The Cystic Fibrosis of Exocrine Pancreas

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) protein is highly expressed in the pancreatic duct epithelia and permits anions and water to enter the ductal lumen. This results in an increased volume of alkaline fluid allowing the highly concentrated proteins secreted by the acinar cells to remain in a soluble state. This work will expound on the pathophysiology and pathology caused by the malfunctioning CFTR protein with special reference to ion transport and acid-base abnormalities both in humans and animal models. We will also discuss the relationship between cystic fibrosis (CF) and pancreatitis, and outline present and potential therapeutic approaches in CF treatment relevant to the pancreas.

The Cystic Fibrosis Intestine

“…Although the intestine is often thought of as an absorbing tissue, it also secretes significant volumes of fluid, largely from the crypts that have high CFTR levels, where it is thought to flush out this cul-de-sac to maintain a sterile environment to protect the stem cells at the bottom of the crypt. In addition, the intestine receives a large volume of bicarbonate-rich fluid from the pancreas (see Wilschanski and Novak 2013).…”

“…About 60% of patients with severe CFTR mutations (see article in this collection by Ferec and Cutting 2012) are born with exocrine pancreatic insufficiency (EPI) (Cipolli et al 2007), which progresses with age to include 85% -90% of patients (see Wilschanski and Novak 2013). Loss of bicarbonate-rich pancreatic fluids in patients with EPI alters the intestinal intraluminal milieu.…”

Purinergic signalling in the pancreas in health and disease

“…CFTR is regulated also by P2Y 2 and other P2Y receptors, as shown for a number of other epithelia (Novak 2011). In the case of a defect in CFTR, anion (Cl K and HCO K 3 ) secretion may be taken over by Ca 2C -activated Cl K channels and these are regulated by a number of P2 receptors (see above), and potentially these could be utilised to 'rescue' pancreatic function (Wilschanski & Novak 2012).…”

Structure-Function Relationships of CFTR in Health and Disease: The Pancreas Story

“…Following the lung, the pancreas is the most affected organ in CF. It has been documented that most of the CF patients have pancreatic exocrine insufficiency, which leads to maldigestion and potentially malnutrition (117). In this context, malabsorption of fat and fat-soluble vitamins are the most common nutritional deficient seen in this disease.…”

“…CFTR acts as a selective ion channel involved in chloride, bicarbonate (HCO 3 -), water transport across the apical membranes of epithelial cells in multiple organs including the pancreas that produces alkaline fluid in pancreatic ducts (30,70,117). HCO 3 -is an important ion in the pancreatic juice.…”