F. Zhu*, Y. Guan and R. Zhang Pages 381 - 387 ( 7 )
Rationale: Studies have implied the positive association of JAK2/STAT3 signaling with the onset and severity of acute pancreatitis (AP). However, definitive functional study of JAK2/STAT3 signaling in the pathogenesis of acute pancreatitis in vivo is missing and its potential as a therapeutic target and the underlying mechanisms remain to be determined.
Objectives: The aim of this study was to explore the role of JAK2/STAT3 signaling in the pathogenesis of hyperlipidemia-intensified caerulin-induced AP and its potential as a therapeutic target.
Methods and Results: Using the caerulin-induced acute pancreatitis rat model, we showed that JAK2/STAT3 signaling was activated in pancreas and systemic inflammation was increased during AP. Pharmacological suppression of JAK2 by its inhibitor AG490 robustly protected against tissue damage, attenuated JAK2/STAT3 signaling and inflammatory responses. Local pancreatic tissue damage and phosphor- JAK2 in the pancreatic tissue were enhanced in animals fed with high fat diet compared to chow-diet fed animals. Interestingly, JAK2 inhibitor AG490 significantly inhibited pancreas necrosis and systemic inflammation in animals fed with high fat or chow-diet, but did not affect STAT3 signaling.
Conclusion: These results establish that JAK2 activation plays a significant role in the pathogenesis of caerulin-induced AP in animals on both chow and high-fat diets by regulating necrosis and systemic inflammation. Thus, our results not only clarify novel signaling mechanisms in AP but also suggest that JAK2 might constitute a target in the management of hyperlipidemia-intensified caerulin-induced AP.
Pancreatitis, JAK2/STAT3 signaling, necrosis, inflammation, hyperlipidemia, caerulin.
Department of Gastroenterology, Shanghai East Hospital, Shanghai Tongji University, No. 150 Jimo Road, Pudong New District, Shanghai 200120, Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai 200120, Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai 200120