Airway Surface Liquid and Respiratory Mucus - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 747

ATP ADP AMP adenosine inosine

mucus

Aqp

CaCC CBEx ELF NHEx

ENaC CFTR ORCC

CNT cilium

P2Y A2b

PIP2

CFTR

HK−ATPase

basal body

−

cAMP

IP3 Cl Na Cl

PKA
PKG

Ca

PKA

CFTR

endosome

H−ATPase

airway epithelial cell

H2O, Cl, Na, K

Fig. 12.1 Ion transport across the apical plasma membrane of airway epithelial cells
(Source: [ 1514 ]). The liquid layer at the luminal surface (airway surface liquid) of the respiratory
epithelium has 2 strata: epithelial lining fluid (ELF) and mucus layer. The respiratory cilium beats
in epithelial lining fluid, but its tip contact overlying mucus. Aquaporins and ion channels that
regulate water and ion transport are involved in production and maintenance of epithelial lining
fluid as well as mucus homeostasis. Chloride ions exit through cystic fibrosis transmembrane
conductance regulator (CFTR) are stimulated by adenosine binding to its receptor A 2B or calcium
ions that excite Ca 2 + -activated Cl − channels (CaCC) after Ca 2 + influx upon stimulation of
nucleotide receptor P2Y 2 by ATP messenger. Channel CFTR also transports transport ATP,
sodium, bicarbonate ions, and water. Channel CFTR is activated by protein kinase-A (PKA),
cAMP, and ATP binding. In addition, CFTR is phosphorylated by protein kinases PKG1a and
PKG2. Sodium ions are imported through epithelial Na + channel (ENaC). Chloride channel CFTR
inhibits ENaC channel. It also regulates Cl − -HCO 3 exchanger (CBEx) and outwardly rectifying
Cl − channels (ORCC). Airway surface liquid pH is regulated by H + -K + AT P a s e a n d C l − -HCO 3
exchanger. Channel CFTR can activate aquaporin (Aqp). It also targets regulator NHERF of Na + -
H + exchanger NHE3 (NHEx). Channel CFTR located in membrane of endosomal vesicles can
counterbalance the activity of H + ATPase. Adenosine and inosine are removed from airway surface
by concentrative nucleoside transporters (CNT).

(Cl − and HCO 3 ) secretion. On the other hand, the passive paracellular ion transfer
depends on adhesion plaques between apposed epithelial cells that confer the
permeability and ion selectivity of the paracellular path. In polarized respiratory
epithelia, the paracellular pathway is limited by tight junctions and scattered
adherens junctions. The latter localize in the lateral intercellular spaces, where
adjacent epithelial cells interdigitate. Circumferential tight junctions form the func-
tional and structural border that separates apical and basolateral compartments. Like
many other epithelia, respiratory epithelia produce multiple claudins, the primary
determinants of paracellular ion conductance. 2

Rapid regulation of transcellular

2 Different cell types of the respiratory epithelium synthesize the same claudin types that form
homo- and hetero-oligomers, both on a given cell and with those of its neighbors. Aldosterone
increases claudin-4 phosphorylation and paracellular Cl − permeability.