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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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Lethal potentiation.Successive administration of small doses of endotoxin can lead to an unresolved inflammatory response. Solid line: LPS(t = 0 hr) = 350. Dotted line: LPS(t = 0 hr) = 100 & LPS(t = 2 hr) = 250.
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pone-0009249-g007: Lethal potentiation.Successive administration of small doses of endotoxin can lead to an unresolved inflammatory response. Solid line: LPS(t = 0 hr) = 350. Dotted line: LPS(t = 0 hr) = 100 & LPS(t = 2 hr) = 250.

Mentions: Endotoxin hypo-responsiveness is associated with an emergent acquired dynamic state of the system that modulates the response of the system not to respond rigorously to the primary endotoxin challenge. On the other hand, the successive administration of sublethal doses of endotoxin can potentiate the system in that, because of the lack of an acquired state in the dynamics of the system, such an insult may dysregulate the host response dynamics leading to an exacerbated inflammation that cannot resolve. Thus, based on our agent-based model we further explore the behavior of the system when it is either pre-exposed to lower levels of endotoxin for “adequate” time as well as when the system has not manifested its “dynamic memory” to tolerate the second endotoxin challenge [48]. In particular, we simulate such a case administering at t = 0 hr low dose of endotoxin which is shortly followed within 2 hr by another “sub-lethal” insult. From a modeling standpoint, this short time interval was characterized by the accumulation of both pro-inflammatory (P) and anti-inflammatory (A) mediators. The response was exaggerated under conditions of the second endotoxin stimulation due to the priming of various inflammation-specific intracellular signaling molecules which further propagated the inflammatory reaction to nearby cells/agents. The effect of this lethal potentiation scenario was demonstrated in Figure 7. Additionally, if the second dosage was administered when the inflammatory mediators are diminishing, then the effect is less prominent due to both the lack of cytokines and the receptor desensitization which occurs due to pre-existing infection.


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)

Lethal potentiation.Successive administration of small doses of endotoxin can lead to an unresolved inflammatory response. Solid line: LPS(t = 0 hr) = 350. Dotted line: LPS(t = 0 hr) = 100 & LPS(t = 2 hr) = 250.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0009249-g007: Lethal potentiation.Successive administration of small doses of endotoxin can lead to an unresolved inflammatory response. Solid line: LPS(t = 0 hr) = 350. Dotted line: LPS(t = 0 hr) = 100 & LPS(t = 2 hr) = 250.
Mentions: Endotoxin hypo-responsiveness is associated with an emergent acquired dynamic state of the system that modulates the response of the system not to respond rigorously to the primary endotoxin challenge. On the other hand, the successive administration of sublethal doses of endotoxin can potentiate the system in that, because of the lack of an acquired state in the dynamics of the system, such an insult may dysregulate the host response dynamics leading to an exacerbated inflammation that cannot resolve. Thus, based on our agent-based model we further explore the behavior of the system when it is either pre-exposed to lower levels of endotoxin for “adequate” time as well as when the system has not manifested its “dynamic memory” to tolerate the second endotoxin challenge [48]. In particular, we simulate such a case administering at t = 0 hr low dose of endotoxin which is shortly followed within 2 hr by another “sub-lethal” insult. From a modeling standpoint, this short time interval was characterized by the accumulation of both pro-inflammatory (P) and anti-inflammatory (A) mediators. The response was exaggerated under conditions of the second endotoxin stimulation due to the priming of various inflammation-specific intracellular signaling molecules which further propagated the inflammatory reaction to nearby cells/agents. The effect of this lethal potentiation scenario was demonstrated in Figure 7. Additionally, if the second dosage was administered when the inflammatory mediators are diminishing, then the effect is less prominent due to both the lack of cytokines and the receptor desensitization which occurs due to pre-existing infection.

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