Modeling the Progression of Epithelial Leak Caused by Overdistension

Abstract

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.

Alveolar leak develops by a rich-get-richer process in ventilator-induced lung injury

“…The modeling results of the present study indicate that VILI develops through the stochastic appearance of new epithelial perforations roughly 50% of the time (0 < r < 0.5) and the widening of an existing hole the remaining 50% of the time (0.5 ≤ r < 1). Since a new hole must presumably be started before it can be subsequently widened, we might speculate that atelectrauma is primarily responsible for the production of new perforations through its direct damaging effects on epithelial cells [ 32 , 33 ], while volutrauma acts to enlarge existing holes via the stretch that it imposes on the alveolar tissues [ 34 ]. This theory may partially explain why recruitment maneuvers and PEEP titration were associated with increased all-cause ARDS mortality in a recent randomized trial [ 35 ].…”

A Physiologically Informed Strategy to Effectively Open, Stabilize, and Protect the Acutely Injured Lung

“…Leak progression in a 45-cell (hexagon) network caused by applied stretch (i.e., Vt). After the force required to initiate the leak was reached, the leak area increased at a constant rate as the force increased further (Hamlington et al, 2016). Atelectrauma caused the initial tears, after which volutrauma expanded those tears.…”

“…Further support for the contention that volutrauma of normal lung tissue is not a primary VILI mechanism comes from the Bates group, who showed that 4 h of mechanical ventilation in mice with high static strain was not associated with lung injury, but when it was combined with high dynamic strain, it caused VILI-induced tissue damage (Seah et al, 2011). Protti et al (2014) showed that a large dynamic strain (atelectrauma) is much more harmful to the normal lung than a large static strain (volutrauma), and when combined, the two work additively or synergistically to greatly accelerate tissue damage (Seah et al, 2011;Hamlington et al, 2016;Ruhl et al, 2019). In addition, the heterogeneous injury caused by ARDS establishes many areas of stress-focus between the open tissue and collapsed or unstable tissue and have been shown to double the stress and strain calculated for the entire lung (Cressoni et al, 2014).…”

“…It is important to note that parenchymal overdistension following acute lung injury is a regional phenomenon and occurs only in open alveoli and alveolar ducts that are adjacent to the unstable or collapsed tissue (Figure 7, PEEP 16, PEEP 5, APRV 10%); it does not occur in homogeneously inflated acutely injured lung tissue (Figure 7, APRV 75%) (Nieman et al, 2017b). It has been shown that combining high pressure with alveolar instability greatly exacerbates tissue tearing in a rich-get-richer fashion (i.e., the larger the initial tear in the epithelial membrane the more that this tear will be expanded by increased airway pressure) (Figure 8) (Hamlington et al, 2016;Ruhl et al, 2019).…”

Microscale distribution and dynamic surface tension of pulmonary surfactant normalize the recruitment of asymmetric bifurcating airways

“…In turn, this can result in a "baby lung" scenario that results in volu-trauma to those portions of the lung that are patent, while other regions remain atelectic. A full understanding of this type of interaction would require a multiscale model that links airway and alveolar fluid-structure behaviors that incorporate physicochemical interactions (2,9,17,32,36,39).…”