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Agent-based modeling of endotoxin-induced acute inflammatory response in human blood leukocytes.

Dong X, Foteinou PT, Calvano SE, Lowry SF, Androulakis IP - PLoS ONE (2010)

Bottom Line: Such scenarios involve either a persistent (non)infectious response or innate immune tolerance and potentiation effects followed by perturbations in intracellular signaling molecules and cascades.The simulation results are in accordance with our prior research effort associated with the development of deterministic human inflammation models that include transcriptional dynamics, signaling, and physiological components.The hypothetical scenarios explored in this study would potentially improve our understanding of how manipulating the behavior of the molecular species could manifest into emergent behavior of the overall system.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, United States of America.

ABSTRACT

Background: Inflammation is a highly complex biological response evoked by many stimuli. A persistent challenge in modeling this dynamic process has been the (nonlinear) nature of the response that precludes the single-variable assumption. Systems-based approaches offer a promising possibility for understanding inflammation in its homeostatic context. In order to study the underlying complexity of the acute inflammatory response, an agent-based framework is developed that models the emerging host response as the outcome of orchestrated interactions associated with intricate signaling cascades and intercellular immune system interactions.

Methodology/principal findings: An agent-based modeling (ABM) framework is proposed to study the nonlinear dynamics of acute human inflammation. The model is implemented using NetLogo software. Interacting agents involve either inflammation-specific molecules or cells essential for the propagation of the inflammatory reaction across the system. Spatial orientation of molecule interactions involved in signaling cascades coupled with the cellular heterogeneity are further taken into account. The proposed in silico model is evaluated through its ability to successfully reproduce a self-limited inflammatory response as well as a series of scenarios indicative of the nonlinear dynamics of the response. Such scenarios involve either a persistent (non)infectious response or innate immune tolerance and potentiation effects followed by perturbations in intracellular signaling molecules and cascades.

Conclusions/significance: The ABM framework developed in this study provides insight on the stochastic interactions of the mediators involved in the propagation of endotoxin signaling at the cellular response level. The simulation results are in accordance with our prior research effort associated with the development of deterministic human inflammation models that include transcriptional dynamics, signaling, and physiological components. The hypothetical scenarios explored in this study would potentially improve our understanding of how manipulating the behavior of the molecular species could manifest into emergent behavior of the overall system.

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Related in: MedlinePlus

Endotoxin tolerance scenario.Pre-existing infection might cause a profound reduction in cell's capacity (hypo-responsiveness) to respond in the main endotoxin challenge. Solid line: LPS(t = 0 hr) = 750. Dotted line: LPS(t = 0 hr) = 100 & LPS(t = 8 hr) = 650.
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pone-0009249-g006: Endotoxin tolerance scenario.Pre-existing infection might cause a profound reduction in cell's capacity (hypo-responsiveness) to respond in the main endotoxin challenge. Solid line: LPS(t = 0 hr) = 750. Dotted line: LPS(t = 0 hr) = 100 & LPS(t = 8 hr) = 650.

Mentions: The pre-exposure of the host to controlled levels of inflammatory agents affects the eventual fate of the response. It has been observed that repeated doses of endotoxin insult might lead to a less vigorous innate immune response [45]. Such an effect can reverse the lethal outcome of a high dose of the inflammatory stimulus. That is to say, in spite of the potent efficacy of LPS, if the system is pre-exposed to lower sub–lethal doses of LPS then this induces an acquired state of resistance to a subsequent endotoxin challenge [46]. This phenomenon, known as endotoxin hypo-responsiveness is a multifactorial problem that can be associated with decreased TLR signaling by proteins that negatively regulate LPS-induced inflammatory responses [47]. From a modeling standpoint, small dose of LPS is administered 8 hours prior to the main endotoxin insult. Such perturbation modulates the dynamic profiles of both pro-inflammatory and anti-inflammatory mediators as well as the energetic state of the macrophage populations towards resolution within 24 hours. The endotoxin hyporesponsiveness was simulated in Figure 6 where pre-existing infection caused a profound reduction in cells' capacity to respond to the main (high) endotoxin challenge. There were no agent rules that specified the time interval between the injections that would yield the emergent attenuated response. From a biological standpoint the prior inflammatory insult desensitizes the endotoxin signaling receptors in a manner that these receptors become less sensitive to the subsequent infectious challenge and therefore the cells have enough time to mitigate the endotoxin challenge and resolve the inflammatory reaction.


