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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

Steatosis Inhomogeneity.The left image shows a histological image of a human liver with selected portal fields and central veins marked as ⊙ and ⊗, respectively. The right image shows a histological whole-slide scan of a steatotic mouse liver and a zoom to one lobe. Macrovesicular steatosis, i.e., lipid accumulations of diameter larger than hepatocyte nuclei, was quantified in all cases using an image analysis method based on [14] and visualized as an overlay to the histological images, using a color map from violet to yellow indicating low to high steatosis. The left example shows a pericentrally zonated state of steatosis. The right example shows both organ-scale and lobe-scale heterogeneity in the steatosis distribution in addition to a periportal zonation not clearly visible at this magnification. The human image data is by Serene Lee and Wolfgang Thasler, Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery Ludwig Maximilians University Munich Medical Center; the mouse image data is by Uta Dahmen, Department of General, Visceral and Vascular Surgery, University Hospital Jena; the analysis overlay was provided by André Homeyer, Fraunhofer MEVIS, Bremen.
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pone.0133653.g001: Steatosis Inhomogeneity.The left image shows a histological image of a human liver with selected portal fields and central veins marked as ⊙ and ⊗, respectively. The right image shows a histological whole-slide scan of a steatotic mouse liver and a zoom to one lobe. Macrovesicular steatosis, i.e., lipid accumulations of diameter larger than hepatocyte nuclei, was quantified in all cases using an image analysis method based on [14] and visualized as an overlay to the histological images, using a color map from violet to yellow indicating low to high steatosis. The left example shows a pericentrally zonated state of steatosis. The right example shows both organ-scale and lobe-scale heterogeneity in the steatosis distribution in addition to a periportal zonation not clearly visible at this magnification. The human image data is by Serene Lee and Wolfgang Thasler, Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery Ludwig Maximilians University Munich Medical Center; the mouse image data is by Uta Dahmen, Department of General, Visceral and Vascular Surgery, University Hospital Jena; the analysis overlay was provided by André Homeyer, Fraunhofer MEVIS, Bremen.

Mentions: Two of these length scales of inhomogeneity are most relevant for metabolic processes. On the sinusoidal length scale, effects occurring in specific regions along sinusoids are denoted by zonation[12, 13]. In case we do not refer to a small number of zones, we will denote this by sinusoid-scale heterogeneity. Furthermore, metabolic effects can differ between lobuli found at different locations in or across lobes. We will denote the latter by organ-scale heterogeneity. Generally, three main reasons for inhomogeneous metabolization can be distinguished: (a) The periportal hepatocytes, those near the inflow to the sinusoid, experience a higher concentration of a compound being metabolized than the pericentral hepatocytes, those near the outflow. This may lead to concentration gradients even if the cells themselves do not differ in terms of their metabolic capability. (b) Different gene expression or enzyme levels depending on the location, either along sinusoids or throughout the organ, may additionally lead to spatial differences in the metabolic capability. (c) Pathological states can furthermore affect the metabolic capability, see the examples in Fig 1 showing steatosis patterns at different length scales.


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)

Steatosis Inhomogeneity.The left image shows a histological image of a human liver with selected portal fields and central veins marked as ⊙ and ⊗, respectively. The right image shows a histological whole-slide scan of a steatotic mouse liver and a zoom to one lobe. Macrovesicular steatosis, i.e., lipid accumulations of diameter larger than hepatocyte nuclei, was quantified in all cases using an image analysis method based on [14] and visualized as an overlay to the histological images, using a color map from violet to yellow indicating low to high steatosis. The left example shows a pericentrally zonated state of steatosis. The right example shows both organ-scale and lobe-scale heterogeneity in the steatosis distribution in addition to a periportal zonation not clearly visible at this magnification. The human image data is by Serene Lee and Wolfgang Thasler, Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery Ludwig Maximilians University Munich Medical Center; the mouse image data is by Uta Dahmen, Department of General, Visceral and Vascular Surgery, University Hospital Jena; the analysis overlay was provided by André Homeyer, Fraunhofer MEVIS, Bremen.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4519332&req=5

pone.0133653.g001: Steatosis Inhomogeneity.The left image shows a histological image of a human liver with selected portal fields and central veins marked as ⊙ and ⊗, respectively. The right image shows a histological whole-slide scan of a steatotic mouse liver and a zoom to one lobe. Macrovesicular steatosis, i.e., lipid accumulations of diameter larger than hepatocyte nuclei, was quantified in all cases using an image analysis method based on [14] and visualized as an overlay to the histological images, using a color map from violet to yellow indicating low to high steatosis. The left example shows a pericentrally zonated state of steatosis. The right example shows both organ-scale and lobe-scale heterogeneity in the steatosis distribution in addition to a periportal zonation not clearly visible at this magnification. The human image data is by Serene Lee and Wolfgang Thasler, Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery Ludwig Maximilians University Munich Medical Center; the mouse image data is by Uta Dahmen, Department of General, Visceral and Vascular Surgery, University Hospital Jena; the analysis overlay was provided by André Homeyer, Fraunhofer MEVIS, Bremen.
Mentions: Two of these length scales of inhomogeneity are most relevant for metabolic processes. On the sinusoidal length scale, effects occurring in specific regions along sinusoids are denoted by zonation[12, 13]. In case we do not refer to a small number of zones, we will denote this by sinusoid-scale heterogeneity. Furthermore, metabolic effects can differ between lobuli found at different locations in or across lobes. We will denote the latter by organ-scale heterogeneity. Generally, three main reasons for inhomogeneous metabolization can be distinguished: (a) The periportal hepatocytes, those near the inflow to the sinusoid, experience a higher concentration of a compound being metabolized than the pericentral hepatocytes, those near the outflow. This may lead to concentration gradients even if the cells themselves do not differ in terms of their metabolic capability. (b) Different gene expression or enzyme levels depending on the location, either along sinusoids or throughout the organ, may additionally lead to spatial differences in the metabolic capability. (c) Pathological states can furthermore affect the metabolic capability, see the examples in Fig 1 showing steatosis patterns at different length scales.

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