Airway Surface Liquid and Respiratory Mucus - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 762

conductance regulator [ 1548 ]. 14 Airway surface liquid is not only isotonic with
plasma [ 1548 ]. In addition, mucus has a similar ion concentration to that of the
periciliary liquid.
Oscillatory-like tidal air flow exerts quasi-cyclic shear and stretch with given
magnitude and frequency on mural cells. Shear stress may activate signaling path-
ways in epithelial cells. In particular, time change in high-magnitude mechanical
stress raises ATP release into the extracellular medium [ 1548 ]. The shear frequency
influences more time-varying ion motions than the shear magnitude to maintain a
constant overall volume of airway surface liquid, some amount possibly being swept
away duting expiration.
Locally, the volume of the periciliary fluid layer is controlled by the concen-
trations of adenyl and uridyl nucleotides and their metabolite adenosine. Adenine
nucleotides (AMP, ADP, and ATP) are released from ciliated cells that sense
mechanical stress during ventilation via dedicated carriers such as pannexons and
vesicular liberation as well as coexocytosis with uridyl nucleotides from secretory
cells. Hydrolytic and transphosphorylating ectoenzymes then convert triphosphate
nucleotides into ADP, AMP, and adenosine, UDP, UMP, and uridine.
Mechanical stresses stimulate cosecretion of nucleotides (ATP and UTP) and
mucin from goblet cells [ 1549 ]. Pannexin-1 (but not Panx3) is synthesized in
normal human airway epithelial cells [ 1550 ]. Apical pannexons of airway epithelial
cells contribute to ATP release. Pannexons open at resting membrane potentials
in response to long-range intercellular calcium wave initiated by mechanical
stress [ 1551 ]. 15 In addition, Panx1 colocalized with P2Y receptors open in response
to extracellular ATP via intracellular Ca 2 + ion [ 1552 ].
Adenosine triphosphate and its metabolite adenosine regulate secretion via acti-
vation of Gq-coupled P2Y 2 and Gs-coupled A 2B receptors on the apical membrane
of ciliated cells, in addition to P2X 4 channel and P2Y 2 receptors on goblet cells,
causing changes in intracellular second messengers that promote chloride release
and inhibit sodium absorption, thereby favoring water flux into the airway lumen.
Activated A 2B receptor launches cAMP-dependent activation of CFTR Cl −
channel and stimulates ciliary beat frequency [ 1553 ]. The adenosine-cAMP axis
regulates CFTR positively and ENaC negatively [ 1548 ].
Liganded P2Y 2 receptor prevents Na + absorption as well as CFTR-dependent
Cl − secretion, in addition to precluding ciliary beating and mucin secretion. On
the other hand, ATP stimulates Ca 2 + -mediated CL − secretion through CaCC
channels [ 1548 ].
14 The coordinated action of ion channels, pumps, and transporters, maintains secretion by highly
water-permeable airway epithelia. These leaky epithelia are capable of both absorbing Na + and
secreting Cl − ion, thereby controlling the airway surface liquid (ASL) volume and generating an
efficient mucus clearance. When the airway epithelium secretes more salts into the airway surface
liquid, water follows passively; the ASL volume rapidly increases to maintain isotonicity with
plasma; and vice versa.
15 Long-range communication using intercellular calcium wave results from the flux of IP 3 through
connexons (gap junctions) as well as an extracellular release of ATP messenger through pannexons.