Pankteratitida

Adequate HCO3 - secretion by CFTR protein

• Is essential for preventing premature autoactivation of trypsin by protons within the ductal tree, and therefore inhibiting autodigestion of the gland.
• Trypsin itself has been shown to reduce CFTR-dependent HCO3 - secretion from duct cells [124], through activation of apical proteinase-activated receptor-2, which leads to further trypsin autoactivation. Furthermore, a fall in ductal HCO3 - secretion appears particularly important in protecting the pancreas from developing acute pancreatitis induced by stresses such as bile and alcohol

Alcohol, bile

• Induce stress/inflammation of the exocrine pancreas (pancreatitis)
• Bile and alcohol, caused marked changes in HCO3 - and fluid secretion
• Based on in vitro intracellular pH and fluid transport studies from isolated microdissected ducts.
• At low concentrations
• Both agents increased HCO3 - secretion
• Response that required CFTR and Cl-/HCO3 - exchange activity
• Higher levels of these agents
• Led to a severe inhibition of CFTR-dependent HCO3 - secretion
• Due to profound mitochondrial damage
• Consequent reduction in intracellular ATP levels
• link.springer.com/article/10.1007/s00018-016-2391-y

CFTR

• Patients with autoimmune or acute and chronic alcohol-induced pancreatitis
• Marked abnormalities in membrane localisation and expression levels of CFTR
• Significant correlation between the development of pancreatitis and variants in the CFTR gene
• Do not cause a typical CF phenotype
• But appear to have impaired HCO3 - secretion
• link.springer.com/article/10.1007/s00018-016-2391-y

Pancreatic diseases and hydrogen

• HRS also significantly attenuated the severity of acute pancreatitis (AP)
• Via inhibiting the activation of NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome
• Paralleled with the decreased oxidative stress and inflammatory cascades
• Molecular mechanism of hydrogen in the treatment of AP by proteomic analysis

Hydrogen

• Ameliorated the inflammatory response
• Reduced the expression of inflammatory mediators during the early phase of AP
• By inhibiting the mitogen activated protein kinases (MAPK) pathways
• Increasing heat shock protein 70 expression
• www.medgasres.com/article.asp?issn=2045-9912;year=2017;volume=7;issue=4;spage=265;epage=272;aulast=Li

Class 3 CFTR potentiator, Ivacaftor

• Over 24 weeks, have shown a significant restoration of enzyme-secreting capacity (increased faecal elastase-1 levels)
• By inference, pancreatic tissue regeneration
• Variants (SNPs) in the SLC26A9 anion transporter can influence disease severity in the CF lungs and gut (meconium ileus)
• Act as gene modifiers
• SNPs in SLC26A9 can also influence the degree of pancreatic insufficiency
• Opens up the possibility of targeting this anion transporter as a potential therapeutic target
• To slow the progression of exocrine dysfunction in CF (in addition to the lungs and ileum).
• link.springer.com/article/10.1007/s00018-016-2391-y

Lumacaftor

• Restoring cell surface expression and activity of CFTR may partly alleviate the ethanol-induced damage. This potentially could be through the use of the FDA approved drug
• Which improves folding and processing of F508del-CFTR to the plasma membrane, as well as Ivacaftor to improve channel activity.
• link.springer.com/article/10.1007/s00018-016-2391-y