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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

Temporal responses in a persistent infectious inflammatory response.Solid lines correspond to LPS(t = 0 hr) = 1000 which accounts for a prolonged inflammatory activity causing a malfunction in LPS clearance rate. Dashed lines refer to equation-based model predictions for the case of a persistent infectious challenge which can be achieved by manipulating the first order degradation rate of LPS as discussed in the original analysis [34]. The output of both modeling approaches is normalized so that numerically it ranges between (0,1).
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pone-0009249-g005: Temporal responses in a persistent infectious inflammatory response.Solid lines correspond to LPS(t = 0 hr) = 1000 which accounts for a prolonged inflammatory activity causing a malfunction in LPS clearance rate. Dashed lines refer to equation-based model predictions for the case of a persistent infectious challenge which can be achieved by manipulating the first order degradation rate of LPS as discussed in the original analysis [34]. The output of both modeling approaches is normalized so that numerically it ranges between (0,1).

Mentions: An acute pro-inflammatory cytokine “burst” results from intravenous administration of high concentration of LPS into the system of healthy subjects. The subsequent effect is associated with the host's inability to resolve the inflammatory reaction followed by the persistent infectious challenge (unsuccessful clearance of endotoxin) [40], [41]. Accordingly, the prolonged exposure of the system to bacterial infection leads to a significant down-regulation of the endotoxin signaling receptor which further accounts for a slower decay rate causing a dysregulation in the phagocytic capabilities of macrophages [42]. The relevant agent rule that captured such scenario was the “sensitivity” parameter of the endotoxin signaling receptors. As these receptors become saturated during the presence of high amounts of endotoxin, the sensitivity parameter decreases which thereby influences the probability of LPS receptors to be occupied with LPS molecules. During an overwhelming endotoxin challenge, the LPS receptors eventually lose their capability to form additional complexes with LPS, and therefore the LPS agents remain in the system. Although decreased degradation of LPS is not associated with a distinct, well-defined, clinical condition, it is possible that this phenomenon may exist. It is known that triglyceride-rich lipoproteins bind to LPS and that these complexes are cleared by binding to lipoprotein receptors [43]. Furthermore, these receptors are abundant in the liver where ∼70% of lipoproteins are cleared from the circulation. Such malfunction in LPS clearance rate was simulated in Figure 5. Similar to the progression of the increased insult scenario as shown in Figure 4, the progression of a persistent infectious response was simulated due to the activation of the feedforward loop regarding the activation of IKK which drives downstream an aberrant transcriptional activity of NF-kB and thereby affecting the transcriptional rate of the critical pro-inflammatory mediators, e.g. TNF-a. The secretion of TNF-a further amplified the activity of NF-kB through the critical IKK node [44]. These interactions perturb the dynamics associated with the energetic state of the system. Furthermore, we speculated that a switch-like rule related to the energetic state of the cell can be responsible for the disturbance of the homeostatic production of anti-inflammatory mediators. Such rule has been implemented in the ABM framework in that when the energetic state is below 25% of its original value the production of the anti-inflammatory mediators should increase.


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)

Temporal responses in a persistent infectious inflammatory response.Solid lines correspond to LPS(t = 0 hr) = 1000 which accounts for a prolonged inflammatory activity causing a malfunction in LPS clearance rate. Dashed lines refer to equation-based model predictions for the case of a persistent infectious challenge which can be achieved by manipulating the first order degradation rate of LPS as discussed in the original analysis [34]. The output of both modeling approaches is normalized so that numerically it ranges between (0,1).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0009249-g005: Temporal responses in a persistent infectious inflammatory response.Solid lines correspond to LPS(t = 0 hr) = 1000 which accounts for a prolonged inflammatory activity causing a malfunction in LPS clearance rate. Dashed lines refer to equation-based model predictions for the case of a persistent infectious challenge which can be achieved by manipulating the first order degradation rate of LPS as discussed in the original analysis [34]. The output of both modeling approaches is normalized so that numerically it ranges between (0,1).
Mentions: An acute pro-inflammatory cytokine “burst” results from intravenous administration of high concentration of LPS into the system of healthy subjects. The subsequent effect is associated with the host's inability to resolve the inflammatory reaction followed by the persistent infectious challenge (unsuccessful clearance of endotoxin) [40], [41]. Accordingly, the prolonged exposure of the system to bacterial infection leads to a significant down-regulation of the endotoxin signaling receptor which further accounts for a slower decay rate causing a dysregulation in the phagocytic capabilities of macrophages [42]. The relevant agent rule that captured such scenario was the “sensitivity” parameter of the endotoxin signaling receptors. As these receptors become saturated during the presence of high amounts of endotoxin, the sensitivity parameter decreases which thereby influences the probability of LPS receptors to be occupied with LPS molecules. During an overwhelming endotoxin challenge, the LPS receptors eventually lose their capability to form additional complexes with LPS, and therefore the LPS agents remain in the system. Although decreased degradation of LPS is not associated with a distinct, well-defined, clinical condition, it is possible that this phenomenon may exist. It is known that triglyceride-rich lipoproteins bind to LPS and that these complexes are cleared by binding to lipoprotein receptors [43]. Furthermore, these receptors are abundant in the liver where ∼70% of lipoproteins are cleared from the circulation. Such malfunction in LPS clearance rate was simulated in Figure 5. Similar to the progression of the increased insult scenario as shown in Figure 4, the progression of a persistent infectious response was simulated due to the activation of the feedforward loop regarding the activation of IKK which drives downstream an aberrant transcriptional activity of NF-kB and thereby affecting the transcriptional rate of the critical pro-inflammatory mediators, e.g. TNF-a. The secretion of TNF-a further amplified the activity of NF-kB through the critical IKK node [44]. These interactions perturb the dynamics associated with the energetic state of the system. Furthermore, we speculated that a switch-like rule related to the energetic state of the cell can be responsible for the disturbance of the homeostatic production of anti-inflammatory mediators. Such rule has been implemented in the ABM framework in that when the energetic state is below 25% of its original value the production of the anti-inflammatory mediators should increase.

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