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In silico simulation of corticosteroids effect on an NFkB- dependent physicochemical model of systemic inflammation.

Foteinou PT, Calvano SE, Lowry SF, Androulakis IP - PLoS ONE (2009)

Bottom Line: However, if such an intervention occurs long before the inflammatory insult a symptomatic effect is observed instead of a protective relief while a steroid infusion after inducing inflammation requires much higher drug doses.Timing of intervention and dosage regimes appears to be key determinants for the protective or symptomatic effect of exogenous corticosteroids.Such results lie in qualitative agreement with in vivo human studies exposed both to LPS and corticosteroids under various time intervals thus improving our understanding of how interacting modules generate a behavior.

View Article: PubMed Central - PubMed

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

ABSTRACT

Background: During the onset of an inflammatory response signaling pathways are activated for "translating" extracellular signals into intracellular responses converging to the activation of nuclear factor (NF)-kB, a central transcription factor in driving the inflammatory response. An inadequate control of its transcriptional activity is associated with the culmination of a hyper-inflammatory response making it a desired therapeutic target. Predicated upon the nature of the response, a systems level analysis might provide rational leads for the development of strategies that promote the resolution of the response.

Methodology and findings: A physicochemical host response model is proposed to integrate biological information in the form of kinetic rules and signaling cascades with pharmacokinetic models of drug action for the modulation of the response. The unifying hypothesis is that the response is triggered by the activation of the NFkB signaling module and corticosteroids serve as a template for assessing anti-inflammatory strategies. The proposed in silico model is evaluated through its ability to predict and modulate uncontrolled responses. The pre-exposure of the system to hypercortisolemia, i.e. 6 hr before or simultaneously with the infectious challenge "reprograms" the dynamics of the host towards a balanced inflammatory response. However, if such an intervention occurs long before the inflammatory insult a symptomatic effect is observed instead of a protective relief while a steroid infusion after inducing inflammation requires much higher drug doses.

Conclusions and significance: We propose a reversed engineered inflammation model that seeks to describe how the system responds to a multitude of external signals. Timing of intervention and dosage regimes appears to be key determinants for the protective or symptomatic effect of exogenous corticosteroids. Such results lie in qualitative agreement with in vivo human studies exposed both to LPS and corticosteroids under various time intervals thus improving our understanding of how interacting modules generate a behavior.

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Simulation of a knock-out in silico experiment (IkBa−/−).Manipulating the model so that there is no de novo transcriptional synthesis of NF-kB inhibitor (IkBa) which is responsible for the absence of NF-kB auto-regulatory feedback loop. Such a scenario accounts for maladapted activity of NFkBn that triggers an uncompensated inflammatory response.
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pone-0004706-g004: Simulation of a knock-out in silico experiment (IkBa−/−).Manipulating the model so that there is no de novo transcriptional synthesis of NF-kB inhibitor (IkBa) which is responsible for the absence of NF-kB auto-regulatory feedback loop. Such a scenario accounts for maladapted activity of NFkBn that triggers an uncompensated inflammatory response.

Mentions: Kinetic parameters are estimated in order to best reproduce the essential transcriptional responses associated with experimental measurements, (Table 1). The reconstructed dynamic profiles associated with a self-limited inflammatory response, of the major transcriptional signatures coupled with the elementary signaling molecules of NF-kB pathway are presented in Figure 2. In essence, a self-limited inflammatory response involves the successful elimination of the inflammatory stimulus within the first 2 hr post-endotoxin administration while followed by a subsequent resolution within 24 hr. We assess the appropriateness of the structure of the proposed model by simulating a malfunction in the clearance rate of pathogen-derived endotoxin, Figure 3. Such a case is simulated by manipulating (decreasing) the parameter associated with the degradation rate of LPS, kLPS,2. Although decreased degradation of LPS is not associated with a defined clinical condition it is possible that this phenomenon may exist. For example, it is known that triglyceride-rich lipoproteins bind to LPS and that these complexes are cleared by binding to lipoprotein receptors. Furthermore, these receptors are abundant in the liver which clears ∼70% of lipoproteins from the circulation. Therefore, it can be postulated that patients with liver dysfunction may have impaired clearance of LPS. As shown in Figure 3 the inflammatory stimulus persists and leads to an aberrant NFkB activity that drives downstream a chronic inflammatory response. We further evaluate the proposed in silico model by exploring the possibility of a mechanistic maladaption in the dynamics of the regulatory NFkB signaling module. As illustrated in Figure 4, performing an in silico IkBa−/− knock-out experiment we simulate a sustained inflammatory response that fails to resolve. Another mode of perturbation of the underlying dynamics of the probed system is related to the presence of a “prior” insult that coupled with the LPS stimulus account for an overwhelming production of pro-inflammatory mediators, Figure 5. Such a sustained pro-inflammatory signaling deregulates the NFkB signaling module leading to a persistent NFkB activity. Such persistence implies that the nuclear concentration of NFkB cannot be further constrained by its primary inhibitor, IkBa and eventually settle to a steady state far away from their equilibrium (homeostasis). We simulate such a scenario by manipulating the zero order production rate of the pro-inflammatory response (Kin,P) and particularly increasing it twice its initial value.


