Total neutrophil and total macrophage concentrations for inflammatory mediator inhibition at different time points.

Green and red lines represent model predictions for acute and chronic inflammation, respectively. We simulated chronic inflammation by increasing the initial platelet concentration by 100 fold, increasing the macrophage influx rate parameter by 1.5 fold, and simultaneously decreasing the platelet degradation rate parameter by 1.5 fold. In all the subplots, the time points of inhibitor addition (represented by the black lines) are as follows: dotted, 24 h; dashed, 48 h; and solid, 72 h. Shown are normalized neutrophil (a-c) and normalized macrophage (d-f) kinetics for CXCL8, TNF-α, and combined CXCL8 + TNF-α inhibition. The concentration of each of the considered inhibitors was equal to 200 nM. All model-predicted values were normalized to the respective maximum values from the chronic inflammation simulations. In our simulations, the 72 h time point was chosen for mediator inhibitor addition based on an experimental study that evaluated the efficacy of several pro-resolution drugs in a mouse peritoneal infection model [17]. Furthermore, we chose the 24 h and 48 h time points for mediator inhibitor addition because they represent the times at which the neutrophil and macrophage concentrations peak, respectively, in our acute inflammation simulation [11].