anti-TNF-treated model (red), and in the model with enhanced M2 behavior (blue), compared to growth of collagen in the baseline model (black).

Mentions: Next, the LFABM was used to test specific hypotheses regarding two potential anti-fibrotic therapies: modulation of M1/M2 Kupffer cell phenotype, and the administration of neutralizing anti-TNF-α antibodies. Although it is well-established that Kupffer cells play a key role in the pathogenesis of liver fibrosis, their participation has classically been associated with hepatic inflammation and activation of HSCs (Bataller and Brenner, 2005). Prior studies have explored the efficacy of anti-TNF-α treatments to reduce hepatic fibrosis, with some experimental evidence suggesting that inhibition of TNF-α signaling during liver injury may be efficacious (Bahcecioglu et al., 2008; Rockey, 2008). Kupffer cells that have differentiated to an M2 phenotype, characterized by release of the anti-inflammatory cytokine TGF-β1, also inhibit TNF-α signaling. However, experimental evidence has shown that M2 Kupffer cells can promote fibrogenesis (Lopez-Navarrete et al., 2011). To test the effect of these two mechanisms of anti-inflammatory treatment on the growth of fibrosis, the growth of collagen in the LFABM was examined under two new conditions: first, in response to the presence of an anti-TNF-α treatment (simulated by increasing the degradation rate of local TNF-α); second, in response to increased production of TGF-β1 by the Kupffer cell agents (thereby simulating enhanced M2 activation). TGF-β1 levels were reduced in anti-TNF-α simulations (Figure 6A, red), and elevated in the simulations of enhanced M2 behavior (Figure 6A, blue). TNF-α levels were reduced in both the anti-TNF simulations (Figure 6B, red) and the simulations of enhanced M2 behavior (Figure 6B, blue). The amount of collagen in the anti-TNF simulations (Figure 6C, red) was lower than untreated baseline, while the simulations of enhanced M2 behavior showed substantially greater accumulation of collagen (Figure 6C, blue) compared to untreated baseline.


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)

Effect of anti-TNF treatment or M2 enhancement of Kupffer cells in the simulations (n = 10, mean ± SD). (A) TGF-β1 levels in the model with anti-TNF treatment (red), and in the model with enhanced M2 behavior (blue), compared to TGF-β1 levels in the baseline model (black); (B) TNF-α levels in the model with anti-TNF treatment (red), and in the model with enhanced M2 behavior (blue), compared to TNF-α levels in the baseline model (black); (C) growth of collagen in the anti-TNF-treated model (red), and in the model with enhanced M2 behavior (blue), compared to growth of collagen in the baseline model (black).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Effect of anti-TNF treatment or M2 enhancement of Kupffer cells in the simulations (n = 10, mean ± SD). (A) TGF-β1 levels in the model with anti-TNF treatment (red), and in the model with enhanced M2 behavior (blue), compared to TGF-β1 levels in the baseline model (black); (B) TNF-α levels in the model with anti-TNF treatment (red), and in the model with enhanced M2 behavior (blue), compared to TNF-α levels in the baseline model (black); (C) growth of collagen in the anti-TNF-treated model (red), and in the model with enhanced M2 behavior (blue), compared to growth of collagen in the baseline model (black).
Mentions: Next, the LFABM was used to test specific hypotheses regarding two potential anti-fibrotic therapies: modulation of M1/M2 Kupffer cell phenotype, and the administration of neutralizing anti-TNF-α antibodies. Although it is well-established that Kupffer cells play a key role in the pathogenesis of liver fibrosis, their participation has classically been associated with hepatic inflammation and activation of HSCs (Bataller and Brenner, 2005). Prior studies have explored the efficacy of anti-TNF-α treatments to reduce hepatic fibrosis, with some experimental evidence suggesting that inhibition of TNF-α signaling during liver injury may be efficacious (Bahcecioglu et al., 2008; Rockey, 2008). Kupffer cells that have differentiated to an M2 phenotype, characterized by release of the anti-inflammatory cytokine TGF-β1, also inhibit TNF-α signaling. However, experimental evidence has shown that M2 Kupffer cells can promote fibrogenesis (Lopez-Navarrete et al., 2011). To test the effect of these two mechanisms of anti-inflammatory treatment on the growth of fibrosis, the growth of collagen in the LFABM was examined under two new conditions: first, in response to the presence of an anti-TNF-α treatment (simulated by increasing the degradation rate of local TNF-α); second, in response to increased production of TGF-β1 by the Kupffer cell agents (thereby simulating enhanced M2 activation). TGF-β1 levels were reduced in anti-TNF-α simulations (Figure 6A, red), and elevated in the simulations of enhanced M2 behavior (Figure 6A, blue). TNF-α levels were reduced in both the anti-TNF simulations (Figure 6B, red) and the simulations of enhanced M2 behavior (Figure 6B, blue). The amount of collagen in the anti-TNF simulations (Figure 6C, red) was lower than untreated baseline, while the simulations of enhanced M2 behavior showed substantially greater accumulation of collagen (Figure 6C, blue) compared to untreated baseline.

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