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

Pallagi, Petra; Venglovecz, Viktória; Rakonczay, Zoltán; Borka, Katalin; Korompay, Anna; Ózsvári, Béla; Judák, Linda; Sahin–Tóth, Miklós; Geisz, Andrea; Schnúr, Andrea; Maléth, József; Takács, Tamás; Gray, Michael A.; Argent, Barry E.; Mayerle, Julia; Lerch, Markus M.; Wittmann, Tibor; Hegyi, Péter

doi:10.1053/j.gastro.2011.08.039

Cited by 83 publications

(86 citation statements)

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“…Although the toxic effects of ethanol and POA were similar to those of a high concentration of bile acids, 27,28 in this study chelation of [Ca 2+ ] i abolished the inhibitory effect of ethanol and POA on HCO 3 − secretion. This observation indicates that ethanol and POA, in a similar manner to trypsin, 29 inhibit HCO 3 − secretion via a sustained increase in [Ca 2+ ] i . Importantly, CFTR single channel parameters do not change as a result of use of ethanol (personal communication, Aleksandrov Andrei and John R. Riordan), suggesting that the effects of a high dose of ethanol do not alter the biophysical characteristics of CFTR.…”

Section: Discussionmentioning

confidence: 75%

Alcohol Disrupts Levels and Function of the Cystic Fibrosis Transmembrane Conductance Regulator to Promote Development of Pancreatitis

et al. 2015

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BACKGROUND & AIMS Excessive consumption of ethanol is one of the most common causes of acute and chronic pancreatitis. Alterations to the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) also cause pancreatitis. However, little is known about the role of CFTR in the pathogenesis of alcohol-induced pancreatitis. METHODS We measured CFTR activity based on chloride concentrations in sweat from patients with cystic fibrosis, patients admitted to the emergency department because of excessive alcohol consumption, and healthy volunteers. We measured CFTR levels and localization in pancreatic tissues and in patients with acute or chronic pancreatitis induced by alcohol. We studied the effects of ethanol, fatty acids, and fatty acid ethyl esters on secretion of pancreatic fluid and HCO3− , levels and function of CFTR, and exchange of Cl− for HCO3− in pancreatic cell lines as well as in tissues from guinea pigs and CFTR knockout mice after administration of alcohol. RESULTS Chloride concentrations increased in sweat samples from patients who acutely abused alcohol but not in samples from healthy volunteers, indicating that alcohol affects CFTR function. Pancreatic tissues from patients with acute or chronic pancreatitis had lower levels of CFTR than tissues from healthy volunteers. Alcohol and fatty acids inhibited secretion of fluid and HCO3− , as well as CFTR activity, in pancreatic ductal epithelial cells. These effects were mediated by sustained increases in concentrations of intracellular calcium and adenosine 3’,5’-cyclic monophosphate, depletion of adenosine triphosphate, and depolarization of mitochondrial membranes. In pancreatic cell lines and pancreatic tissues of mice and guinea pigs, administration of ethanol reduced expression of CFTR messenger RNA, reduced the stability of CFTR at the cell surface, and disrupted folding of CFTR at the endoplasmic reticulum. CFTR knockout mice given ethanol or fatty acids developed more severe pancreatitis than mice not given ethanol or fatty acids. CONCLUSIONS Based on studies of human, mouse, and guinea pig pancreata, alcohol disrupts expression and localization of the CFTR. This appears to contribute to development of pancreatitis. Strategies to increase CFTR levels or function might be used to treat alcohol-associated pancreatitis.

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Section: Discussionmentioning

confidence: 75%

Alcohol Disrupts Levels and Function of the Cystic Fibrosis Transmembrane Conductance Regulator to Promote Development of Pancreatitis

et al. 2015

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“…Overexpression of trypsin(ogen), including but not restricted to hereditary pancreatitis-relevant mutant trypsinogen isoforms, leads to pancreatic injury or more severe pancreatitis (37,50), but the deletion of other trypsinogen isoforms does not have the expected opposite effect of reducing disease severity (27). Although our experiments do not exclude CTSB effects in nonacinar cells or extrapancreatic effects of CTSB-induced trypsin activation (38), our data regarding the role of CTSB activation inside the vesicular compartment of acinar cells are quite unequivocal. CTSB activation induces apoptosis rather than necrosis of acinar cells in a pancreas-specific mechanism.…”

Section: Figurementioning

confidence: 80%

“…Recent experimental studies in rodents have suggested that the role of trypsin is probably more complex than just being a triggering event when the enzyme is activated or that of a disease driver when its activity persists. They found that activation and inhibition of trypsin does not necessarily affect the acute, recurrent, and chronic phase of the disease in the same manner (26,37) and even suggested that some injurious effects of trypsin may be extra-rather than intracellular (38).…”

