Age-dependent ventilator-induced lung injury: Mathematical modeling, experimental data, and statistical analysis

A variety of pulmonary insults can result in the necessity for mechanical ventilation, which, when misused, used for prolonged periods of time, or associated with an excessive inflammatory response, can result in ventilator-induced lung injury. Older patients have been observed to have an increased risk for respiratory distress with ventilation and more recent studies suggest that this could be linked to disparities in the inflammatory response. To address this, we ventilated young (2-3 months) and old (20-25 months) mice for 2 hours using high pressure mechanical ventilation and extracted data for inflammatory cell ratios, namely macrophage phenotypes, and lung tissue integrity. A large difference in naive macrophages at baseline, alternatively-activated (M2) macrophages at baseline, and airspace enlargement after ventilation was observed in the old mice. The experimental data was used to fit a mathematical model for the inflammatory response to lung injury. Model variables include inflammatory markers and cells, namely neutrophils and macrophages, epithelial cells at varying states, and repair mediators. Parameter sampling was performed using an iterative sampling method and parameter sets were selected based on their ability to fit either the old or young macrophage phenotype percentages and epithelial variables at zero and two hours. Classification methods were performed to identify influential parameters separating the old and young parameter sets as well as user-defined health states. Parameters involved in repair and damage to epithelial cells and parameters regulating the pro-inflammatory response were shown to be important. Local sensitivity analysis preformed for the different epithelial cell variables produced similar results. A pseudo-intervention was also performed on the parameter sets. The results were most influential for the old parameter sets, specifically those with poorer lung health. These results indicate potential targets for therapeutic interventions prior to and during ventilation, particularly for old subjects. Author summary A variety of inhaled pathogens and other pulmonary insults prompt the need for mechanical ventilation; a procedure that has become increasingly necessary following the 2019 coronavirus pandemic. A proportion of patients respond poorly to ventilation, some resulting in ventilator-induced lung injury. Observational data has shown increased instance of severe disease in older patients as well as differences in the inflammatory response to injury, although more research is needed to confirm this. We performed high-pressure ventilation on young (2-3 months) and old (20-25 months) mice and observed large disparities in inflammatory cell ratios at baseline and lung tissue integrity after ventilation. The experimental data was then used to fit a mathematical model of the inflammatory response to lung injury. We used a variety of analysis methods to identify important parameters separating the young and old parameter sets and user-defined health states of the resulting simulations. Parameters involved in damage and repair of epithelial cells in the lung as well as parameters controlling the pro-inflammatory response to injury were important in both classifying between old and young sets and determining predicted health after ventilation. These results indicate potential targets for therapeutic interventions prior to and during ventilation. ### Competing Interest Statement The authors have declared no competing interest.