Rhein Mitigates Lung Injury in Severe Acute Pancreatitis Through the Inhibition of MARK4-Mediated Microtubule Destabilization

Abstract

Zhenxuan Sun,1– 3,* Jie Liu,1– 3,* Peng Ge,1– 3,* Yinan Cao,4 Jin Liu,1– 3 Haiyun Wen,1– 3 Xinyu Luo,1– 3 Boliang Pei,1– 3 Zuocang Jin,1,3 Huijuan Li,3 Lu Xun,1– 3 Yalan Luo,5 Qi Yang,6 Hailong Chen1– 3 1Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 2Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 3Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 4Day Surgery Center, Dalian Municipal Central Hospital, Dalian, Liaoning, 116033, People’s Republic of China; 5Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 6Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116023, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hailong Chen, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Zhongshan Road 222, Dalian, Liaoning, 116011, People’s Republic of China, Tel [phone], Fax [phone], Email [email protected]: Explore the therapeutic effect and molecular mechanism of rhein on severe acute pancreatitis associated acute lung injury (SAP-ALI).Methods: The SAP-ALI rat model was constructed by retrograde injection of 5% sodium taurocholate into the pancreaticobiliary duct, and pulmonary microvascular endothelial cell (PMVEC) injury model was induced by LPS. The potential therapeutic effects and appropriate dosages of rhein on SAP-ALI and PMVEC were investigated in both in vivo and in vitro experiments. Furthermore, the regulatory role of MARK4 in the related pathological process were confirmed by some experimental methods. RNA sequencing analysis was performed to explore the potential downstream genes of MARK4. Moreover, the regulatory effect of rhein on MARK4 was validated through molecular docking and rescue experiments.Results: Rhein intervention had potential therapeutic effects on acute lung injury triggered by SAP and pulmonary endothelial cell injury induced by LPS. MARK4 may contribute to pulmonary endothelial cell injury through the modulation of microtubule structure. Compared with LPS stimulation, a total of 2081 differentially expressed genes were identified after MARK4 knockdown. The results of molecular docking and rescue experiments indicated that rhein may exert its protective effects by targeting MARK4.Conclusion: Rhein may regulate the microtubule structure by targeting MARK4, thereby alleviating SAP-ALI and LPS-induced pulmonary endothelial cell injury. Keywords: rhein, microtubule, severe acute pancreatitis, acute lung injury

Keywords

• rhein
• microtubule
• severe acute pancreatitis
• acute lung injury