Synergistic cycles of protease activity and inflammation via PPARγ degradation in chronic obstructive pulmonary disease

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 (PPAR gamma), which is known to regulate IL-8 production in the nucleus. Treatment with a PPAR gamma agonist and overexpression of PPAR gamma reversed the NE-induced synergistic increase in LPS-induced IL-8 production. Moreover, PPAR gamma 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, PPAR gamma 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 PPAR gamma degradation plays a role in the pathogenesis of COPD. Lung disease: getting to the root of inflammation Tracing how a protein-degrading enzyme called neutrophil elastase (NE) interacts with cytokines, molecules that trigger inflammation, has revealed a potential new treatment target for chronic obstructive pulmonary disease (COPD). COPD is a progressive disease in which chronic inflammation damages lung function. Although it was known that cytokines play key roles in COPD, the detailed molecular mechanism was not well understood. Chul-Gyu Yoo at Seoul National University College of Medicine in South Korea and co-workers investigated the role that NE plays in inflammation in COPD. They found that NE degraded peroxisome proliferator-activated receptor gamma (PPAR gamma), a transcription factor that keeps cytokine production in check. Patients with COPD showed low levels of PPAR gamma, and boosting PPAR gamma or suppressing NE in cultured cells showed potential for reducing inflammation. These results highlight PPAR gamma as a candidate for development of COPD treatments.