The Role of Pancreatic Ductal Secretion in Protection Against Acute Pancreatitis in Mice*

Pallagi, Petra; Balla, Zsolt; Singh, Anurag Kumar; Dósa, Sándor; Iványi, Béla; Kukor, Zoltán; Tóth, Anna Zsófia; Riederer, Brigitte; Liu, Yongjian; Engelhardt, Regina; Jármay, K.; Szabó, Andrea; Janovszky, Ágnes; Perides, George; Venglovecz, Viktória; Maléth, József; Wittmann, Tibor; Takács, Tamás; Gray, Michael A.; Gácser, Attila; Hegyi, Péter; Seidler, Ursula; Rakonczay, Zoltán

doi:10.1097/ccm.0000000000000101

Cited by 50 publications

(84 citation statements)

References 51 publications

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“…A recent study show that ductal secretion protects the pancreas from acute pancreatitis, suggesting that improved ductal function may help to prevent and treat the disease (32). However, in our study, the sole infusion of secretin, which acts on receptors in acinar and duct cells, enhanced trypsinogen activation.…”

Section: Discussioncontrasting

confidence: 51%

Blockade of Multidrug Resistance-Associated Proteins Aggravates Acute Pancreatitis and Blunts Atrial Natriuretic Factor’s Beneficial Effect in Rats: Role of MRP4 (ABCC4)

Ventimiglia

Najenson

Perazzo

et al. 2015

Mol Med

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Section: Discussioncontrasting

confidence: 51%

Blockade of Multidrug Resistance-Associated Proteins Aggravates Acute Pancreatitis and Blunts Atrial Natriuretic Factor’s Beneficial Effect in Rats: Role of MRP4 (ABCC4)

Ventimiglia

Najenson

Perazzo

et al. 2015

Mol Med

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“…Deletion of Nherf1 reduced expression of CFTR at the apical membrane of the duct and consequently reduced fluid and HCO 3 − secretion. Furthermore, it resulted in more severe acute pancreatitis induced by cerulein hyperstimulation and sodium taurocholate in mice [75]. These findings have potential clinical relevance, since we detected markedly decreased CFTR protein and mRNA expression in small pancreatic ducts in tissue samples from patients diagnosed with alcoholinduced acute pancreatitis [53,75].…”

Section: Cftr Dysfunction In Pancreatitis a Acute Pancreatitissupporting

confidence: 48%

“…Furthermore, it resulted in more severe acute pancreatitis induced by cerulein hyperstimulation and sodium taurocholate in mice [75]. These findings have potential clinical relevance, since we detected markedly decreased CFTR protein and mRNA expression in small pancreatic ducts in tissue samples from patients diagnosed with alcoholinduced acute pancreatitis [53,75].Together, these observations suggest that diminished CFTR function, due to either reduced expression or activity, may have crucial importance in the pathogenesis of pancreatitis ( Figure 5). …”

supporting

confidence: 56%

“…injection of ethanol and palmitic acid, including more extensive necrosis [53]. The role of CFTR in acute pancreatitis was further demonstrated in a study examining the scaffolding protein Na + /H + exchanger regulatory factor-1 (NHERF-1) in ductal function [75]. Deletion of Nherf1 reduced expression of CFTR at the apical membrane of the duct and consequently reduced fluid and HCO 3 − secretion.…”

mentioning

confidence: 99%

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CFTR: A new horizon in the pathomechanism and treatment of pancreatitis