Section: Figurementioning

confidence: 99%

Cathepsin B Activity Initiates Apoptosis via Digestive Protease Activation in Pancreatic Acinar Cells and Experimental Pancreatitis

Sendler

Maertin

John

et al. 2016

Journal of Biological Chemistry

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Pancreatitis is associated with premature activation of digestive proteases in the pancreas. The lysosomal hydrolase cathepsin B (CTSB) is a known activator of trypsinogen, and its deletion reduces disease severity in experimental pancreatitis. Here we studied the activation mechanism and subcellular compartment in which CTSB regulates protease activation and cellular injury. Cholecystokinin (CCK) increased the activity of CTSB, cathepsin L, trypsin, chymotrypsin, and caspase 3 in vivo and in vitro and induced redistribution of CTSB to a secretory vesicleenriched fraction. Neither CTSB protein nor activity redistributed to the cytosol, where the CTSB inhibitors cystatin-B/C were abundantly present. Deletion of CTSB reduced and deletion of cathepsin L increased intracellular trypsin activation. CTSB deletion also abolished CCK-induced caspase 3 activation, apoptosis-inducing factor, as well as X-linked inhibitor of apoptosis protein degradation, but these depended on trypsinogen activation via CTSB. Raising the vesicular pH, but not trypsin inhibition, reduced CTSB activity. Trypsin inhibition did not affect apoptosis in hepatocytes. Deletion of CTSB affected apoptotic but not necrotic acinar cell death. In summary, CTSB in pancreatitis undergoes activation in a secretory, vesicular, and acidic compartment where it activates trypsinogen. Its deletion or inhibition regulates acinar cell apoptosis but not necrosis in two models of pancreatitis. Caspase 3-mediated apoptosis depends on intravesicular trypsinogen activation induced by CTSB, not CTSB activity directly, and this mechanism is pancreas-specific.Acute pancreatitis has long been regarded as a disease that is characterized by autodigestion of the pancreas by its own proteases (1). This hypothesis appears plausible because no other organ synthesizes and secretes such large amounts of serine and cysteine proteases as the exocrine pancreas (2, 3). However, under physiological conditions, serine proteases are discharged from the pancreas as inactive precursor zymogens, and, most prominently, trypsinogen only undergoes activation when in contact with the intestinal brush border and its enzyme enterokinase. Two discoveries have given new relevance to the autodigestion hypothesis. One is the observation that the autosomal dominant inherited form of pancreatitis is associated with germline mutations in the cationic trypsinogen (PRSS1) gene (4, 5) and that most inherited risk factors for pancreatitis involve alterations in digestive proteases (6, 7). The other is the fact that the mechanism of premature intracellular protease activation and its contributing biochemical and immunological factors are increasingly better understood (8, 9) and have parallels in experimental models that mimic human pancreatitis (10 -12), allowing the conclusion that CTSB 3 is a critical intracellular player. CTSB is a lysosomal hydrolase that has long been shown to activate trypsinogen in vitro (13) but has also been found to be involved in the pathophysiology of experimental models of pa...

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“…The presence of active trypsin in the pancreatic duct lumen may lead to additional reduction in bicarbonate secretion due to inhibition of CFTR and other luminal anion exchangers (e.g. SLC26) via proteinase-activated receptor 2 [24]. Further reduction in bicarbonate secretion by the ductal epithelium generates a vicious cycle and environment of falling pH, enhanced trypsinogen activation and decreased intraluminal fluid volume, which promotes the development of pancreatitis.…”

Section: Pathogenesismentioning

confidence: 99%

Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis

Ooi

Durie

2012

Journal of Cystic Fibrosis

102

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The genotype-phenotype correlation in pancreatitis is unique compared to other organ manifestations but still consistent with the complex monogenic nature of CF. Paradoxically, genotypes associated with otherwise mild phenotypic effects have a greater risk for causing pancreatitis; compared with genotypes associated with moderate to severe disease phenotypes. Greater understanding into the underlying mechanisms of disease is much needed. The emergence of CFTR-assist therapies may potentially play a future role in the treatment of CFTR-mutation associated pancreatitis.

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

Cited by 83 publications

References 50 publications

Alcohol Disrupts Levels and Function of the Cystic Fibrosis Transmembrane Conductance Regulator to Promote Development of Pancreatitis

Alcohol Disrupts Levels and Function of the Cystic Fibrosis Transmembrane Conductance Regulator to Promote Development of Pancreatitis

Cathepsin B Activity Initiates Apoptosis via Digestive Protease Activation in Pancreatic Acinar Cells and Experimental Pancreatitis

Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis

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