Patients with serious lung infections (including COVID-19) suffer from a disease called the acute respiratory distress syndrome (ARDS). During ARDS, the alveolar-capillary barrier is damaged leading to fluid occlusion of the lung (pulmonary edema). Although these patients must be mechanically ventilation to survive, the mechanical ventilation of patients with pulmonary edema generates a complex set of fluid mechanical forces on the airway/alveolar epithelium. The Ghadiali lab has used a) computational fluid dynamic techniques to characterize these mechanical forces, b) novel in-vitro systems to understand how lung cells respond to these forces and c) molecular biology techniques to identify the mechanotransduction mechanisms that lead to ventilation induced lung injury. More recently, the lab has used a novel “ventilator-on-a-chip” system to account for both multicellular interactions and the complex mechanical environment that exists in-vivo. Using these in-vitro “lung-on-a-chip” systems we have demonstrated that specific changes in the cell’s cytoskeletal mechanical properties can be used to prevent this injury and that clinically approved pharmaceuticals (i.e. Statins) can prevent cell injury by altering cell mechanics. We have also demonstrated that changes in matrix mechanics and structure, as occurs during other pulmonary diseases, may be an important determinate of cell injury during mechanical ventilation. We have also developed a humanized in-vitro system which not only expose co-cultures of primary human cells (epithelial, endothelial and immune cells) to complex mechanical forces but also to recapitulate the clinical conditions that precipitate ARDS and ventilation induced lung injury (VILI). Our long term goal is to use these in-vitro models to identify which therapeutic strategies may be most effective at reducing VILI in a given patient.
Selected Publications:
Gabela-Zuniga, B., Shukla, V.C., Bobba, C., Higuita-Castro, N., Powell, H.M., Englert, J.E., Ghadiali, S.N., A Micro-scale Humanized Ventilator-on-a-Chip to Examine the Injurious Effects of Mechanical Ventilation, preprint at bioRxiv, submitted to Lab-on-a-Chip, 26 February 2024, doi: https://doi.org/10.1101/2024.02.26.582200