International Session (Workshop)1(JSGE・JGES・JSGS)
November 3 (Thu.), 14:00–17:00, Room 8 (Portopia Hotel Main Building Kairaku 2)
IS-W1-Keynote Lecture1

Recent Insights into Pathophysiology of Chronic Pancreatitis

A. K. Saluja
Department of Surgery, Sylvester Pancreatic Cancer Research Institute, University of Miami Miller School of Medicine
Chronic pancreatitis (CP) is a fibro-inflammatory disease of the pancreas with significant morbidity and mortality. Its pathogenesis remains poorly understood with the current theories heavily based on extrapolations from acute pancreatitis. However, the relationship between acute and chronic pancreatitis has not been well established either. Pathologic intra-acinar trypsinogen activation has been regarded as the key event of pancreatitis for more than a century. The identification of a trypsinogen (PRSS1) mutation in hereditary pancreatitis (an uncommon form of CP) in 1996 has served to further consolidate support by many experts of this paradigm. However, no evidence exists to convincingly establish this paradigm of trypsin-based pancreatic injury as the pathogenic mechanism of CP.

In our recent studies, we have explored the currently accepted paradigm of trypsin-based pancreatic injury as the pathogenic mechanism of CP. We have used novel models that lack pathologic trypsinogen activation. Using Trypsin-7 and cathepsin B null mice, we have established that the pathogenesis of chronic pancreatitis does not require intra-acinar trypsinogen activation. Activation of NFκB pathway has been previously recognized during early pancreatic injury in experimental models. However, its relationship with trypsinogen activation has been a matter of heated debate with conflicting results complicated by limitations of existing models. Using T-/- and CB-/- mice, we have established that intra-acinar NFκB activation occurs early during pancreatitis independent of trypsinogen activation. Importantly, persistent activation of NFκB was also seen in human CP, which confirms the experimental findings.

Furthermore, our results also establish that ER stress is chronically activated in CP and is induced early in pancreatic injury through pathologic calcium signaling independent of trypsinogen activation. ER stress may be an important pathogenic mechanism in pancreatitis that needs to be explored in future studies.

In conclusion, our results establish that intra-acinar trypsinogen activation is not required for chronic pancreatitis. Independent of trypsinogen activation, persistent activation of NFκB and ER stress pathway occurs in CP and may be important in its pathogenesis.
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