Modeling the Progression of Epithelial Leak Caused by Overdistension

Mechanical ventilation is necessary for treatment of the acute respiratory distress syndrome but leads to overdistension of the open regions of the lung and produces further damage. Although we know that the excessive stresses and strains disrupt the alveolar epithelium, we know little about the relationship between epithelial strain and epithelial leak. We have developed a computational model of an epithelial monolayer to simulate leak progression due to overdistension and to explain previous experimental findings in mice with ventilator-induced lung injury. We found a nonlinear threshold-type relationship between leak area and increasing stretch force. After the force required to initiate the leak was reached, the leak area increased at a constant rate with further increases in force. Furthermore, this rate was slower than the rate of increase in force, especially at end-expiration. Parameter manipulation changed only the leak-initiating force; leak area growth followed the same trend once this force was surpassed. These results suggest that there is a particular force (analogous to ventilation tidal volume) that must not be exceeded to avoid damage and that changing cell physical properties adjusts this threshold. This is relevant for the development of new ventilator strategies that avoid inducing further injury to the lung.