Inflammation, oxidative stress, and protease–antiprotease imbalance have been suggested to be a pathogenic triad in chronic obstructive pulmonary disease (COPD). However, it is not clear how proteases interact with components of inflammatory pathways. Therefore, this study aimed to evaluate the effect of neutrophil elastase (NE) on lipopolysaccharide (LPS)-induced interleukin 8 (IL-8) production and determine the molecular mechanism in human bronchial epithelial cells (HBECs). Immortalized bronchial epithelial cells and primary HBECs were used to investigate the impact of NE on LPS-induced IL-8 production. The molecular mechanism by which NE modulated LPS-induced IL-8 production was confirmed in elastase-treated C57BL/6 mice and primary HBECs obtained from COPD patients and healthy controls. The results showed that NE treatment synergistically augmented LPS-induced IL-8 production in both immortalized bronchial epithelial cells and primary HBECs. NE partially degraded peroxisome proliferator-activated receptor gamma (PPARγ), which is known to regulate IL-8 production in the nucleus. Treatment with a PPARγ agonist and overexpression of PPARγ reversed the NE-induced synergistic increase in LPS-induced IL-8 production. Moreover, PPARγ levels were lower in lung homogenates and lung epithelial cells from elastase-treated mice than in those from saline-treated mice. In accordance with the findings in mice, PPARγ levels were lower in primary HBECs from COPD patients than in those from healthy never-smokers or healthy smokers. In conclusion, a vicious cycle of mutual augmentation of protease activity and inflammation resulting from PPARγ degradation plays a role in the pathogenesis of COPD.

炎症、氧化应激和蛋白酶-抗蛋白酶失衡被认为是慢性阻塞性肺病 (COPD) 的致病三联征。然而，尚不清楚蛋白酶如何与炎症通路的成分相互作用。因此，本研究旨在评估中性粒细胞弹性蛋白酶 (NE) 对脂多糖 (LPS) 诱导的白细胞介素 8 (IL-8) 产生的影响，并确定人支气管上皮细胞 (HBEC) 的分子机制。永生化支气管上皮细胞和原代 HBEC 用于研究 NE 对 LPS 诱导的 IL-8 产生的影响。NE 调节 LPS 诱导的 IL-8 产生的分子机制在弹性蛋白酶处理的 C57BL/6 小鼠和从 COPD 患者和健康对照获得的原发性 HBEC 中得到证实。结果表明，NE 治疗协同增强了 LPS 诱导的永生化支气管上皮细胞和原代 HBEC 中 IL-8 的产生。NE 部分降解过氧化物酶体增殖物激活受体 γ (PPARγ)，已知其可调节细胞核中 IL-8 的产生。用 PPARγ 激动剂治疗和 PPARγ 的过表达逆转了 NE 诱导的 LPS 诱导的 IL-8 产生的协同增加。此外，弹性蛋白酶处理小鼠的肺匀浆和肺上皮细胞中的 PPARγ 水平低于生理盐水处理的小鼠。根据在小鼠中的发现，COPD 患者的原发性 HBEC 中的 PPARγ 水平低于健康的从不吸烟者或健康吸烟者的 PPARγ 水平。综上所述，