Thrombospondin-1-mediated crosstalk between autophagy and oxidative stress orchestrates repair of blast lung injury.

Coal mining carries inherent risks of catastrophic gas explosions capable of inflicting severe lung injury. Using complementary in vivo and in vitro models, we explored mechanisms underlying alveolar epithelial damage and repair following a gas explosion in this study. In a rat model, the gas explosion was demonstrated to trigger inflammation and injury within the alveolar epithelium. The following scRNA-sequencing revealed that alveolar epithelial cells exhibited the most profound transcriptomic changes after gas explosion compared to other pulmonary cell types. In the L2 alveolar epithelial cells, the blast was found to cause autophagic flux by inducing autophagosome formation, LC3 lipidation, and p62 degradation. Transcriptomic profiling of the L2 cells identified PI3K-Akt and p53 pathways as critical modulators governing autophagic and oxidative stress responses to blast damage. Notably, Thrombospondin-1 (Thbs1) was determined for the first time as a pivotal node interconnecting these two pathways. The findings of this study illuminate intricate mechanisms of alveolar epithelial injury and recovery after blast trauma, highlighting autophagic and oxidative stress responses mediated by Thbs1-associated PI3K-Akt and p53 pathways as high-value therapeutic targets, and strategic modulation of these pathways in future studies may mitigate lung damage by reducing oxidative stress while engaging endogenous tissue repair processes like autophagy.