MTOR Suppresses Cigarette Smoke-Induced Airway Inflammation and MMP12 Expression in Macrophage in Chronic Obstructive Pulmonary Disease

Abstract

Lingling Dong,1,* Yong Wang,1,* Haipin Chen,1 Zhouyang Li,1 Xuchen Xu,1 Jiesen Zhou,1 Huahao Shen,1,2 Zhihua Chen1 1Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhihua Chen, Department of Respiratory and Critical Care Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, People’s Republic of China, Tel [phone], Fax [phone], Email [email protected]: Macrophage-derived matrix metalloproteinase 12 (MMP12) can cause destruction of lung tissue structure and plays a significant role in the development and progression of chronic obstructive pulmonary disease (COPD). MTOR is a serine/threonine kinase that plays a crucial role in cell growth and metabolism. The activity of MTOR in the lung tissues of COPD patients also shows significant changes. However, it is unclear whether MTOR can regulate the development and progression of COPD by controlling MMP12. This study primarily investigates whether MTOR in macrophages can affect the expression of MMP12 and participate in the progression of COPD.Methods: We tested the changes in MTOR activity in macrophages exposed to cigarette smoke (CS) both in vivo and in vitro. Additionally, we observed the effect of MTOR on the expression of MMP12 in macrophages and on lung tissue inflammation and structural damage in mice, both in vivo and in vitro, using MTOR inhibitors or gene knockout mice. Finally, we combined inhibitor treatment with gene knockout to demonstrate that MTOR primarily mediates the expression of MMP12 through the NF-κB signaling pathway.Results: Exposure to CS can enhance MTOR activity in mouse alveolar macrophages. Inhibiting the activity of MTOR or suppressing its expression leads to increased expression of MMP12. Myeloid-specific knockout of MTOR expression can promote the occurrence of CS-induced pulmonary inflammation and emphysema in mice. Inhibiting the activity of NF-κB can eliminate the effect of MTOR on MMP12.Conclusion: Macrophage MTOR can reduce the expression of MMP12 by inhibiting NF-κB, thereby inhibiting the occurrence of COPD inflammation and destruction of lung tissue structure. Activating the activity of macrophage MTOR may be beneficial for the treatment of COPD.Keywords: matrix metalloproteinase 12, MMP12, pulmonary emphysema, cigarette smoke, CS, mechanistic target of rapamycin, MTOR

Keywords

• matrix metalloproteinase 12
• mmp12
• pulmonary emphysema
• cigarette smoke
• cs
• mechanistic target of rapamycin
• mtor