Dataset Information

A computational model of liver tissue damage and repair.

ABSTRACT: Drug induced liver injury (DILI) and cell death can result from oxidative stress in hepatocytes. An initial pattern of centrilobular damage in the APAP model of DILI is amplified by communication from stressed cells and immune system activation. While hepatocyte proliferation counters cell loss, high doses are still lethal to the tissue. To understand the progression of disease from the initial damage to tissue recovery or death, we computationally model the competing biological processes of hepatocyte proliferation, necrosis and injury propagation. We parametrize timescales of proliferation (?), conversion of healthy to stressed cells (?) and further sensitization of stressed cells towards necrotic pathways (?) and model them on a Cellular Automaton (CA) based grid of lattice sites. 1D simulations show that a small ?/? (fast proliferation), combined with a large ?/? (slow death) have the lowest probabilities of tissue survival. At large ?/?, tissue fate can be described by a critical ?/?* ratio alone; this value is dependent on the initial amount of damage and proportional to the tissue size N. Additionally, the 1D model predicts a minimum healthy population size below which damage is irreversible. Finally, we compare 1D and 2D phase spaces and discuss outcomes of bistability where either survival or death is possible, and of coexistence where simulated tissue never completely recovers or dies but persists as a mixture of healthy, stressed and necrotic cells. In conclusion, our model sheds light on the evolution of tissue damage or recovery and predicts potential for divergent fates given different rates of proliferation, necrosis, and injury propagation.

SUBMITTER: Adhyapok P

PROVIDER: S-EPMC7752149 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A computational model of liver tissue damage and repair.

Adhyapok Priyom P Fu Xiao X Sluka James P JP Clendenon Sherry G SG Sluka Victoria D VD Wang Zemin Z Dunn Kenneth K Klaunig James E JE Glazier James A JA

PloS one 20201221 12

Drug induced liver injury (DILI) and cell death can result from oxidative stress in hepatocytes. An initial pattern of centrilobular damage in the APAP model of DILI is amplified by communication from stressed cells and immune system activation. While hepatocyte proliferation counters cell loss, high doses are still lethal to the tissue. To understand the progression of disease from the initial damage to tissue recovery or death, we computationally model the competing biological processes of hep ...[more]

PMID: 33347443

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Project description:Altered lung tissue bioenergetics plays a key role in the pathogenesis of lung diseases. A wealth of information exists regarding the bioenergetic processes in mitochondria isolated from rat lungs, cultured pulmonary endothelial cells, and intact rat lungs under physiological and pathophysiological conditions. However, the interdependence of those processes makes it difficult to quantify the impact of a change in a single or multiple process(es) on overall lung tissue bioenergetics. Integrated computational modeling provides a mechanistic and quantitative framework for the bioenergetic data at different levels of biological organization. The objective of this study was to develop and validate an integrated computational model of lung bioenergetics using existing experimental data from isolated perfused rat lungs. The model expands our recently developed computational model of the bioenergetics of mitochondria isolated from rat lungs by accounting for glucose uptake and phosphorylation, glycolysis, and the pentose phosphate pathway. For the mitochondrial region of the model, values of kinetic parameters were fixed at those estimated in our recent model of the bioenergetics of mitochondria isolated from rat lungs. For the cytosolic region of the model, intrinsic parameters such as apparent Michaelis constants were determined based on previously published enzyme kinetics data, whereas extrinsic parameters such as maximal reaction and transport velocities were estimated by fitting the model solution to published data from isolated rat lungs. The model was then validated by assessing its ability to predict existing experimental data not used for parameter estimation, including relationships between lung nucleotides content, lung lactate production rate, and lung energy charge under different experimental conditions. In addition, the model was used to gain novel insights on how lung tissue glycolytic rate is regulated by exogenous substrates such as glucose and lactate, and assess differences in the bioenergetics of mitochondria isolated from lung tissue and those of mitochondria in intact lungs. To the best of our knowledge, this is the first model of lung tissue bioenergetics. The model provides a mechanistic and quantitative framework for integrating available lung tissue bioenergetics data, and for testing novel hypotheses regarding the role of different cytosolic and mitochondrial processes in lung tissue bioenergetics.

Project description:The extent of senescence due to damage accumulation-or aging-is evidently evolvable as it differs hugely between species and is not universal, suggesting that its fitness advantages depend on life history and environment. In contrast, repair of damage is present in all organisms studied. Despite the fundamental trade-off between investing resources into repair or into growth, repair and segregation of damage have not always been considered alternatives. For unicellular organisms, unrepaired damage could be divided asymmetrically between daughter cells, leading to senescence of one and rejuvenation of the other. Repair of "unicells" has been predicted to be advantageous in well-mixed environments such as chemostats. Most microorganisms, however, live in spatially structured systems, such as biofilms, with gradients of environmental conditions and cellular physiology as well as a clonal population structure. To investigate whether this clonal structure might favor senescence by damage segregation (a division-of-labor strategy akin to the germline-soma division in multicellular organisms), we used an individual-based computational model and developed an adaptive repair strategy where cells respond to their current intracellular damage levels by investing into repair machinery accordingly. Our simulations showed that the new adaptive repair strategy was advantageous provided that growth was limited by substrate availability, which is typical for biofilms. Thus, biofilms do not favor a germline-soma-like division of labor between daughter cells in terms of damage segregation. We suggest that damage segregation is beneficial only when extrinsic mortality is high, a degree of multicellularity is present, and an active mechanism makes segregation effective.IMPORTANCE Damage is an inevitable consequence of life. For unicellular organisms, this leads to a trade-off between allocating resources into damage repair or into growth coupled with segregation of damage upon cell division, i.e., aging and senescence. Few studies considered repair as an alternative to senescence. None considered biofilms, where the majority of unicellular organisms live, although fitness advantages in well-mixed systems often turn into disadvantages in spatially structured systems such as biofilms. We compared the fitness consequences of aging versus an adaptive repair mechanism based on sensing damage, using an individual-based model of a generic unicellular organism growing in biofilms. We found that senescence is not beneficial provided that growth is limited by substrate availability. Instead, it is useful as a stress response to deal with damage that failed to be repaired when (i) extrinsic mortality was high; (ii) a degree of multicellularity was present; and (iii) damage segregation was effective.

Dataset Information

A computational model of liver tissue damage and repair.

Publications

A computational model of liver tissue damage and repair.

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