Browsing by Author "Sluka, James P."

Now showing 1 - 4 of 4
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    A computational model of liver tissue damage and repair
    (Public Library of Science, 2020-12-21) Adhyapok, Priyom; Fu, Xiao; Sluka, James P.; Clendenon, Sherry G.; Sluka, Victoria D.; Wang, Zemin; Dunn, Kenneth; Klaunig, James E.; Glazier, James A.; Medicine, School of Medicine
    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 (α), conversion of healthy to stressed cells (β) and further sensitization of stressed cells towards necrotic pathways (γ) and model them on a Cellular Automaton (CA) based grid of lattice sites. 1D simulations show that a small α/β (fast proliferation), combined with a large γ/β (slow death) have the lowest probabilities of tissue survival. At large α/β, tissue fate can be described by a critical γ/β* 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.
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    Mitochondrial depolarization and repolarization in the early stages of acetaminophen hepatotoxicity in mice
    (Elsevier, 2020-06) Dunn, Kenneth W.; Martinez, Michelle M.; Wang, Zemin; Mang, Henry E.; Clendenon, Sherry G.; Sluka, James P.; Glazier, James A.; Klaunig, James E.; Medicine, School of Medicine
    Mitochondrial injury and depolarization are primary events in acetaminophen hepatotoxicity. Previous studies have shown that restoration of mitochondrial function in surviving hepatocytes, which is critical to recovery, is at least partially accomplished via biogenesis of new mitochondria. However, other studies indicate that mitochondria also have the potential to spontaneously repolarize. Although repolarization was previously observed only at a sub-hepatotoxic dose of acetaminophen, we postulated that mitochondrial repolarization in hepatocytes outside the centrilobular regions of necrosis might contribute to recovery of mitochondrial function following acetaminophen-induced injury. Our studies utilized longitudinal intravital microscopy of millimeter-scale regions of the mouse liver to characterize the spatio-temporal relationship between mitochondrial polarization and necrosis early in acetaminophen-induced liver injury. Treatment of male C57BL/6J mice with a single intraperitoneal 250 mg/kg dose of acetaminophen resulted in hepatotoxicity that was apparent histologically within 2 h of treatment, leading to 20 and 60-fold increases in serum aspartate aminotransferase and alanine aminotransferase, respectively, within 6 h. Intravital microscopy of the livers of mice injected with rhodamine123, TexasRed-dextran, propidium iodide and Hoechst 33342 detected centrilobular foci of necrosis within extended regions of mitochondrial depolarization within 2 h of acetaminophen treatment. Although regions of necrosis were more apparent 6 h after acetaminophen treatment, the vast majority of hepatocytes with depolarized mitochondria did not progress to necrosis, but rather recovered mitochondrial polarization within 6 h. Recovery of mitochondrial function following acetaminophen hepatotoxicity thus involves not only biogenesis of new mitochondria, but also repolarization of existing mitochondria. These studies also revealed a spatial distribution of necrosis and mitochondrial depolarization whose single-cell granularity is inconsistent with the hypothesis that communication between neighboring cells plays an important role in the propagation of necrosis during the early stages of APAP hepatotoxicity. Small islands of healthy, intact cells were frequently found surrounded by necrotic cells, and small islands of necrotic cells were frequently found surrounded by healthy, intact cells. Time-series studies demonstrated that these "islands", consisting in some cases of single cells, are persistent; over a period of hours, injury does not spread from individual necrotic cells to their neighbors.
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    Multiscale Model of Antiviral Timing, Potency, and Heterogeneity Effects on an Epithelial Tissue Patch Infected by SARS-CoV-2
    (MDPI, 2022-03-14) Gianlupi, Juliano Ferrari; Mapder, Tarunendu; Sego, T.J.; Sluka, James P.; Quinney, Sara K.; Craig, Morgan; Stratford, Robert E., Jr.; Glazier, James A.; Medicine, School of Medicine
    We extend our established agent-based multiscale computational model of infection of lung tissue by SARS-CoV-2 to include pharmacokinetic and pharmacodynamic models of remdesivir. We model remdesivir treatment for COVID-19; however, our methods are general to other viral infections and antiviral therapies. We investigate the effects of drug potency, drug dosing frequency, treatment initiation delay, antiviral half-life, and variability in cellular uptake and metabolism of remdesivir and its active metabolite on treatment outcomes in a simulated patch of infected epithelial tissue. Non-spatial deterministic population models which treat all cells of a given class as identical can clarify how treatment dosage and timing influence treatment efficacy. However, they do not reveal how cell-to-cell variability affects treatment outcomes. Our simulations suggest that for a given treatment regime, including cell-to-cell variation in drug uptake, permeability and metabolism increase the likelihood of uncontrolled infection as the cells with the lowest internal levels of antiviral act as super-spreaders within the tissue. The model predicts substantial variability in infection outcomes between similar tissue patches for different treatment options. In models with cellular metabolic variability, antiviral doses have to be increased significantly (>50% depending on simulation parameters) to achieve the same treatment results as with the homogeneous cellular metabolism.
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    A simple automated method for continuous fieldwise measurement of microvascular hemodynamics
    (Elsevier, 2019-05) Clendenon, Sherry G.; Fu, Xiao; Von Hoene, Robert A.; Clendenon, Jeffrey L.; Sluka, James P.; Winfree, Seth; Mang, Henry; Martinez, Michelle; Filson, Adele J.; Klaunig, James E.; Glazier, James A.; Dunn, Kenneth W.; Medicine, School of Medicine
    Microvascular perfusion dynamics are vital to physiological function and are frequently dysregulated in injury and disease. Typically studies measure microvascular flow in a few selected vascular segments over limited time, failing to capture spatial and temporal variability. To quantify microvascular flow in a more complete and unbiased way we developed STAFF (Spatial Temporal Analysis of Fieldwise Flow), a macro for FIJI open-source image analysis software. Using high-speed microvascular flow movies, STAFF generates kymographs for every time interval for every vascular segment, calculates flow velocities from red blood cell shadow angles, and outputs the data as color-coded velocity map movies and spreadsheets. In untreated mice, analyses demonstrated profound variation even between adjacent sinusoids over seconds. In acetaminophen-treated mice we detected flow reduction localized to pericentral regions. STAFF is a powerful new tool capable of providing novel insights by enabling measurement of the complex spatiotemporal dynamics of microvascular flow.