Regulation of Endothelial Cell Death in Inflammatory Lung Injury

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are heterogeneous and potentially fatal consequences of serious conditions such as trauma and sepsis, an exacerbated inflammatory response to infection. There are no effective treatments for ALI/ARDS, partly due to an incomplete understanding of its pathogenesis across different patient sub-populations, contributing to mortality rates of 25-40%. ALI/ARDS is characterized by lung hypoxia, inflammatory cell infiltration, edema, and endothelial cell injury and death. Lung endothelial viability is essential for gas exchange, nutrient delivery, and immune cell migration, as well as the prevention of proteinaceous fluid accumulation. Given that lung endothelial death is a predominant feature of ALI/ARDS, its inhibition could represent a novel therapeutic strategy. In this article, we review studies examining pulmonary endothelium death during sepsis-induced ALI/ARDS, including studies of lung endothelium apoptosis, pyroptosis, necroptosis, and ferroptosis. We also highlight gaps in current knowledge that, if addressed, could facilitate the development of effective treatments for sepsis-induced ALI/ARDS. Future studies of the mechanisms regulating lung endothelial death may uncover novel therapeutic targets for ALI/ARDS. These targets could be leveraged in precision medicine approaches to treat patient sub-populations most likely to benefit from inhibiting specific forms of lung endothelial death.