Physiology of epithelial chloride and fluid secretion

Abstract

Epithelial salt and water secretion serves a variety of functions in different organ systems, such as the airways, intestines, pancreas, and salivary glands. In cystic fibrosis (CF), the volume and/or composition of secreted luminal fluids are compromised owing to mutations in the gene encoding CFTR, the apical membrane anion channel that is responsible for salt secretion in response to cAMP/PKA stimulation. This article examines CFTR and related cellular transport processes that underlie epithelial anion and fluid secretion, their regulation, and how these processes are altered in CF disease to account for organ-specific secretory phenotypes.

Figure 1.

Schematic of the transport pathways in secretory epithelia. As shown in the “Classical model,” Cl⁻ entry across the basolateral membrane is driven primarily via Na⁺ cotransport. Apical Cl⁻ efflux is mediated by cAMP- and Ca²⁺-activated anion conductances. The scheme labeled “Recent additions” identifies the numerous transporters and channels proposed to mediate ion and fluid secretion in various epithelia. Accordingly, basolateral Cl⁻ loading may occur via both NKCC1 and AE2. Cl⁻ and HCO₃⁻ exit involves apical CFTR, TMEM16A, and probably other Cl⁻ channels/transporters, such as members of the SLC26A family (data not shown). NBC1-mediated HCO₃⁻ entry during cAMP stimulation maintains intracellular pH and generates electrogenic trans-epithelial HCO₃⁻ secretion. NHE1 maintains intracellular pH during stimulation by Ca²⁺ secretagogues when cells are hyperpolarized and net Cl⁻ secretion is favored. There is evidence for apical H⁺ secretion mediated by vacuolar proton pumps, H⁺/K⁺-ATPase, and also apical K channels, which contribute to apical hyperpolarization and thus enhance the driving force for anion secretion. Most trans-epithelial Na⁺ flux occurs passively through the paracellular pathway driven by the lumen-negative voltage arising from electrogenic anion secretion. In both schemes, regulated apical anion conductance is rate-limiting at low/medium levels of anion secretion, but basolateral K conductance becomes increasingly limiting at higher secretory rates, explaining the additive nature of secretagogues that operate via different second-messenger pathways.

Figure 2.

Simplest equivalent circuit that can describe ionic currents across epithelia. Net electromotive forces (EMFs) that result from ion concentration gradients across the apical membrane (E_a), basolateral membrane (E_b), and paracellular “shunt” pathway (E_s) are shown as batteries. Membrane conductances that mediate electrogenic (non-neutral) ion flows driven by those EMFs are depicted as resistors.

Figure 3.

Cartoon illustrating the impact of impaired airway secretion on mucociliary clearance. Contributions to the volume and composition of the airway surface liquid (ASL) emerge from the surface epithelium and submucosal glands. The surface epithelium of non-CF airways adjusts the depth of the periciliary liquid layer (PCL) to a level that enables ciliary beating and effective mucociliary clearance. In CF, the absence of sufficient CFTR function compromises salt and water secretion, PCL regulation, and mucus clearance from the surface epithelium and gland ducts. Mucus accumulation leads to infection, inflammation, and bronchiectasis.