Framework for interpretation of trypsin-antitrypsin imbalance and genetic heterogeneity in pancreatitis.

Abstract

Early intracellular premature trypsinogen activation was interpreted as the key initiator of pancreatitis. When the balance in the homeostasis of trypsin and antitrypsin system is disequilibrated, elevated aggressive enzymes directly attack the pancreatic tissue, which leads to pancreatic destruction and inflammation. However, trypsin alone is not enough to cause complications in pancreatitis, which may play a crucial role in modulating signaling events in the initial phase of the disease. NFκB activation is the major inflammatory pathway involved in the occurrence and development of pancreatitis and it can be induced by intrapancreatic activation of trypsinogen. Synthesis of trypsinogen occurs in endoplasmic reticulum (ER), and ER stress is an important early acinar cell event. Components of ER stress response are known to be able to trigger cell death as well as NFκB signaling cascade. The strongest evidence supporting the trypsin-centered theory is that gene mutations, which lead to the generation of more trypsin, or reduce the activity of trypsin inhibitors or trypsin degradation, are associated with pancreatitis. Thus, trypsin-antitrypsin imbalance may be the first step leading to pancreatic autodigestion and inducing other pathways. Continued experimental studies are necessary to determine the specific relationships between trypsin-antitrypsin imbalance and genetic heterogeneity in pancreatitis. In this article, we review the latest advances that contributed to the understanding of the basic mechanisms behind the occurrence and development of pancreatitis with a focus on the interpretation of trypsin-antitrypsin imbalance and their relationships with other inflammation pathways. We additionally highlight genetic predispositions to pancreatitis and possible mechanisms associated with them.

• Authors: Kun Lin, Feng Gao, Qingquan Chen, Qicai Liu, Shu Chen
• Journal: Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association (Saudi J Gastroenterol) 2015 Jul-Aug Vol. 21 Issue 4 Pg. 198-207 ISSN: 1998-4049 [Electronic] India
• PMID: 26228362 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Trypsinogen
• Trypsin

Topics

• Genetic Heterogeneity
• Genetic Predisposition to Disease
• Humans
• Mutation
• Pancreatitis (etiology, pathology)
• Trypsin (physiology)
• Trypsinogen (physiology)