Agent-based modeling of endotoxin-induced acute inflammatory response in human blood leukocytes.

Dong X, Foteinou PT, Calvano SE, Lowry SF, Androulakis IP - PLoS ONE (2010)

Endotoxin tolerance scenario.Pre-existing infection might cause a profound reduction in cell's capacity (hypo-responsiveness) to respond in the main endotoxin challenge. Solid line: LPS(t = 0 hr) = 750. Dotted line: LPS(t = 0 hr) = 100 & LPS(t = 8 hr) = 650.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2823776&req=5

pone-0009249-g006: Endotoxin tolerance scenario.Pre-existing infection might cause a profound reduction in cell's capacity (hypo-responsiveness) to respond in the main endotoxin challenge. Solid line: LPS(t = 0 hr) = 750. Dotted line: LPS(t = 0 hr) = 100 & LPS(t = 8 hr) = 650.
Mentions: The pre-exposure of the host to controlled levels of inflammatory agents affects the eventual fate of the response. It has been observed that repeated doses of endotoxin insult might lead to a less vigorous innate immune response [45]. Such an effect can reverse the lethal outcome of a high dose of the inflammatory stimulus. That is to say, in spite of the potent efficacy of LPS, if the system is pre-exposed to lower sub–lethal doses of LPS then this induces an acquired state of resistance to a subsequent endotoxin challenge [46]. This phenomenon, known as endotoxin hypo-responsiveness is a multifactorial problem that can be associated with decreased TLR signaling by proteins that negatively regulate LPS-induced inflammatory responses [47]. From a modeling standpoint, small dose of LPS is administered 8 hours prior to the main endotoxin insult. Such perturbation modulates the dynamic profiles of both pro-inflammatory and anti-inflammatory mediators as well as the energetic state of the macrophage populations towards resolution within 24 hours. The endotoxin hyporesponsiveness was simulated in Figure 6 where pre-existing infection caused a profound reduction in cells' capacity to respond to the main (high) endotoxin challenge. There were no agent rules that specified the time interval between the injections that would yield the emergent attenuated response. From a biological standpoint the prior inflammatory insult desensitizes the endotoxin signaling receptors in a manner that these receptors become less sensitive to the subsequent infectious challenge and therefore the cells have enough time to mitigate the endotoxin challenge and resolve the inflammatory reaction.

Bottom Line: Such scenarios involve either a persistent (non)infectious response or innate immune tolerance and potentiation effects followed by perturbations in intracellular signaling molecules and cascades.The simulation results are in accordance with our prior research effort associated with the development of deterministic human inflammation models that include transcriptional dynamics, signaling, and physiological components.The hypothetical scenarios explored in this study would potentially improve our understanding of how manipulating the behavior of the molecular species could manifest into emergent behavior of the overall system.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, United States of America.

ABSTRACT

Background: Inflammation is a highly complex biological response evoked by many stimuli. A persistent challenge in modeling this dynamic process has been the (nonlinear) nature of the response that precludes the single-variable assumption. Systems-based approaches offer a promising possibility for understanding inflammation in its homeostatic context. In order to study the underlying complexity of the acute inflammatory response, an agent-based framework is developed that models the emerging host response as the outcome of orchestrated interactions associated with intricate signaling cascades and intercellular immune system interactions.

Methodology/principal findings: An agent-based modeling (ABM) framework is proposed to study the nonlinear dynamics of acute human inflammation. The model is implemented using NetLogo software. Interacting agents involve either inflammation-specific molecules or cells essential for the propagation of the inflammatory reaction across the system. Spatial orientation of molecule interactions involved in signaling cascades coupled with the cellular heterogeneity are further taken into account. The proposed in silico model is evaluated through its ability to successfully reproduce a self-limited inflammatory response as well as a series of scenarios indicative of the nonlinear dynamics of the response. Such scenarios involve either a persistent (non)infectious response or innate immune tolerance and potentiation effects followed by perturbations in intracellular signaling molecules and cascades.

Conclusions/significance: The ABM framework developed in this study provides insight on the stochastic interactions of the mediators involved in the propagation of endotoxin signaling at the cellular response level. The simulation results are in accordance with our prior research effort associated with the development of deterministic human inflammation models that include transcriptional dynamics, signaling, and physiological components. The hypothetical scenarios explored in this study would potentially improve our understanding of how manipulating the behavior of the molecular species could manifest into emergent behavior of the overall system.

Show MeSH
Related in: MedlinePlus