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

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.