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Representative Sinusoids for Hepatic Four-Scale Pharmacokinetics Simulations.

Schwen LO, Schenk A, Kreutz C, Timmer J, Bartolomé Rodríguez MM, Kuepfer L, Preusser T - PLoS ONE (2015)

Bottom Line: This approach results in an integrated four-scale model, from single cells via sinusoids and the organ to the whole organism, capable of mechanistically representing metabolization inhomogeneity in livers at different spatial scales.Moreover, the model shows circulatory mixing effects due to a delayed recirculation through the surrounding organism.In particular, our results show that simultaneously considering variations at all relevant spatial scales may be necessary to understand their impact on observations at the organism scale.

View Article: PubMed Central - PubMed

Affiliation: Fraunhofer MEVIS, Bremen, Germany.

ABSTRACT
The mammalian liver plays a key role for metabolism and detoxification of xenobiotics in the body. The corresponding biochemical processes are typically subject to spatial variations at different length scales. Zonal enzyme expression along sinusoids leads to zonated metabolization already in the healthy state. Pathological states of the liver may involve liver cells affected in a zonated manner or heterogeneously across the whole organ. This spatial heterogeneity, however, cannot be described by most computational models which usually consider the liver as a homogeneous, well-stirred organ. The goal of this article is to present a methodology to extend whole-body pharmacokinetics models by a detailed liver model, combining different modeling approaches from the literature. This approach results in an integrated four-scale model, from single cells via sinusoids and the organ to the whole organism, capable of mechanistically representing metabolization inhomogeneity in livers at different spatial scales. Moreover, the model shows circulatory mixing effects due to a delayed recirculation through the surrounding organism. To show that this approach is generally applicable for different physiological processes, we show three applications as proofs of concept, covering a range of species, compounds, and diseased states: clearance of midazolam in steatotic human livers, clearance of caffeine in mouse livers regenerating from necrosis, and a parameter study on the impact of different cell entities on insulin uptake in mouse livers. The examples illustrate how variations only discernible at the local scale influence substance distribution in the plasma at the whole-body level. In particular, our results show that simultaneously considering variations at all relevant spatial scales may be necessary to understand their impact on observations at the organism scale.

No MeSH data available.


Related in: MedlinePlus

Necrosis and Regeneration.The plot shows how the spatial extent of the necrotic region evolves according to our model of the effect of CCl4 intoxication along a representative sinusoid of a mouse liver. The representative hepatocytes are separated by vertical black lines in this plot, A color range from white to red indicates zero to full necrotic damage of the respective representative hepatocyte. Necrosis develops during the first day, until a maximally necrotic state is attained. Subsequent regeneration starting on the second day leads to a shrinkage of the necrotic region until the end of day 7.
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pone.0133653.g006: Necrosis and Regeneration.The plot shows how the spatial extent of the necrotic region evolves according to our model of the effect of CCl4 intoxication along a representative sinusoid of a mouse liver. The representative hepatocytes are separated by vertical black lines in this plot, A color range from white to red indicates zero to full necrotic damage of the respective representative hepatocyte. Necrosis develops during the first day, until a maximally necrotic state is attained. Subsequent regeneration starting on the second day leads to a shrinkage of the necrotic region until the end of day 7.

Mentions: Synthetic Necrosis Data: A CCl4 dose of 1.6 mg g−1 body weight leads to necrotic areas reported in Fig 1S (manually derived data) in the supporting material to [34], with piecewise affine-linear interpolation in time and the assumption of full regeneration after 7 days. We use this data as the basis for defining a time-dependent necrotic zone in our representative sinusoids, converting, as explained in Eq 16, from pericentral area as visible in the histological images to pericentral length in the representative sinusoid model. The evolution of the necrotic area as input for our simulations is shown in Fig 6. A necrosis value between 0% and 100% is proportionally mapped to a change of volume fractions as described above.


Representative Sinusoids for Hepatic Four-Scale Pharmacokinetics Simulations.

Schwen LO, Schenk A, Kreutz C, Timmer J, Bartolomé Rodríguez MM, Kuepfer L, Preusser T - PLoS ONE (2015)

Necrosis and Regeneration.The plot shows how the spatial extent of the necrotic region evolves according to our model of the effect of CCl4 intoxication along a representative sinusoid of a mouse liver. The representative hepatocytes are separated by vertical black lines in this plot, A color range from white to red indicates zero to full necrotic damage of the respective representative hepatocyte. Necrosis develops during the first day, until a maximally necrotic state is attained. Subsequent regeneration starting on the second day leads to a shrinkage of the necrotic region until the end of day 7.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4519332&req=5

pone.0133653.g006: Necrosis and Regeneration.The plot shows how the spatial extent of the necrotic region evolves according to our model of the effect of CCl4 intoxication along a representative sinusoid of a mouse liver. The representative hepatocytes are separated by vertical black lines in this plot, A color range from white to red indicates zero to full necrotic damage of the respective representative hepatocyte. Necrosis develops during the first day, until a maximally necrotic state is attained. Subsequent regeneration starting on the second day leads to a shrinkage of the necrotic region until the end of day 7.
Mentions: Synthetic Necrosis Data: A CCl4 dose of 1.6 mg g−1 body weight leads to necrotic areas reported in Fig 1S (manually derived data) in the supporting material to [34], with piecewise affine-linear interpolation in time and the assumption of full regeneration after 7 days. We use this data as the basis for defining a time-dependent necrotic zone in our representative sinusoids, converting, as explained in Eq 16, from pericentral area as visible in the histological images to pericentral length in the representative sinusoid model. The evolution of the necrotic area as input for our simulations is shown in Fig 6. A necrosis value between 0% and 100% is proportionally mapped to a change of volume fractions as described above.

Bottom Line: This approach results in an integrated four-scale model, from single cells via sinusoids and the organ to the whole organism, capable of mechanistically representing metabolization inhomogeneity in livers at different spatial scales.Moreover, the model shows circulatory mixing effects due to a delayed recirculation through the surrounding organism.In particular, our results show that simultaneously considering variations at all relevant spatial scales may be necessary to understand their impact on observations at the organism scale.

View Article: PubMed Central - PubMed

Affiliation: Fraunhofer MEVIS, Bremen, Germany.

ABSTRACT
The mammalian liver plays a key role for metabolism and detoxification of xenobiotics in the body. The corresponding biochemical processes are typically subject to spatial variations at different length scales. Zonal enzyme expression along sinusoids leads to zonated metabolization already in the healthy state. Pathological states of the liver may involve liver cells affected in a zonated manner or heterogeneously across the whole organ. This spatial heterogeneity, however, cannot be described by most computational models which usually consider the liver as a homogeneous, well-stirred organ. The goal of this article is to present a methodology to extend whole-body pharmacokinetics models by a detailed liver model, combining different modeling approaches from the literature. This approach results in an integrated four-scale model, from single cells via sinusoids and the organ to the whole organism, capable of mechanistically representing metabolization inhomogeneity in livers at different spatial scales. Moreover, the model shows circulatory mixing effects due to a delayed recirculation through the surrounding organism. To show that this approach is generally applicable for different physiological processes, we show three applications as proofs of concept, covering a range of species, compounds, and diseased states: clearance of midazolam in steatotic human livers, clearance of caffeine in mouse livers regenerating from necrosis, and a parameter study on the impact of different cell entities on insulin uptake in mouse livers. The examples illustrate how variations only discernible at the local scale influence substance distribution in the plasma at the whole-body level. In particular, our results show that simultaneously considering variations at all relevant spatial scales may be necessary to understand their impact on observations at the organism scale.

No MeSH data available.


Related in: MedlinePlus