hydrolyzes ATP to exchange 3 Na + in for 2 K + out generate the transcellular Na + and K + gradients provides the electrochemical gradient

Transcription

1 Regulation of pancreatic excretory function by ion channels Viktoria Venglovecz 2015

2 Morphology of the pancreas

3 Composition of pancreatic juice 1 2 liters of pancreatic juice per day acini secrete isotonic, plasma- like fluid pancreatic duct absorbs most of the Cl - and secrete HCO + 3 Human, 140 mm HCO + 3 Mouse and rat, 50 70mM HCO + 3 The cation composition of the juice is nearly constant

4 Fluid and electrolyte secretion by acinar cells

5 Na + /K + ATPase hydrolyzes ATP to exchange 3 Na + in for 2 K + out generate the transcellular Na + and K + gradients provides the electrochemical gradient determines the membrane potential.

6 K + channels Ca 2+ -activated K + channel BK channels IK channels

7 Na + /K + /2Cl - channels NKCC1 is ubiquitous activated by cell shrinkage restore cell volume inhibited by the diuretics furosemide and bumetanide mediates 70% of the Cl - uptake provide most of the Na + necessary to fuel the Na + /K + pump

8 Na + /H + and Cl - /HCO + 3 NHE1 and AE2 NHE1 and AE2 are ubiquitous housekeepers of cytoplasmic ph activated by small changes in intracellular ph NHE1 is activated by acidic phi AE2 is activated by alkaline phi NHE1 and AE2 are involved in many cellular functions including mediation of acinar cell fluid and electrolyte secretion

9 TMEM16A apical Ca 2+ -activated Cl - channel

10 AQUAPORINS AQP family consists of 13 members water channels glyceroporins AQPs functions: cell adhesion, proliferation, migration, and cell survival Diseases: Sjögren s syndrome and pancreatitis Deletion of AQP5 disrupted the integrity of the tight junction and reduced the paracellular water permeability

11 Fluid and electrolyte secretion by acinar cells Secretion is fueled by the basolateral Na + /K + ATPase pump NKCC1 and NHE1 are the main routes of Na + influx Ca 2+ -activated K + channels set the membrane potential at 50 to 60 mv NKCC1 is the major route of Cl - influx NHE1 and AE2 set cytoplasmic ph at 7.2 Transcellular Na + flux

12 Fluid and electrolyte secretion by ductal cells

13 TRANSPORTERS AT THE BASOLATERAL MEMBRANE

14 Na + /H + exchanger 1 (NHE1) electroneutral 1Na + /1H + exchangers NHE1 ubiquitous phi homeostasis localized at the basolateral membrane provide a portion of HCO + 3 influx NHE2 and NHE3 localized at the luminal membrane salvage HCO + 3

15 TRANSPORTERS AT THE BASOLATERAL MEMBRANE

16 Na + /HCO + 3 exchanger (NBC) Acid-base homeostasis, Regulation of cell volume and intracellular ph NBC1 expressed at the BASOLATERAL membrane electrogenic transporter 1 Na + -2 HCO + 3 stoichiometry mediates the bulk of basolateral HCO + 3 entry NBC3 expressed at the LUMINAL membrane electroneutral transporter 1 Na + -1 HCO + 3 stoichiometry Salvage HCO + 3

17 TRANSPORTERS AT THE BASOLATERAL MEMBRANE

18 TRANSPORTERS AT THE BASOLATERAL MEMBRANE

19 TRANSPORTERS AT THE LUMINAL MEMBRANE

20 CFTR

21 MECHANISM OF HCO + 3 SECRETION

22 MECHANISM OF HCO + 3 SECRETION

23 RELATIONSHIP BETWEEN ACINAR AND DUCTAL CELLS

24 Physiology Pathophysiology STRESS activating enzymes enzymes Alcohol 45% Bile 45% Others 10% fluid and HCO - 3 AUTODIGESTION DIGESTION INFLAMMATION CELL DEATH

25 Development of Acute Pancreatitis Inducing Factor Intracinar Events Immun Response - Bile acid - Ethanol -Other factors NO SPECIFIC THERAPY -Pathological Ca 2+ signal -Colocalization of lysosomal enzymes and zymogens -Intrapancreatic trypsinogen activation -Autodigestion, Inflammation ACUTE PANCREATITIS -Leukocyte activation -Cytocines (IL-6, TNFα, etc.) -ROS

26 The Pancreas

27 Ductal cells Acinar cells Insufficient electrolyte and fluid secretion by ductal cells in CF Destruction of acinar cells Primary defect Pancreatic duct in membrane trafficking obstruction of zymogens Correction of the luminal ph reverses the membrane trafficking defects and largely restores the membrane dynamics Freedman SD, Gastroenterology, 2001 Model of post-ercp pancreatitis in rats ph 6.0 ph 6.9 ph 7.3 Pancreatic damage c Noble MD, Gut, 2008 Lower extracellular ph Mislocalization of CFTR in AIP Bhoomagoud M, Gastroenterology, 2009 enhances secretagogue-induced zymogen activation Decreased pancreatic ductal function Reversal by corticosteroid treatment Ko SB, Gastroenterology, 2010

28 Ductal cells Acinar cells alterations in pancreatic ductal fluid and bicarbonate secretion can increase patients risk to pancreatitis restoration of pancreatic ductal bicarbonate and fluid secretion may have therapeutic benefits

29 ETIOLOGICAL FACTORS IN ACUTE PANCREATITIS Gallstone (bile acid) Alcohol Trypsinogen Trypsin?

30 Venglovecz V et al. Gut 2008;57: Ignath I. et al. Pancreas 2009;38: Venglovecz V, et al. Gut 2011;60: Maleth J et al. Gut 2011;60:136-8.

31 Hegyi P. et al. Gut 2011;60: Maléth J. et al.unpiblished

32 The trypsin vicious cycle Pallagi et al, Gastroenterology 2011 Dec;141(6):

33 What are the roles of bicarbonate secretion? To neutralize the acid content secreted by acinar cells To curtail trypsinogen autoactivation within the pancreatic ductal system To neutralise the acid chyme entering the duodenum from the stomach To defend the pancreas by washing out the toxic agents HCO - 3 HCO - 3 HCO - 3 HCO - 3 HCO - 3 The main pancreatitis-inducing factors HCO (bile - acids and ethanol) are strong 3 inhibitors of pancreatic ductal bicarbonate secretion