The Physiology and Pathophysiology of Pancreatic Ductal Secretion the Background for Clinicians
Total Page:16
File Type:pdf, Size:1020Kb
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by SZTE Publicatio Repozitórium - SZTE - Repository of Publications REVIEW The Physiology and Pathophysiology of Pancreatic Ductal Secretion The Background for Clinicians Petra Pallagi, PhD,* Péter Hegyi, MD, PhD, DSc,*† and Zoltán Rakonczay, Jr, MD, PhD, DSc* and basolateral transporters involved in the secretory process. Abstract: The human exocrine pancreas consists of 2 main cell types: In all cases, the physiological function of this alkaline fluid is acinar and ductal cells. These exocrine cells interact closely to contribute to neutralize the acidic content secreted by acinar cells, to pro- to the secretion of pancreatic juice. The most important ion in terms of − vide an optimal pH for digestive enzymes, to flush down diges- the pancreatic ductal secretion is HCO3. In fact, duct cells produce an alka- − tive enzyme into the duodenum, and also to neutralize the line fluid that may contain up to 140 mM NaHCO3, which is essential for 7 − gastric acid entering the duodenum. Importantly, HCO3 has normal digestion. This article provides an overview of the basics of pancre- a crucial biochemical role in the physiological pH buffering atic ductal physiology and pathophysiology. In the first part of the article, system and is a chaotropic agent that prevents the denaturing we discuss the ductal electrolyte and fluid transporters and their regulation. of proteins such as digestive enzymes and mucins so it facili- The central role of cystic fibrosis transmembrane conductance regulator 4,8 − tates their solubilization in biological fluid. (CFTR) is highlighted, which is much more than just a Cl channel. We − Investigating the mechanisms of pancreatic ductal HCO3 also review the role of pancreatic ducts in severe debilitating diseases such and fluid secretion also helps us to better understand pancreatic as cystic fibrosis (caused by various genetic defects of cftr), pancreatitis, diseases.4 Impaired ductal secretion can result in pancreatic and diabetes mellitus. Stimulation of ductal secretion in cystic fibrosis damage, as seen in cystic fibrosis (CF),3,9 and may contribute and pancreatitis may have beneficial effects in their treatment. to the development of other diseases such as acute and chronic Key Words: pancreas, ductal secretion, cystic fibrosis, CFTR, pancreatitis, pancreatitis.10 diabetes mellitus The aim of this review is to summarize the physiology and – pathophysiology of pancreatic ductal epithelial cells (PDECs). (Pancreas 2015;44: 1211 1233) We will try to keep things simple and not go into too much molec- ular detail. These have been discussed in recent reviews by distin- he human exocrine pancreas consists of 2 main cell types: ac- 11 3 inar and ductal cells. These exocrine cells interact closely to guished experts in the field such as Argent et al, Ishiguro et al, T 6 12 13 contribute to the secretion of pancreatic juice.1 Acinar cells (which Lee et al, group of Muallem, and Novak et al. With respect to make up >80% of the pancreatic mass) secrete an isotonic, NaCl- ductal pathophysiology, only CF, pancreatitis, and diabetes and H+-rich fluid containing various digestive enzymes.2 The se- mellitus are discussed, and we will not deal with pancreatic adeno- − − carcinoma (mainly arising from ductal cells). creted Cl is then exchanged to HCO3 by duct cells to produce − an alkaline fluid that may contain up to 140 mM NaHCO3,which is essential for normal digestion.3–5 Although volume-wise the MECHANISM OF PANCREATIC ducts cells account for approximately only 5% of the pancreas, DUCTAL SECRETION a large proportion of the secreted pancreatic fluid is due to the For a long time, it was believed that the main function of duct cells. Under stimulated conditions, duct cells secrete a PDECs is to ensure mechanical frame for acinar cells. In 1986, large quantity of electrolytes, which is followed by fluid move- Barry Argent and his colleagues14 have worked out a method that − ment. Ductal HCO3 concentration in guinea pig (which is a made it possible to isolate intact pancreatic ducts and PDECs. This commonly used model animal to study pancreatic secretion) was a landmark discovery, because until then, ductal function can be as high as in humans; however, rats or mice can secrete could be investigated only in intact animals. From then on, it − 5,6 only70to80mMHCO3. Although the exact mechanism of was possible to separately study the function of duct cells, and nu- − ductal HCO3 and fluid secretion is only partially understood, it merous publications proved that PDECs are responsible not only − is evident that the differences in HCO3 concentration of the for the formation of a mechanical frame for the acini, but also − 3 various species are due to the different expression of apical for the HCO3 and fluid secretion of the pancreatic juice. The de- velopment of pancreatic ductal cell