Endogenous “Time Bomb” – Mislocalized Phospholipase A2 as a Critical Mediator of Ultra‐Rapid Mortality in Sepsis and Acute Lung Injury

ABSTRACT This study reveals that phospholipase A2 (PLA2), normally stable and nontoxic, can be activated specifically within the alveolar environment to induce rapid, “electric shock‐like” lethality, akin to chemical toxins, while also exhibiting extreme toxicity comparable to that of biological toxins, and functioning as a potential “time bomb” in the body. When exacerbated inflammation impairs the pulmonary barrier, PLA2 from the circulation can penetrate into the lungs. Once activated in the alveolar space, it rapidly hydrolyzes pulmonary surfactant phospholipids, causing a drastic decline in surface tension (>30%). This leads to alveolar overdistension, instantaneous respiratory failure, and asphyxiation—an acute mortality effect strikingly similar to that observed in sepsis and severe pulmonary diseases. PLA2 penetration and lethality are more pronounced in aged animals. Based on these findings, a combination therapy comprising phospholipase (dioleoylphosphatidylserine) and an inhibitor (varespladib) was developed, which significantly improved survival rates from 0% to over 90% in mice with sepsis, acute lung injury, and PLA2 poisoning. This study provides critical theoretical foundations and intervention strategies for the clinical treatment of related diseases.