Interrelationship between autophagosomal zymogen activation and the inflammation cascade in chronic pancreatitis

• Applicant: Dr. Thomas Wartmann
• Subject Area: General and Visceral Surgery
• Term: from 2012 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 228530019

In the recent 15 years a number of chronic pancreatitis associated mutations in genes were identified which code for digestive proteases or their inactivating enzymes and inhibitors. These findings support the hypothesis that the premature activation of zymogens within the acinar cell plays a pivotal role in the pathogenesis of pancreatitis. The pathophysiological mechanisms of this activation process leading to acinar cell injury are to some extent characterized for experimental models of acute pancreatitis. For the pathogenesis of chronic pancreatitis a sequence of tissue necrosis and inflammation is hypothesized that includes that repetitive attacks of acute pancreatitis lead to progressive acinar cell atrophy and fibrosis. Necrosis in the exocrine pancreatic tissue is associated with the appearance of activated pancreatic hydrolytic enzyme, especially proteases. However, the activation process and the role of defence factors in the course of relapsing acute pancreatitis are not investigated.Although the principal pathways and the factors involved in zymogen activation are somewhat understood, the subcellular compartment of the activation process was found only recently. We and other groups could demonstrate that the autophagolysosome represents the organelle in which trypsin activity appears, but at a relatively late time-point in the course of experimental acute pancreatitis. The pathophysiological role of autophagolysosomal zymogen activation in detail is currently under investigation. Published results indicate that experimental acute pancreatitis is associated with an impaired autophagolysosomal formation and function. Therefore, we hypothesize that unimpaired autophagy represents a protective mechanism, and an impairment of this process leads to pathophysiological zymogen activation, acinar cell injury, initially acute, and later chronic pancreatitis. Presently, little is known about the role of key cellular signalling pathways and initiation factors of the autophagic process in the pathogenesis of pancreatitis. We therefore wish to study the pathophysiological role of autophagy in chronic pancreatitis using various strains of mice in which key regulator genes were genetically deleted and which allow us to study their role in the course of the disease. They include ATG5-deleted animals defective in autophagosome formation, and p62-deleted mice with impaired function in cargo selection. The possible role of NF(kappa)B signalling in pancreatitis-linked autophagy will be studied using RelA/p65-deleted and I(kappa)B(alpha)-deleted mice.The results will allow a much better understanding of the pathogenesis of chronic pancreatitis and allow the identification of key factors of the pathways involved. These factors can be confirmed as candidate genes in patients cohorts with pancreatitis and represent potential targets for a therapeutic intervention in chronic pancreatitis patients.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Walter Halangk (†)