Total neutrophil and total macrophage concentrations for inflammatory mediator inhibition by different inhibitor concentrations.

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. We chose to increase the macrophage flux rate and decrease the platelet degradation rate because these rates were identified as robust regulators of the Ψmax and Tact indices for many inflammatory cellular and molecular components, as seen in our sensitivity and correlation analysis results (Table 2 and Figs 2 and 3). Moreover, the role of macrophage influx rate as a chronic inflammation driver has been shown in our previous computational analysis [11]. Experimental studies indicate that a relatively higher inflammation-inducing stimulus often results in chronic inflammation [17, 34]. Thus, we chose to modify the initial platelet concentration, which reflects injury severity in our model. The fold increase/decrease in these parameters was chosen based on the ability of the parametric changes to simulate the experimentally determined inflammatory trajectories from [34]. Black lines represent model predictions for different inhibitor concentrations for the respective mediators. Each inhibitor concentration was added at the time of inflammation initiation (t = 0) during chronic inflammation. a and d: Normalized neutrophil and macrophage concentrations during CXCL8 inhibition for inhibitor concentrations of 10 nM (dotted black), 100 nM (dashed black), and 500 nM (solid black). b and e: Normalized neutrophil and macrophage concentrations during TNF-α inhibition for inhibitor concentrations of 10 nM (dotted black), 100 nM (dashed black), and 500 nM (solid black). c and f: Normalized neutrophil and macrophage concentration during combined inhibition of both CXCL8 and TNF-α, with each inhibitor concentration set to 200 nM (solid black). Also shown are the normalized neutrophil and macrophage concentrations for individual inhibition of CXCL8 (dotted black) and TNF-α (dashed black), with the respective inhibitor concentrations equal to 200 nM. All model-predicted values were normalized to the respective maximum values from the chronic inflammation simulations.