Markus M. Lerch

Trypsin Reduces Pancreatic Ductal Bicarbonate Secretion by Inhibiting CFTR Cl− Channels and Luminal Anion Exchangers

BACKGROUND & AIMSnThe effects of trypsin on pancreatic ductal epithelial cells (PDECs) vary among species and depend on the localization of proteinase-activated receptor 2 (PAR-2). We compared PAR-2 localization in human and guinea-pig PDECs, and used isolated guinea pig ducts to study the effects of trypsin and a PAR-2 agonist on bicarbonate secretion.nnnMETHODSnPAR-2 localization was analyzed by immunohistochemistry in guinea pig and human pancreatic tissue samples (from 15 patients with chronic pancreatitis and 15 without pancreatic disease). Functionally, guinea pig PDECs were studied by microperfusion of isolated ducts, measurements of intracellular pH and intracellular Ca(2+) concentration, and patch clamp analysis. The effect of pH on trypsinogen autoactivation was assessed using recombinant human cationic trypsinogen.nnnRESULTSnPAR-2 localized to the apical membrane of human and guinea pig PDECs. Trypsin increased intracellular Ca(2+) concentration and intracellular pH and inhibited secretion of bicarbonate by the luminal anion exchanger and the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel. Autoactivation of human cationic trypsinogen accelerated when the pH was reduced from 8.5 to 6.0. PAR-2 expression was strongly down-regulated, at transcriptional and protein levels, in the ducts of patients with chronic pancreatitis, consistent with increased activity of intraductal trypsin. Importantly, in PAR-2 knockout mice, the effects of trypsin were markedly reduced.nnnCONCLUSIONSnTrypsin reduces pancreatic ductal bicarbonate secretion via PAR-2-dependent inhibition of the apical anion exchanger and the CFTR Cl(-) channel. This could contribute to the development of chronic pancreatitis by decreasing luminal pH and promoting premature activation of trypsinogen in the pancreatic ducts.

Pathogenese und Pathophysiologie der akuten Pankreatitis

Die Pankreatitis ist eine primar sterile Entzundung des Pankreas, deren Ursprung in einer vorzeitigen intrazellularen Proteaseaktivierung liegt. Eine wichtige Rolle nimmt hierbei die Serinprotease Trypsin ein. Die pathologische intrazellulare Proteaseaktivierung fuhrt zu einer ausgedehnten Zellschadigung. Ausgelost durch den lokalen Zellschaden kommt es zu einer systemischen Immunantwort. Die lokale Immunantwort unterstutzt den lokalen pankreatischen Schaden und fuhrt zu einer weiter gesteigerten Aktivierung von Proteasen. Auf der anderen Seite kann die systemische Immunantwort zu einem Multiorganversagen, verbunden mit einer erhohten Mortalitat, fuhren. Sowohl die lokale als auch die systemische Immunantwort definieren letztendlich den Schweregrad der Erkrankung.

Autoimmune Pancreatitis in Europe

Although the first description of chronic sclerosing pancreatitis with increased serum immunoglobulin came from the group of Henri Sarles in Marseilles [1, 2], the concept of autoimmune pancreatitis as a distinct disease entity [3] as well as the early case series originated from Japan, and it took almost half a century until AIP was established as a separate variety of chronic pancreatitis in Europe.

Peripankreatische Flüssigkeitsansammlungen: Wann ist eine interventionelle Therapie indiziert?

Peripankreatische Flussigkeitsansammlungen sind eine haufige Komplikation der akuten Pankreatitis, dennoch stellen sie selten eine Indikation fur eine Therapie da. Die Revision der Atlanta-Klassifikation von 1992 im Jahr 2013 versucht, durch eine einfache Klassifikation die Indikationsstellung zur Therapie zu erleichtern. Das nachfolgende Kapitel soll dies erlautern.

