Agent-Based Modeling Figure 5. 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). doi:10.1371/journal.pone.0009249.g005 Following lysis of erythrocytes and isolation of total RNA from leukocyte pellets, [57], biotin-labeled cRNA was hybridized to the Hu133A and Hu133B arrays containing a total of 44,924 probes for measuring the expression level of genes that can be either activated or repressed in response to endotoxin. A set of 5,093 probe sets were characterized by significant variation (corresponding to 0.1% false discovery rate) across the time course of the experiment using the SAM software [59]. The data are publicly available through the GEO Omnibus Database (http://www.ncbi.nlm.nih.gov/geo/) under the accession number GSE3284. The data have been appropriately de-identified, and appropriate IRB approval and informed, written consent were obtained by the glue grant investigators [57]. In order to integrate high-throughput transcriptional data we recently introduced a systems level approach [32,60] that decomposes high-dimensional microarray data into a critical set of dynamic features that are considered to be the elementary inflammatory responses triggered by the endotoxin stimulus in peripheral blood leukocytes (PBLs). Our fundamental assumption is that the transcriptional signatures capture the cellular dynamics in response to the inflammatory agent. These constitutive dynamics features are considered to be the ‘‘blueprints’’ of the orchestrated dynamics of the perturbed biological system and include the pro- inflammatory response; a later transcriptional event indicative of anti-inflammation and ultimately the energetic response. The potential of a physicochemical host response model that integrates transcriptional profiling, intricate signaling cascades and indirect response models is demonstrated in [33,34]. Predicated upon the essential interactions that define the propagation of LPS signaling across the system, we opt to translate them into an integrated ABM framework. Developing an Agent Based Model of Endotoxin Induced Human Inflammation The inflammatory response is activated when endotoxin is recognized by pathogen recognition receptors [61]. Such recognition process involves the induction of a signal transduction cascade that triggers downstream critical signaling modules for the activation of transcriptional factors that play a critical role for the transcriptional initiation of inflammatory genes. LPS molecules collide with their receptor, TLR4, on the surface of the macrophages. If the receptor is unoccupied, the LPS molecule will have a probability to bind to its signaling receptor, forming a complex. A receptor that is already bound to a LPS molecule will be unable to receive another one. The bound receptor is also considered activated, in that it will up-regulate the production of TNF-a molecules stimulating downstream intricate signaling cascades. Such a cascade involves the activation of kinase (IKK) activity, which in turn phosphorylates the inhibitor protein IkBa and leads to the activation of the transcription factor NF-kB. The transcriptional end result of this signaling pathway is the production of pro-inflammatory cytokines including IL-12, TNF-a, and IkBa. The IkBa molecules effectively terminate the pathway by forming an inactive complex with nuclear NF-kB in the cytosol. The production of IL-12 initiates the production of IL-4 molecules. These two cytokines populate the system and bind to their respective receptors on the macrophages or type T0 helper cells. The fate of Th-0 cells is determined by the number of either IL-4 or IL-12 on its surface receptors [28]. PLoS ONE | www.plosone.org 8 February 2010 | Volume 5 | Issue 2 | e9249