Hegyi

2016

Pancreatology

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Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that conducts chloride and bicarbonate ions across epithelial cell membranes. Mutations in the CFTR gene diminish the ion channel function and lead to impaired epithelial fluid transport in multiple organs such as the lung and the pancreas resulting in cystic fibrosis. Heterozygous carriers of CFTR mutations do not develop cystic fibrosis but exhibit increased risk for pancreatitis and associated pancreatic damage characterized by elevated mucus levels, fibrosis and cyst formation. Importantly, recent studies demonstrated that pancreatitis causing insults, such as alcohol, smoking or bile acids strongly inhibit CFTR function. Furthermore, human studies showed reduced levels of CFTR expression and function in all forms of pancreatitis. These findings indicate that impairment of CFTR is critical in the development of pancreatitis; therefore, correcting CFTR function could be the first specific therapy in pancreatitis. In this review, we summarize recent advances in the field and discuss new possibilities for the treatment of pancreatitis.Corresponding author: Prof. Dr. Peter Hegyi, Doctor of the Hungarian Academy of Sciences, First Department of Medicine, University of Szeged, Koranyi fsr. 8-10, SZEGED, H6720, Hungary, TEL: +3662545200, FAX: +3662545185, MOBILE: +36703751031, hegyi.peter@med.u-szeged.hu. Conflict of interest statement: the authors have no conflict of interest to declare HHS Public Access I. Basics of CFTR a. Biosynthesis and degradationThe cystic fibrosis transmembrane conductance regulator (CFTR) protein is a cyclic AMP (cAMP)-regulated chloride (Cl − )/bicarbonate (HCO 3 − ) channel, expressed in the apical plasma membrane (PM) of secretory epithelia in the airways, pancreas, intestine, reproductive organs and exocrine glands [1]. CFTR consists of two homologous halves, each containing a hexa-helical membrane spanning domain (MSD1 and MSD2) and a nucleotide binding domain (NBD1 and NBD2) (Figure 1). The two halves are connected by the R domain [2]. The NBDs contain conserved ATP-binding sequences: Walker A and B motifs, classifying CFTR as a member of the ATP-binding cassette (ABC) transporter family. Structural, biochemical and functional evidence suggest that the two NBD domains interact and the ATP-binding site of one NBD is complemented by the ABC signature motif of the other [2].While NBD1 folds largely co-translationally, the native fold of NBD2 as well as CFTR are attained post-translationally [3]. Assembly of MSD1, NBD1, R domain and MSD2 is necessary and sufficient to form the minimal folding unit of CFTR [4]. These and other observations support the cooperative domain folding model and ensure the dynamic conformational coupling between the cytosolic NBDs and the pore-forming MSDs in the native molecule and provide a structural explanation for the cooperative domain unfolding, caused by cystic fibrosis (CF) mutations [4].Despite interactions with several cytosolic and endoplasmic reticulum (ER) chapero...

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“…There is now compelling evidence to support the importance of ductular secretion in preventing AP pathogenesis [68]. Central to the physiological functioning (bicarbonate secretion) of the pancreatic ductal apparatus is the cystic fibrosis transmembrane conductance regulator (CFTR) e the regulation of the which is mediated by Caþ2 activation [69] and the intracellular chloride sensitive activation of the WNK1-OSR1/SPAK pathway [70].…”

Section: The Ductal Systemmentioning

confidence: 99%

How does cigarette smoking cause acute pancreatitis?

Barreto

2016

Pancreatology

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The Role of Pancreatic Ductal Secretion in Protection Against Acute Pancreatitis in Mice*

Abstract: Our findings provide the first direct evidence for the crucial role of ductal secretion in protecting the pancreas from acute pancreatitis and strongly suggest that improved ductal function should be an important modality in prevention and treatment of the disease.

Cited by 50 publications

References 51 publications

Blockade of Multidrug Resistance-Associated Proteins Aggravates Acute Pancreatitis and Blunts Atrial Natriuretic Factor’s Beneficial Effect in Rats: Role of MRP4 (ABCC4)

Blockade of Multidrug Resistance-Associated Proteins Aggravates Acute Pancreatitis and Blunts Atrial Natriuretic Factor’s Beneficial Effect in Rats: Role of MRP4 (ABCC4)

CFTR: A new horizon in the pathomechanism and treatment of pancreatitis

How does cigarette smoking cause acute pancreatitis?

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