In silico simulation of corticosteroids effect on an NFkB- dependent physicochemical model of systemic inflammation.

Foteinou PT, Calvano SE, Lowry SF, Androulakis IP - PLoS ONE (2009)

Simulation of a knock-out in silico experiment (IkBa−/−).Manipulating the model so that there is no de novo transcriptional synthesis of NF-kB inhibitor (IkBa) which is responsible for the absence of NF-kB auto-regulatory feedback loop. Such a scenario accounts for maladapted activity of NFkBn that triggers an uncompensated inflammatory response.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2651450&req=5

pone-0004706-g004: Simulation of a knock-out in silico experiment (IkBa−/−).Manipulating the model so that there is no de novo transcriptional synthesis of NF-kB inhibitor (IkBa) which is responsible for the absence of NF-kB auto-regulatory feedback loop. Such a scenario accounts for maladapted activity of NFkBn that triggers an uncompensated inflammatory response.
Mentions: Kinetic parameters are estimated in order to best reproduce the essential transcriptional responses associated with experimental measurements, (Table 1). The reconstructed dynamic profiles associated with a self-limited inflammatory response, of the major transcriptional signatures coupled with the elementary signaling molecules of NF-kB pathway are presented in Figure 2. In essence, a self-limited inflammatory response involves the successful elimination of the inflammatory stimulus within the first 2 hr post-endotoxin administration while followed by a subsequent resolution within 24 hr. We assess the appropriateness of the structure of the proposed model by simulating a malfunction in the clearance rate of pathogen-derived endotoxin, Figure 3. Such a case is simulated by manipulating (decreasing) the parameter associated with the degradation rate of LPS, kLPS,2. Although decreased degradation of LPS is not associated with a defined clinical condition it is possible that this phenomenon may exist. For example, it is known that triglyceride-rich lipoproteins bind to LPS and that these complexes are cleared by binding to lipoprotein receptors. Furthermore, these receptors are abundant in the liver which clears ∼70% of lipoproteins from the circulation. Therefore, it can be postulated that patients with liver dysfunction may have impaired clearance of LPS. As shown in Figure 3 the inflammatory stimulus persists and leads to an aberrant NFkB activity that drives downstream a chronic inflammatory response. We further evaluate the proposed in silico model by exploring the possibility of a mechanistic maladaption in the dynamics of the regulatory NFkB signaling module. As illustrated in Figure 4, performing an in silico IkBa−/− knock-out experiment we simulate a sustained inflammatory response that fails to resolve. Another mode of perturbation of the underlying dynamics of the probed system is related to the presence of a “prior” insult that coupled with the LPS stimulus account for an overwhelming production of pro-inflammatory mediators, Figure 5. Such a sustained pro-inflammatory signaling deregulates the NFkB signaling module leading to a persistent NFkB activity. Such persistence implies that the nuclear concentration of NFkB cannot be further constrained by its primary inhibitor, IkBa and eventually settle to a steady state far away from their equilibrium (homeostasis). We simulate such a scenario by manipulating the zero order production rate of the pro-inflammatory response (Kin,P) and particularly increasing it twice its initial value.

Bottom Line: However, if such an intervention occurs long before the inflammatory insult a symptomatic effect is observed instead of a protective relief while a steroid infusion after inducing inflammation requires much higher drug doses.Timing of intervention and dosage regimes appears to be key determinants for the protective or symptomatic effect of exogenous corticosteroids.Such results lie in qualitative agreement with in vivo human studies exposed both to LPS and corticosteroids under various time intervals thus improving our understanding of how interacting modules generate a behavior.

View Article: PubMed Central - PubMed

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

ABSTRACT

Background: During the onset of an inflammatory response signaling pathways are activated for "translating" extracellular signals into intracellular responses converging to the activation of nuclear factor (NF)-kB, a central transcription factor in driving the inflammatory response. An inadequate control of its transcriptional activity is associated with the culmination of a hyper-inflammatory response making it a desired therapeutic target. Predicated upon the nature of the response, a systems level analysis might provide rational leads for the development of strategies that promote the resolution of the response.

Methodology and findings: A physicochemical host response model is proposed to integrate biological information in the form of kinetic rules and signaling cascades with pharmacokinetic models of drug action for the modulation of the response. The unifying hypothesis is that the response is triggered by the activation of the NFkB signaling module and corticosteroids serve as a template for assessing anti-inflammatory strategies. The proposed in silico model is evaluated through its ability to predict and modulate uncontrolled responses. The pre-exposure of the system to hypercortisolemia, i.e. 6 hr before or simultaneously with the infectious challenge "reprograms" the dynamics of the host towards a balanced inflammatory response. However, if such an intervention occurs long before the inflammatory insult a symptomatic effect is observed instead of a protective relief while a steroid infusion after inducing inflammation requires much higher drug doses.

Conclusions and significance: We propose a reversed engineered inflammation model that seeks to describe how the system responds to a multitude of external signals. Timing of intervention and dosage regimes appears to be key determinants for the protective or symptomatic effect of exogenous corticosteroids. Such results lie in qualitative agreement with in vivo human studies exposed both to LPS and corticosteroids under various time intervals thus improving our understanding of how interacting modules generate a behavior.

Show MeSH
Related in: MedlinePlus