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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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Dynamic evolution of model elements that constitute the mechanistic pharmacokinetic model of corticosteroids action given the parameters and initial conditions extracted from [52].
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pone-0004706-g006: Dynamic evolution of model elements that constitute the mechanistic pharmacokinetic model of corticosteroids action given the parameters and initial conditions extracted from [52].

Mentions: The in silico model of inflammation enables us to predict an inflammatory response that does not properly abate making it a critical enabler for the evaluation of corticosteroid-based intervention strategies. Characteristic dynamics of the profiles of the signaling molecules that constitute the corticosteroid intervention envelope are presented in Figure 6. An intravenous injection of the drug, via the activation of intermediate signaling steps, eventually leads to the up-regulation of the active complex, DR(N). Based on the mode of corticosteroids action defined, to be discussed in detailed in the Methods section, we explore the potential of the active signal, DR(N)norm, in modulating the progression of an unresolved inflammation, Figure 7. We observe that such a signal mediates the corticosteroid effect on the transcriptional response level primes the dynamic state of NFkB inhibitor so that it suffices to promote resolution of the inflammatory response. Despite the high initial LPS concentration which perturbs the dynamics of inflammation (dashed lines), the corticosteroid intervention in the form of an intravenous (i.v.) injection initiated at t = 0 hr “reprograms” the dynamic state of the system in favor of a balanced regulation (solid lines). While comparing the dashed and solid lines in Figure 7 we observe that the intervention strategy plays a critical role in the dynamics of IkBa during the first 4 hrs post-LPS where suffices to control the intrinsic inflammmatory dynamics favoring homeostasis within 24 hrs. On the other hand, prior to any intervention the system seems to have lost any potential for attenuation and its inability to adapt to high LPS concentration is mathematically translated into unconstrained responses (dashed lines). Therefore, the intervention envelope based on corticosteroids serves as a critical enabler to explore the capability of different intervention strategies in modulating the progression of systemic inflammation. Another illustration of the protective effect of corticosteroids is shown in Figure 8. We simulate a continuous infusion of the steroid drug that is initiated at t = 0 hr (simultaneously with LPS) and continues for 6 hr post-LPS administration (CORT-LPS strategy). As seen in Figure 8 such treatment strategy suffices to reverse the deleterious outcome of a persistent non-infectious inflammatory response (high initial LPS concentration). Moreover, pre-exposing the system before endotoxin challenge for 6 hr to hypercortisolemia we observe a proper modulation on the progression of the inflammatory response as well, Figure 9. The corticosteroid intervention occurs at t = −6 hr followed by the concomitant administration of the endotoxin stimulus at t = 0 hr and the infusion continues for 6 hr after the endotoxin challenge. In addition, similar responses are observed for the system if it is pre-exposed to hypercortisolemia for 6 hr but the steroid intervention is initiated at t = −12 hr (CORT-6-LPS), Figure 10. However, if the system is pre-exposed to hypercortisolemia for the same duration as previously mentioned (6 hr) but the time interval between the termination of infusion and LPS administration is greater (12 h), Figure 11, we observe a blunted effect of the corticosteroid treatment on the progression of inflammation (Cort-12-LPS). Similar results are obtained if the system is exposed to a continuous infusion of hypercortisolemia initiated at t>0 hr after the administration of endotoxin (i.e. t = 1 hr), dashed lines in Figure 12. On the other hand, as shown in Figure 12 the progression of the inflammatory response is differently perturbed on a dose-dependent manner (dashed lines versus solid). Preserving the route of drug administration the active signal DR(N) must increase in magnitude in order for the system to respond to a multitude of external signals (LPS, Drug).Therefore, dose-dependent profiles are simulated in Figure 12 and Figure 13 where there exists a dosage regime that modulates the dynamics of the system towards resolution.


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)

Dynamic evolution of model elements that constitute the mechanistic pharmacokinetic model of corticosteroids action given the parameters and initial conditions extracted from [52].
© Copyright Policy
Related In: Results  -  Collection

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

pone-0004706-g006: Dynamic evolution of model elements that constitute the mechanistic pharmacokinetic model of corticosteroids action given the parameters and initial conditions extracted from [52].
Mentions: The in silico model of inflammation enables us to predict an inflammatory response that does not properly abate making it a critical enabler for the evaluation of corticosteroid-based intervention strategies. Characteristic dynamics of the profiles of the signaling molecules that constitute the corticosteroid intervention envelope are presented in Figure 6. An intravenous injection of the drug, via the activation of intermediate signaling steps, eventually leads to the up-regulation of the active complex, DR(N). Based on the mode of corticosteroids action defined, to be discussed in detailed in the Methods section, we explore the potential of the active signal, DR(N)norm, in modulating the progression of an unresolved inflammation, Figure 7. We observe that such a signal mediates the corticosteroid effect on the transcriptional response level primes the dynamic state of NFkB inhibitor so that it suffices to promote resolution of the inflammatory response. Despite the high initial LPS concentration which perturbs the dynamics of inflammation (dashed lines), the corticosteroid intervention in the form of an intravenous (i.v.) injection initiated at t = 0 hr “reprograms” the dynamic state of the system in favor of a balanced regulation (solid lines). While comparing the dashed and solid lines in Figure 7 we observe that the intervention strategy plays a critical role in the dynamics of IkBa during the first 4 hrs post-LPS where suffices to control the intrinsic inflammmatory dynamics favoring homeostasis within 24 hrs. On the other hand, prior to any intervention the system seems to have lost any potential for attenuation and its inability to adapt to high LPS concentration is mathematically translated into unconstrained responses (dashed lines). Therefore, the intervention envelope based on corticosteroids serves as a critical enabler to explore the capability of different intervention strategies in modulating the progression of systemic inflammation. Another illustration of the protective effect of corticosteroids is shown in Figure 8. We simulate a continuous infusion of the steroid drug that is initiated at t = 0 hr (simultaneously with LPS) and continues for 6 hr post-LPS administration (CORT-LPS strategy). As seen in Figure 8 such treatment strategy suffices to reverse the deleterious outcome of a persistent non-infectious inflammatory response (high initial LPS concentration). Moreover, pre-exposing the system before endotoxin challenge for 6 hr to hypercortisolemia we observe a proper modulation on the progression of the inflammatory response as well, Figure 9. The corticosteroid intervention occurs at t = −6 hr followed by the concomitant administration of the endotoxin stimulus at t = 0 hr and the infusion continues for 6 hr after the endotoxin challenge. In addition, similar responses are observed for the system if it is pre-exposed to hypercortisolemia for 6 hr but the steroid intervention is initiated at t = −12 hr (CORT-6-LPS), Figure 10. However, if the system is pre-exposed to hypercortisolemia for the same duration as previously mentioned (6 hr) but the time interval between the termination of infusion and LPS administration is greater (12 h), Figure 11, we observe a blunted effect of the corticosteroid treatment on the progression of inflammation (Cort-12-LPS). Similar results are obtained if the system is exposed to a continuous infusion of hypercortisolemia initiated at t>0 hr after the administration of endotoxin (i.e. t = 1 hr), dashed lines in Figure 12. On the other hand, as shown in Figure 12 the progression of the inflammatory response is differently perturbed on a dose-dependent manner (dashed lines versus solid). Preserving the route of drug administration the active signal DR(N) must increase in magnitude in order for the system to respond to a multitude of external signals (LPS, Drug).Therefore, dose-dependent profiles are simulated in Figure 12 and Figure 13 where there exists a dosage regime that modulates the dynamics of the system towards resolution.

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