Mathematical modeling of ventilator-induced lung inflammation

Abstract

Despite the benefits of mechanical ventilators, prolonged or misuse of ventilators may lead to ventilation-associated/ventilation-induced lung injury (VILI). Lung insults, such as respiratory infections and lung injuries, can damage the pulmonary epithelium, with the most severe cases needing mechanical ventilation for effective breathing and survival. Damaged epithelial cells within the alveoli trigger a local immune response. A key immune cell is the macrophage, which can differentiate into a spectrum of phenotypes ranging from pro- to anti-inflammatory. To gain a greater understanding of the mechanisms of the immune response to VILI and post-ventilation outcomes, we developed a mathematical model of interactions between the immune system and site of damage while accounting for macrophage phenotype. Through Latin hypercube sampling we generated a collection of parameter sets that are associated with a numerical steady state. We then simulated ventilation-induced damage using these steady state values as the initial conditions in order to evaluate how baseline immune state and lung health affect outcomes. We used a variety of methods to analyze the resulting parameter sets, transients, and outcomes, including a random forest decision tree algorithm and parameter sensitivity with eFAST. Analysis shows that parameters and properties of transients related to epithelial repair and M1 activation are important factors. Using the results of this analysis, we hypothesized interventions and used these treatment strategies to modulate the response to ventilation for particular parameters sets.

Keywords: immune response; macrophages; mathematical modeling; mechanical ventilation.