Crystalline silica (CS), an airborne particulate, is a major global occupational health hazard. While it is known as an important pathogenic factor in many severe lung diseases, the underlying mechanisms of its toxicity are still unclear. In the present study, we found that intra-tracheal instillation of CS caused rapid emergence of necrotic alveolar macrophages. Cell necrosis was a consequence of the release of cathepsin B in CS-treated macrophages, which caused dysfunction of the mitochondrial membrane. Damage to mitochondria disrupted Na⁺/K⁺ ATPase activity in macrophages, leading to intracellular sodium overload and the subsequent cell necrosis. Further studies indicate that CS-induced macrophage necrosis and the subsequent release of mitochondrial DNA could trigger the recruitment of neutrophils in the lung, which was regulated by the TLR9 signaling pathway. In conclusion, our results suggest a novel mechanism whereby CS leads to rapid macrophage necrosis through cathepsin B release, following the leakage of mitochondrial DNA as a key event in the induction of pulmonary neutrophilic inflammation. This study has important implications for the early prevention and treatment of diseases induced by CS.

结晶二氧化硅 (CS) 是一种空气悬浮颗粒物，是一种主要的全球职业健康危害。虽然它被认为是许多严重肺部疾病的重要致病因素，但其毒性的潜在机制仍不清楚。在本研究中，我们发现气管内滴注 CS 导致坏死肺泡巨噬细胞迅速出现。细胞坏死是 CS 处理的巨噬细胞中组织蛋白酶 B 释放的结果，这导致线粒体膜功能障碍。线粒体损伤破坏了 Na ⁺ /K ⁺巨噬细胞中的 ATP 酶活性，导致细胞内钠超载和随后的细胞坏死。进一步的研究表明，CS 诱导的巨噬细胞坏死和随后线粒体 DNA 的释放可以触发肺中中性粒细胞的募集，这受 TLR9 信号通路的调节。总之，我们的研究结果表明了一种新的机制，即在线粒体 DNA 泄漏作为诱导肺中性粒细胞炎症的关键事件之后，CS 通过组织蛋白酶 B 的释放导致巨噬细胞快速坏死。该研究对CS诱发疾病的早期防治具有重要意义。