CFTR: A New Horizon in the Pathomechanism and Treatment of Pancreatitis

Abstract

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.

Role of CFTR in epithelial physiology

“…Indeed, trypsin itself has been shown to reduce CFTR-dependent HCO 3 − secretion from duct cells [124], through activation of apical proteinase-activated receptor-2, which leads to further trypsin autoactivation. Furthermore, a fall in ductal HCO 3 − secretion appears particularly important in protecting the pancreas from developing acute pancreatitis induced by stresses such as bile and alcohol [125], the two most common causes of pancreatitis in man (see below).…”

“…This potentially could be through the use of the FDA approved drug, Lumacaftor (see Chapter “Cystic Fibrosis: a clinical view”), which improves folding and processing of F508del-CFTR to the plasma membrane, as well as Ivacaftor to improve channel activity. Another goal here would be to find ways of preventing the marked reduction in ATP levels in ductal (and acinar) cells [125, 183]. A potential clinical strategy would be to try and improve nutritional support at a very early stage in acute pancreatitis, although a recent trial looking at the benefits of nasoenteric feeding after ~20 h of admission did not show any improvement in outcome compared to those patients that had on-demand oral feeding commencing at 24 h [184].…”

Ca2+ Influx Channel Inhibitor SARAF Protects Mice From Acute Pancreatitis

“…Acinar cell damage is a critical driver of acute and chronic pancreatitis. The pancreatic duct is the first line of defense 37,38 , protecting the acini from damaging mediators by secreting HCO3 --rich fluid 37 . In all forms of pancreatitis, mislocalization and degradation of CFTR 6 breaches the ductal guard, causing retention and activation of digestive enzymes within acinar cells and cell damage [5][6][7] .…”

Pancreatitis and pancreatic cystosis in Cystic Fibrosis

“…constipation, distal intestinal obstruction syndrome, intussusception, small bowel bacterial overgrowth). Approximately 20% of PS CF patients will develop pancreatitis during their lifetime, typically developing in their teens or adulthood [5,33]. Of these patients, only 18% will experience a single episode of AP while 60% will develop ARP with the remaining 22% advancing to CP [5].…”