Ventilator-Induced Lung Injury: Mechanotransduction and Potential Therapeutic Targets

Mechanical ventilation (MV) serves as a critical intervention to maintain adequate gas exchange. Unfortunately, MV often leads to the development of ventilator-induced lung injury (VILI). VILI pathogenesis involves alveolar-capillary barrier disruption, dysregulated inflammation, and mechanotransduction-driven cellular dysfunction, but the interplay of these mechanisms remains incompletely understood. Here, we review the types of mechanical stress in VILI, key signaling pathways implicated in MV-induced lung injury, with particular emphasis on the impact of altered mechanical forces in VILI. Furthermore, we discuss the cell-specific mechanisms in VILI. We also delineate the intricate molecular mechanisms that orchestrate intercellular communication in VILI. In addition, we discuss the limitations of current clinical strategies, and the identification of novel drug targets with transformative potential for treatment of VILI. Moreover, we summarize the current and emerging therapeutic strategies and discuss the existing knowledge gaps and future directions for VILI prevention. By integrating mechanical mechanistic insights with translational perspectives, this review identifies novel biomarkers and potential therapeutics to mitigate VILI. Our synthesis not only advances the understanding of VILI pathophysiology but also provides a framework for precision medicine approaches in critical care, ultimately optimizing MV outcomes.