Role of CFTR in epithelial physiology

Abstract

Salt and fluid absorption and secretion are two processes that are fundamental to epithelial function and whole body fluid homeostasis, and as such are tightly regulated in epithelial tissues. The CFTR anion channel plays a major role in regulating both secretion and absorption in a diverse range of epithelial tissues, including the airways, the GI and reproductive tracts, sweat and salivary glands. It is not surprising then that defects in CFTR function are linked to disease, including life-threatening secretory diarrhoeas, such as cholera, as well as the inherited disease, cystic fibrosis (CF), one of the most common life-limiting genetic diseases in Caucasian populations. More recently, CFTR dysfunction has also been implicated in the pathogenesis of acute pancreatitis, chronic obstructive pulmonary disease (COPD), and the hyper-responsiveness in asthma, underscoring its fundamental role in whole body health and disease. CFTR regulates many mechanisms in epithelial physiology, such as maintaining epithelial surface hydration and regulating luminal pH. Indeed, recent studies have identified luminal pH as an important arbiter of epithelial barrier function and innate defence, particularly in the airways and GI tract. In this chapter, we will illustrate the different operational roles of CFTR in epithelial function by describing its characteristics in three different tissues: the airways, the pancreas, and the sweat gland.

Keywords: Bicarbonate; CFTR; Chloride; Epithelial transport; Physiology.

Fig. 1

Basic characteristics of an epithelial layer. a Epithelial cells are joined together by junctions [tight junctions (TJ), gap junctions (GJ)]. Uptake of nutrients and oxygen, and removal of cellular waste products occur on the basolateral surface. Water and ion transport can occur through the transcellular or paracellular pathways. b Absorption is mainly driven by active Na⁺ absorption through ENaC in the apical membrane and the Na⁺/K⁺-ATPase in the basolateral membrane creating an electrochemical driving force for paracellular passive Cl⁻ transport. Water then follows either through aquaporins or the paracellular pathway. c Secretion is mainly driven by Cl⁻ secretion through CFTR and other Cl⁻ channels in the apical membrane. NKCC1 and the coupled action of an anion exchanger and NBC in the basolateral membrane accumulate Cl⁻ in the cell. Active Cl⁻ secretion creates the driving force for Na⁺ movement across the epithelium through the paracellular pathway and water transport occurs paracellularly and/or transcellularly. Red and green arrows show active transport, and yellow arrows show passive transport

Fig. 2

Cellular components of the airways. The airways are composed of the conducting airways (a) and the respiratory airways (b). a The conducting airways are covered by an aqueous film called the airway surface liquid (ASL) which is composed of the periciliary layer (PCL) and the mucus layer (M). Three types of cells constitute the conducting airways: the ciliated cells (CC), goblet cells (GC), and basal cells (BC). b The respiratory airways are composed of the alveolar type I (ATI) and type II (ATII) cells and are covered by the alveolar lining fluid (ALF) that prevent alveoli from collapsing

Fig. 3

Ion transport in the airways. On the apical surface, CFTR drives Cl⁻ and HCO₃ ⁻ secretion and regulates Na⁺ absorption by inhibiting ENaC. CFTR also positively regulates the Cl⁻ channels ANO1 and SLC26A9 as well as the anion exchanger SLC26A4, increasing Cl⁻ and HCO₃ ⁻ secretion and therefore increasing ASL hydration and pH. Na⁺ and water follow the electrochemical gradient through the paracellular pathway. On the basolateral membrane, NKCC1 accumulates Cl⁻ intracellularly supported by the Na⁺/K⁺-ATPase. K⁺ recycling across the basolateral membrane occurs for proper function of the Na⁺/K⁺-pump

Fig. 4

Simplified structure of the pancreas. The exocrine pancreas is composed of acini that surround a central lumen open to the duct system. Acinar cells (AC) secrete digestive enzymes into small intercalated ducts (ICD) where the pancreatic duct cells (PDC) raise the pH of the pancreatic juice (PJ). These ducts are directly connected to increasingly larger intralobular (intraLD) and interlobular (interLD) ducts that join the main pancreatic duct

Fig. 5

Ion transport in acinar (a) and pancreatic duct cells (b). a Upon stimulation with acetylcholine, cholecystokinin or other agonists, intracellular [Ca²⁺] increases and stimulates NaCl and fluid secretion, as well as the exocytosis of enzyme-containing secretory granules. As these granules also contain H⁺, the local pH falls to approximately 6.8. Cl⁻ secretion occurs through a CaCC on the apical membrane. b CFTR conducts Cl⁻ and HCO₃ ⁻ and works in concert with a Cl⁻/HCO₃ ⁻ apical exchanger, to mediate net transepithelial HCO₃ ⁻ secretion, with Cl⁻ recycling across the apical membrane. Na⁺ moves paracellularly in response to transepithelial HCO₃ ⁻ secretion, and water follows osmotically, to produce a HCO₃ ⁻-rich isotonic fluid. Cl⁻ accumulates across the basolateral membrane via NKCC1 and accumulation of HCO₃ ⁻ inside the cells occurs through the hydration of CO₂ to HCO₃ ⁻ and H⁺ by carbonic anhydrase (CA), together with backward transport of H⁺ via the basolateral Na⁺/H exchanger (NHE). This is driven by the Na⁺ gradient established by the Na⁺/K⁺-ATPase. The Na⁺-Bicarbonate cotransporter (NBC) helps accumulate HCO₃ ⁻ within the cell and maintain an electrical driving force for efflux of HCO₃ ⁻ across the apical membrane. It also works with K⁺ channels to maintain a negative membrane potential

Fig. 6

Schematic representation of an eccrine sweat gland. The human sweat gland is a simple-coiled tubular exocrine gland that resides in the dermis and connects to the surface of the skin by a straight absorptive duct. a The secretory coil duct epithelium is composed of clear (CC), dark (DC), and myoepithelial cells (MEC), and is responsible for producing the primary secretion. b The reabsorptive duct epithelium is composed of two layers of cuboidal cells which absorb salt but not water

Fig. 7

Ion transport in the sweat gland. a Secretory coil duct epithelial cells secrete NaCl and water mainly in response to cholinergic (acetylcholine, ACh) stimulation. b The reabsorptive duct epithelial cells express a constitutively active CFTR on both apical and basolateral membranes. Both Na⁺ and Cl⁻ move transcellularly and both ENaC and CFTR work together to regulate net transepithelial NaCl absorption. Na⁺ is pumped out of the cell across the basolateral membrane to the interstitial fluid by the Na⁺/K⁺-pump, generating a transepithelial electrical gradient favouring Cl⁻ absorption