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1.
Math Med Biol ; 2024 Apr 11.
Article in English | MEDLINE | ID: mdl-38604176

ABSTRACT

Macrophages play a wide range of roles in resolving the inflammatory damage that underlies many medical conditions, and have the ability to adopt different phenotypes in response to different environmental stimuli. Categorising macrophage phenotypes exactly is a difficult task, and there is disparity in the literature around the optimal nomenclature to describe these phenotypes; however, what is clear is that macrophages can exhibit both pro- and anti-inflammatory behaviours dependent upon their phenotype, rendering mathematical models of the inflammatory response potentially sensitive to their description of the macrophage populations that they incorporate. Many previous models of inflammation include a single macrophage population with both pro- and anti-inflammatory functions. Here, we build upon these existing models to include explicit descriptions of distinct macrophage phenotypes and examine the extent to which this influences the inflammatory dynamics that the models emit. We analyse our models via numerical simulation in Matlab and dynamical systems analysis in XPPAUT, and show that models that account for distinct macrophage phenotypes separately can offer more realistic steady state solutions than precursor models do (better capturing the anti-inflammatory activity of tissue resident macrophages), as well as oscillatory dynamics not previously observed. Finally, we reflect on the conclusions of our analysis in the context of the ongoing hunt for potential new therapies for inflammatory conditions, highlighting manipulation of macrophage polarisation states as a potential therapeutic target.

2.
Math Med Biol ; 40(1): 24-48, 2023 03 13.
Article in English | MEDLINE | ID: mdl-36197900

ABSTRACT

Hepatitis is the term used to describe inflammation in the liver. It is associated with a high rate of mortality, but the underlying disease mechanisms are not completely understood and treatment options are limited. We present a mathematical model of hepatitis that captures the complex interactions between hepatocytes (liver cells), hepatic stellate cells (cells in the liver that produce hepatitis-associated fibrosis) and the immune components that mediate inflammation. The model is in the form of a system of ordinary differential equations. We use numerical techniques and bifurcation analysis to characterize and elucidate the physiological mechanisms that dominate liver injury and its outcome to a healthy or unhealthy, chronic state. This study reveals the complex interactions between the multiple cell types and mediators involved in this complex disease and highlights potential problems in targeting inflammation in the liver therapeutically.


Subject(s)
Hepatitis , Liver , Humans , Hepatitis/metabolism , Hepatocytes/metabolism , Inflammation , Systems Analysis
3.
PLoS Comput Biol ; 16(11): e1008413, 2020 11.
Article in English | MEDLINE | ID: mdl-33137107

ABSTRACT

Many common medical conditions (such as cancer, arthritis, chronic obstructive pulmonary disease (COPD), and others) are associated with inflammation, and even more so when combined with the effects of ageing and multimorbidity. While the inflammatory response varies in different tissue types, under disease and in response to therapeutic interventions, it has common interactions that occur between immune cells and inflammatory mediators. Understanding these underlying inflammatory mechanisms is key in progressing treatments and therapies for numerous inflammatory conditions. It is now considered that constituent mechanisms of the inflammatory response can be actively manipulated in order to drive resolution of inflammatory damage; particularly, those mechanisms related to the pro-inflammatory role of neutrophils and the anti-inflammatory role of macrophages. In this article, we describe the assembly of a hybrid mathematical model in which the spatial spread of inflammatory mediators is described through partial differential equations, and immune cells (neutrophils and macrophages) are described individually via an agent-based modelling approach. We pay close attention to how immune cells chemotax toward pro-inflammatory mediators, presenting a model for cell chemotaxis that is calibrated against experimentally observed cell trajectories in healthy and COPD-affected scenarios. We illustrate how variations in key model parameters can drive the switch from resolution of inflammation to chronic outcomes, and show that aberrant neutrophil chemotaxis can move an otherwise healthy outcome to one of chronicity. Finally, we reflect on our results in the context of the on-going hunt for new therapeutic interventions.


Subject(s)
Inflammation/etiology , Inflammation/immunology , Leukocytes/immunology , Models, Biological , Systems Analysis , Apoptosis/immunology , Cell Movement/immunology , Chemotaxis, Leukocyte/immunology , Computational Biology , Computer Simulation , Humans , Inflammation/therapy , Inflammation Mediators/immunology , Macrophages/immunology , Neutrophils/immunology , Phagocytosis/immunology , Pulmonary Disease, Chronic Obstructive/etiology , Pulmonary Disease, Chronic Obstructive/immunology , Pulmonary Disease, Chronic Obstructive/therapy
4.
BMC Syst Biol ; 8: 66, 2014 Jun 12.
Article in English | MEDLINE | ID: mdl-24923486

ABSTRACT

BACKGROUND: Sexually-transmitted pathogens often have severe reproductive health implications if treatment is delayed or absent, especially in females. The complex processes of disease progression, namely replication and ascension of the infection through the genital tract, span both extracellular and intracellular physiological scales, and in females can vary over the distinct phases of the menstrual cycle. The complexity of these processes, coupled with the common impossibility of obtaining comprehensive and sequential clinical data from individual human patients, makes mathematical and computational modelling valuable tools in developing our understanding of the infection, with a view to identifying new interventions. While many within-host models of sexually-transmitted infections (STIs) are available in existing literature, these models are difficult to deploy in clinical/experimental settings since simulations often require complex computational approaches. RESULTS: We present STI-GMaS (Sexually-Transmitted Infections - Graphical Modelling and Simulation), an environment for simulation of STI models, with a view to stimulating the uptake of these models within the laboratory or clinic. The software currently focuses upon the representative case-study of Chlamydia trachomatis, the most common sexually-transmitted bacterial pathogen of humans. Here, we demonstrate the use of a hybrid PDE-cellular automata model for simulation of a hypothetical Chlamydia vaccination, demonstrating the effect of a vaccine-induced antibody in preventing the infection from ascending to above the cervix. This example illustrates the ease with which existing models can be adapted to describe new studies, and its careful parameterisation within STI-GMaS facilitates future tuning to experimental data as they arise. CONCLUSIONS: STI-GMaS represents the first software designed explicitly for in-silico simulation of STI models by non-theoreticians, thus presenting a novel route to bridging the gap between computational and clinical/experimental disciplines. With the propensity for model reuse and extension, there is much scope within STI-GMaS to allow clinical and experimental studies to inform model inputs and drive future model development. Many of the modelling paradigms and software design principles deployed to date transfer readily to other STIs, both bacterial and viral; forthcoming releases of STI-GMaS will extend the software to incorporate a more diverse range of infections.


Subject(s)
Models, Biological , Sexually Transmitted Diseases/prevention & control , Software , Adolescent , Chlamydia/immunology , Chlamydia/physiology , Female , Humans , Vaccination
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