Trypsinogen might not be the sole culprit in acute pancreatitis, contradicting a century-old model of this disease; a new model is published in the December issue of Gastroenterology.
Trypsinogen is a pancreatic protein that is converted in acinar cells to the enzyme trypsin—a protease that is important for digestion and that activates other proteases. Patients with pancreatitis have increased levels of trypsinogen and other digestive enzymes, so research has focused for many decades on how these enzymes are regulated and activated to damage the pancreas.
Rajinder Dawra and colleagues created and analyzed mice that do not produce trypsinogen-7, the equivalent gene of human cationic trypsinogen. Surprisingly, the T−/− mice still developed acute pancreatitis following administration of cerulein, a reagent that activates trypsinogen and has other inflammatory effects. The T−/− mice and wild-type mice had similar degrees of local and systemic inflammation during the progression of pancreatitis. They also had comparable levels of acinar cell activation of the transcription factor NF-κB, which has been shown to occur concurrently with trypsinogen activation during early stages of pancreatitis.
However, acinar cell necrosis was reduced by 50% in T−/− mice given cerulein, compared with wild-type mice given cerulein. So loss of trypsingen-7 prevented some, but not all of the pancreatic damage. Dawra et al. conclude that trypsinogen activation leads to acinar cell death during early stages of pancreatitis and is responsible for half of eventual pancreatic injury in patients with this disease.
In an accompanying editorial, Baoan Ji and Craig Logsdon point out that it is not clear if trypsinogen-7 is the only isoform activated by cerulein—reducing the total level of trypsinogen might not have the same effects. The T−/− mice had no phenotypic abnormalities, indicating trypsinogen expression levels of wild-type mice could be in excess of what is actually needed, physiologically. It is also possible that T−/− mice developed mechanisms to compensate for their reduced levels of trypsinogen.
In previous studies, pharmacologic reagents that inhibit trypsinogen activation reduced acute pancreatitis, and mutations in the human gene that encodes cationic trypsinogen have been associated with hereditary pancreatitis. Ji and Logsdon warn that experimental models of acute pancreatitis cause generalized, nonspeciﬁc damage, rather than speciﬁc activation of trypsinogen. Better models are needed.
Trypsin activation appears to be one component of a complex response of acinar cells to injury (see figure).
Ji and Logsdon remind us that acute pancreatitis involves not only direct damage to pancreatic tissue, but also edema, coagulation, vascular complications, inﬁltration of immune cells, and local and systemic inﬂammation. It is therefore time to broaden the focus of pancreatitis research from trypsinogen activation to other mechanisms that contribute to disease.
More Information on Acute Pancreatitis:
Read the article online.
Dawra R, Sah R, Dudeja V, et al. Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis. Gastroenterology 2011;141: 2210-2217.e2
Read the accompanying editorial.
Ji B, Logsdon C. Digesting new information about the role of trypsin in pancreatitis. Gastroenterology 2011;141: 1972–1975.