Many patients who suffer from pulmonary diseases cannot inflate their lungs normally, as they need mechanical ventilation (MV) to assist them . The stress associated with MV can damage the delicate epithelium in small airways and alveoli, which can cause complications resulting in ventilation-induced lung injuries (VILIs) in many cases, especially in patients with acute respiratory distress syndrome (ARDS). Therefore, efforts were directed to develop safe modes for MV . In our work, we propose a different approach to decrease injuries of epithelial cells (EpCs) upon MV . We alter EpCs' cytoskeletal structure to increase their survival rate during airway reopening conditions associated with MV . We tested two anti-inflammatory drugs dexamethasone (DEX) and transdehydroandrosterone (DHEA) to alter the cytoskeleton . Cultured rat L2 alveolar EpCs were exposed to airway reopening conditions using a parallel-plate perfusion chamber . Cells were exposed to a single bubble propagation to simulate stresses associated with mechanical ventilation in both control and study groups . Cellular injury and cytoskeleton reorganization were assessed via fluorescence microscopy, whereas cell topography was studied via atomic force microscopy (AFM). Our results indicate that culturing cells in media, DEX solution, or DHEA solution did not lead to cell death (static cultures). Bubble flows caused significant cell injury . Preexposure to DEX or DHEA decreased cell death significantly . The AFM verified alteration of cell mechanics due to actin fiber depolymerization . These results suggest potential beneficial effects of DEX and DHEA for ARDS treatment for patients with COVID-19 . They are also critical for VILIs and applicable to future clinical studies.NEW & NOTEWORTHY Preexposure of cultured cells to either dexamethasone or transdehydroandrosterone significantly decreases cellular injuries associated with mechanical ventilation due to their ability to alter the cell mechanics . This is an alternative protective method against VILIs instead of common methods that rely on modification of mechanical ventilator modes.