lines have also helped us in understanding the secretory process, but as these are mainly de- From the *First Department of Medicine, University of Szeged; and †Hungarian rived from adenocarcinomas, their function may be compromised. Academy of Sciences–University of Szeged Translational Gastroenterology Re- Whereas acinar cells have a relatively uniform morphology, search Group, Szeged, Hungary. the structure of duct cells is much more diverse. Perhaps the most Received for publication September 3, 2014; accepted March 2, 2015. Reprints: Zoltán Rakonczay, MD, PhD, DSc, First Department of Medicine, enigmatic cell type of the exocrine pancreas is the centroacinar University of Szeged, PO Box 427, H-6701 Szeged, Hungary cells, which are localized at the junction of the acini and are (e‐mail: [email protected]). closely associated with the terminal ductal epithelium.15 Epithelia Our research is supported by Hungarian National Development Agency grants are cuboidal along the proximal small ducts and are columnar in (TÁMOP-4.2.2.A-11/1/KONV-2012-0035, TÁMOP-4.2.2-A-11/1/KONV- the distal large ducts.16 Therefore, it is not surprising that proximal 2012-0052, TÁMOP-4.2.2.A-11/1/KONV-2012-0073), the Hungarian − Scientific Research Fund (NF105758), the Hungarian Academy of and distal duct cells also differ in their function. HCO3 secretion is Sciences (MTA-SZTE Momentum grant, LP2014-10/2014), and the thought to occur primarily in the proximal part of the ducts.3 European Union and the State of Hungary, cofinanced by the European − Social Fund in the framework of TÁMOP 4.2.4.A/2-11-1-2012-0001 The Model of Pancreatic Ductal HCO Secretion National Excellence Program. 3 The authors declare no conflict of interest. The exact mechanism how the exocrine pancreas secretes a Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. large amount of the alkaline fluid has long been an enigma. Note Pancreas • Volume 44, Number 8, November 2015 www.pancreasjournal.com 1211 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Pallagi et al Pancreas • Volume 44, Number 8, November 2015 − that the HCO3 concentration of the pancreatic juice in the stimu- nucleotide-binding domains and transmembrane domains, which lated state is more than 5 times that found in the serum. Major contain several membrane-spanning α-helices and a regulatory − milestones in understanding the mechanism of pancreatic HCO3 (R) domain that is phosphorylated by protein kinase A and pro- secretion include the discovery of the acidic pancreatic juice tein kinase C (PKC).27,28 In addition, CFTR contains several in patients with CF,17 the isolation of pancreatic ducts,14 and other domains mediating protein-protein interactions, includ- the molecular identification of several ion channels and trans- ing postsynaptic density 95/disc-large/zonula occludens 1 porters of PDECs, such as the CF transmembrane con- (PDZ)–interacting domains in the C terminus. Proteins that 18 + − ductance regulator (CFTR), the Na /HCO3 cotransporter contain PDZ domains often have other protein-interacting modules (NBCe1-B, also known as pNBC1),19 and the solute carrier (such as ezrin, radixin, moesin-binding domains, and coiled-coil family 26 (SLC26) transporters.20,21 Our knowledge has also domains) and therefore can promote homotypic and heterotypic expanded about how ductal secretion is regulated.6 protein-protein interactions.29 − Pancreatic ductal HCO3 secretion is a complex process that Cystic fibrosis transmembrane conductance regulator is can be broadly divided into 2 separate steps. The first step of found in the epithelial cells of many organs including the pan- − − HCO3 secretion is the accumulation of HCO3 inside the duct creas, lung, liver, digestive tract, reproductive tract, and skin. cell across the basolateral membrane. This can be achieved via Although CFTR is predominantly a Cl− channel, it can also + − 30 a direct mechanism through Na /HCO3 cotransporters or indi- conduct other anions. Gray et al provided clear evidence that − rectly via the passive diffusion of CO2 through the cell mem- CFTR can transport HCO3 in pancreatic duct cells, but CFTR − + − − 31 brane and the conversion of CO2 to HCO3 and H mediated is 3 to 5 times more selective for Cl over HCO3. Interestingly, 22 − − by carbonic anhydrase and backward transport of protons by Cl /HCO3 selectivity of CFTR is dynamic and is regulated by ex- Na+/H+ exchangers (NHEs) and an H+-ATPase.3 The second ternal Cl−.32 According to these studies, when Cl− is present in − step of HCO3 secretion across the apical membrane of PDECs physiologic concentration in the lumen of proximal pancreatic is thought to be mediated by anion channels and transporters ducts, CFTR functions as a Cl− channel and does not carry 3 − − − such as CFTR and SLC26 anion exchangers (Fig. 1). HCO3. However, when luminal [Cl ] and [Cl ]i are low at the − How these transporters act in concert to produce a high distal part of pancreatic ducts, CFTR secretes HCO3 across − 33,34 HCO3 secretion in humans is controversial.