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.

Figure 1.

Pathogenesis of pancreatic disease in CF. Acinar cells secrete large quantities of protein, primarily in the form of digestive enzymes, into the acinar lumen. Under normal circumstances anions (Cl⁻ and HCO₃⁻) are secreted into the ductal lumen (see detailed model in Fig. 3). This provides a driving force for the movement of fluid into the lumen of the duct and maintains the solubility of secreted proteins in a dilute, alkaline solution. In CF, impaired anion transport into the proximal ducts results in decreased secretion of more acidic fluid, which leads to precipitation of secreted proteins. Intraluminal obstruction of the ducts then causes progressive pancreatic damage and atrophy. (From Wilschanski and Durie 2007; reprinted, with permission.)

Figure 2.

The relation between secretory rates and HCO₃⁻ concentrations in pancreatic juice of various species. Secretion was stimulated by secretin and secretory rate was collected for body weight. For details, see Novak et al. (2011).

Figure 3.

Cellular model for HCO₃⁻ secretion in pancreatic ducts. Primary active transporters (pumps) and several secondary active transporters and ion channels, including Ca²⁺ activated K⁺ and Cl⁻ channels, are involved in creating the chemical and electrical driving gradient necessary for production of NaHCO₃-rich pancreatic juice in healthy pancreas, as described in text. The CFTR has central role pancreatic ducts; in CF, pancreatic juice volume and pH are reduced.