Yifan Ren1,2, Wuming Liu1,2, Lin Zhang4, Jia Zhang1,2, Jianbin Bi1,2, Tao Wang1,2, Mengzhou Wang1,2, Zhaoqing Du1,2, Yawen Wang3,4, Lin Zhang4, Zheng Wu2, Yi Lv1,2, Lingzhong Meng5, Rongqian Wu1. 1. National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University., Xi'an, Shaanxi Province, China. 2. Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University., Xi'an, Shaanxi Province, China. 3. Biobank, First Affiliated Hospital of Xi'an Jiaotong University., Xi'an, Shaanxi Province, China. 4. Department of Laboratory Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China. 5. Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut, USA.
Abstract
Acute pancreatitis (AP) remains a significant clinical challenge. Mitochondrial dysfunction contributes significantly to the pathogenesis of AP. Milk fat globule EGF factor 8 (MFG-E8) is an opsonizing protein, which has many biological functions via binding to αvβ3/5 integrins. Ligand-dependent integrin-FAK activation of STAT3 was reported to be of great importance for maintaining a normal mitochondrial function. However, MFG-E8's role in AP has not been evaluated. METHODS: Blood samples were acquired from 69 healthy controls and 134 AP patients. Serum MFG-E8 levels were measured by ELISA. The relationship between serum concentrations of MFG-E8 and disease severity were analyzed. The role of MFG-E8 was evaluated in experimental models of AP. RESULTS: Serum concentrations of MFG-E8 were lower in AP patients than healthy controls. And serum MFG-E8 concentrations were negatively correlated with disease severity in AP patients. In mice, MFG-E8 administration decreased L-arginine-induced pancreatic injury and mortality. MFG-E8's protective effects in experimental AP were associated with improvement in mitochondrial function and reduction in oxidative stress. MFG-E8 knockout mice suffered more severe pancreatic injury and greater mitochondrial damage after l-arginine administration. Mechanistically, MFG-E8 activated the FAK-STAT3 pathway in AP mice. Cilengitide, a specific αvβ3/5 integrin inhibitor, abolished MFG-E8's beneficial effects in AP. PF00562271, a specific FAK inhibitor, blocked MFG-E8-induced STAT3 phosphorylation. APTSTAT3-9R, a specific STAT3 antagonist, also eliminated MFG-E8's beneficial effects under such a condition. CONCLUSIONS: MFG-E8 acts as an endogenous protective mediator in the pathogenesis of AP. MFG-E8 administration protects against AP possibly by restoring mitochondrial function via activation of the integrin-FAK-STAT3 signaling pathway. Targeting the action of MFG-E8 may present a potential therapeutic option for AP.
Acute pancreatitis (AP) remains a significant clinical challenge. Mitochondrial dysfunction contributes significantly to the pathogenesis of AP. Milk fat globule EGF factor 8 (MFG-E8) is an opsonizing protein, which has many biological functions via binding to αvβ3/5 integrins. Ligand-dependent integrin-FAK activation of STAT3 was reported to be of great importance for maintaining a normal mitochondrial function. However, MFG-E8's role in AP has not been evaluated. METHODS: Blood samples were acquired from 69 healthy controls and 134 AP patients. Serum MFG-E8 levels were measured by ELISA. The relationship between serum concentrations of MFG-E8 and disease severity were analyzed. The role of MFG-E8 was evaluated in experimental models of AP. RESULTS: Serum concentrations of MFG-E8 were lower in AP patients than healthy controls. And serum MFG-E8 concentrations were negatively correlated with disease severity in AP patients. In mice, MFG-E8 administration decreased L-arginine-induced pancreatic injury and mortality. MFG-E8's protective effects in experimental AP were associated with improvement in mitochondrial function and reduction in oxidative stress. MFG-E8 knockout mice suffered more severe pancreatic injury and greater mitochondrial damage after l-arginine administration. Mechanistically, MFG-E8 activated the FAK-STAT3 pathway in AP mice. Cilengitide, a specific αvβ3/5 integrin inhibitor, abolished MFG-E8's beneficial effects in AP. PF00562271, a specific FAK inhibitor, blocked MFG-E8-induced STAT3 phosphorylation. APTSTAT3-9R, a specific STAT3 antagonist, also eliminated MFG-E8's beneficial effects under such a condition. CONCLUSIONS: MFG-E8 acts as an endogenous protective mediator in the pathogenesis of AP. MFG-E8 administration protects against AP possibly by restoring mitochondrial function via activation of the integrin-FAK-STAT3 signaling pathway. Targeting the action of MFG-E8 may present a potential therapeutic option for AP.
Authors: Gyorgy Biczo; Eszter T Vegh; Natalia Shalbueva; Olga A Mareninova; Jason Elperin; Ethan Lotshaw; Sophie Gretler; Aurelia Lugea; Sudarshan R Malla; David Dawson; Piotr Ruchala; Julian Whitelegge; Samuel W French; Li Wen; Sohail Z Husain; Fred S Gorelick; Peter Hegyi; Zoltan Rakonczay; Ilya Gukovsky; Anna S Gukovskaya Journal: Gastroenterology Date: 2017-10-23 Impact factor: 22.682
Authors: Matthias Sendler; Cindy van den Brandt; Juliane Glaubitz; Anika Wilden; Janine Golchert; Frank Ulrich Weiss; Georg Homuth; Laura L De Freitas Chama; Neha Mishra; Ujjwal Mukund Mahajan; Lukas Bossaller; Uwe Völker; Barbara M Bröker; Julia Mayerle; Markus M Lerch Journal: Gastroenterology Date: 2019-10-05 Impact factor: 22.682