Pseudozysten bei akuter und chronischer Pankreatitis – Diagnostik, interventionelle und chirurgische Therapie

Die Entwicklung von Pankreaspseudozysten ist eine haufige Komplikation nach akuter oder bei chronischer Pankreatitis. Ihre Einteilung und Definition erfolgt nach der Atlanta-Klassifikation. Die Diagnosestellung erfolgt meist unter Zuhilfenahme bildgebender Verfahren wie dem transabdominellen Ultraschall, dem CT oder dem endoskopischen Ultraschall, wobei letzteres Verfahren die hochste Sensitivitat und Spezifitat aufweist. Unterschiedliche Therapieverfahren tragen zur erfolgreichen Behandlung bei: 1) die endoskopische transpapillare oder transmurale Drainage, 2) die perkutane Drainage oder 3) die chirurgisch laparoskopische oder offene Pseudozysto-Intestinostomie. Eine stadienadaptierte effektive und sichere Therapie von Pankreaspseudozysten kann am besten in einem interdisziplinaren Ansatz erfolgen.

Evidenz der Labor- und bildgebenden Diagnostik bei Autoimmunpankreatitis

Die Autoimmunpankreatitis ist eine seltene Erkrankung, die klinisch haufig nicht von einem Pankreaskarzinom zu unterscheiden ist. Neue internationale Diagnosekriterien schlagen ein stufenweises diagnostisches Vorgehen unter Berucksichtigung von Parenchymkonfiguration, Gallen- und Pankreasgangdarstellung, Serologie, extrapankreatischen Manifestationen und Ansprechen auf eine Steroidtherapie vor. Es werden zwei Subtypen der Erkrankung unterschieden, die sich hinsichtlich ihrer Histologie wie auch des klinischen Profils unterscheiden. Wichtig, um unnotige Operationen zu verhindern, ist das Wissen uber diese Sonderform der chronischen Pankreatitis.

Chapter 21 – Molecular Basis of Diseases of the Exocrine Pancreas

Pancreatitis is characterized as self-digestion of the pancreas by its own proteases. A premature activation of digestive enzymes within pancreatic acinar cells results in necrotic cell death and the activation of the immune system. The serine protease trypsinogen is suggested to play a crucial role in this process. Trypsinogen is activated by the lysosomal hydrolase cathepsin B within the acinar cell and defines the onset of disease. This event is accompanied by a local and systemic immune response. The significant role of trypsinogen is underlined by genetic data; different mutations within PRSS1, the cationic trypsinogen, or other genes that are related to the activation, degradation, or inhibition of trypsin are associated with an increased risk of chronic pancreatitis.

Molecular Basis of Diseases of the Exocrine Pancreas

Publisher Summary Acute pancreatitis presents clinically as a sudden inflammatory disorder of the pancreas and is caused by premature intracellular activation of pancreatic proteases leading to (i) self-destruction of acinar cells and (ii) auto digestion of the organ. Necrotic cell debris resulting from this process produces a systemic inflammatory reaction, which may lead to multiorgan failure in due course. Acute pancreatitis varies considerably in severity and can be categorized into two forms of the disease. The majority of cases (85%) present with a mild form of disease, classified as edematous pancreatitis, with absent or only transient extrapancreatic organ failure. In the remaining minority of cases (15%), pancreatitis follows a severe course accompanied by sustained multiorgan failure. This latter form of pancreatitis is commonly referred to as severe or necrotizing pancreatitis. Severe necrotizing pancreatitis is associated with high mortality (10%–20%) and may lead to long-term complications, such as the formation of pancreatic pseudocysts or impairment of exocrine and endocrine function of the pancreatic gland. This chapter highlights the factors that can contribute to the development of chronic pancreatitis and provides an overview of the molecular basis of diseases of the exocrine pancreas.

Trypsin Activation and Inhibition in Pancreatitis

Pancreatitis is a common disorder in which the passage of gallstones and the consumption of immoderate amounts of alcohol induce an inflammatory process. Recent studies involving animal and isolated cell models have elucidated many of the pathophysiological, cellular and molecular processes involved in the disease onset. More than a century ago it was proposed that pancreatic digestive enzymes are involved in the onset of pancreatitis and that the disease is essentially the result of an auto-digestion of the gland. Why and how digestive zymogens undergo activation, in spite of numerous protective mechanism, has been the topic of intense research efforts and debate. In this chapter we review the most recent progress in this enterprise and will specifically focus on mechanisms involved in gallstone-induced and hereditary pancreatitis.