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Departments of Medicine and Physiology, Cardiovascular Research Institute, University of California, San Francisco, California 94143-0521
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Airway surface liquid (ASL) pH has
been proposed to be important in the pathophysiology of cystic
fibrosis, asthma, and cough. Ratio image analysis was used to measure
pH in the ASL after staining with the fluorescent pH indicator
2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF)-dextran. ASL pH in bovine airway cell cultures grown at an
air-liquid interface was 6.98 ± 0.06 in the absence and 6.81 ± 0.04 in the presence of HCO
replacement but was
not affected by the inhibitors amiloride, glibenclamide, or
4,4'-dinitrostilbene-2,2'-disulfonic acid. In response to sudden
acidification or alkalization of the ASL by ~0.4 pH units by
HCl/NaOH, ASL pH recovered to its initial value at a rate of 0.035 pH
units/min (
HCO transport between the ASL and
basolateral fluid involves amiloride-sensitive Na+/H+ exchange and stilbene-sensitive
Cl/HCO
cystic fibrosis; acidification; trachea; fluorescence microscopy
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE AIRWAY SURFACE
LIQUID (ASL) is the thin layer of liquid at the air-facing
epithelial surface in the upper and lower airways. The regulation of
ASL volume, ionic composition, and pH is believed to be important in
normal airway physiology and in the pathophysiology of genetic and
acquired diseases of the airways such as cystic fibrosis and asthma
(3, 10, 15, 19). Abnormalities of the ASL may induce
bronchoconstriction and the cough reflex and interfere with epithelial
cell ionic homeostasis and airway defense mechanisms such as
antimicrobial activity and bacterial clearance (10, 17, 23,
26). The determination of ASL composition has posed a
considerable challenge because of its small volume (2-3 µl
of ASL per square centimeter of mucosal surface). Invasive sample
methods utilizing filter paper and microcapillary tubes have yielded a
wide range of ionic concentrations (1, 5, 9, 13, 14, 23,
28) and have been criticized because of potential perturbation
of the airway surface and sampling of intracellular and interstitial
fluids by capillary suction (3, 6, 19, 25). We recently
developed a minimally invasive in situ approach to measure ASL volume,
ionic composition, and osmolality (12). The ASL is stained
with ion-sensitive fluorescent indicators and viewed with a microscope
equipped with z-scanning confocal optics and ratio image detection. The
ASL in airway cell cultures and in the in vivo mouse trachea was
approximately isotonic and not dependent on cystic fibrosis
transmembrane conductance regulator (CFTR) Cl channels.
Initial measurements of ASL pH in living anesthetized mice showed a pH
~7 (12).
On the basis of evidence that CFTR may transport HCO
The purpose of this study was to define the principal determinants of ASL pH. Measurements were done on well-differentiated primary cultures of bovine airway epithelial cells grown at an air-liquid interface and in the in vivo mouse trachea. The bovine airway cell culture model was chosen as a well-established system for which there exists a considerable body of data on ion transport mechanisms, including an analysis of intracellular pH regulation (21). The polarized cell culture system permitted measurements of ASL pH in response to transporter agonists/inhibitors, ion substitution, and imposed pH gradients. The mouse trachea was studied as an in vivo model that permitted the testing of transporter agonists/inhibitors as well as clinically important systemic acid-base disturbances. The data reported here establish empirically the major determinants of ASL pH and the transporting systems involved in transepithelial pH equilibration. An important unanticipated finding was the lack of a strict regulatory mechanism maintaining absolute ASL pH.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Cell culture experiments.
Well-differentiated cultures of bovine tracheal cells were grown on
collagen-coated 12-mm-diameter Costar snapwell inserts with
polycarbonate semipermeable membranes at an air-liquid interface at
37°C in a 5% CO2-95% air atmosphere (27).
Culture medium was changed every 2-4 days. Cultures were generally
used 25-30 days after plating, at which time the electrical
resistance was >300 
cm2, and the transepithelial
potential difference was >20 mV. Cell inserts were mounted (cells
facing upward) in a stainless steel perfusion chamber in which the
undersurface of the insert was perfused as described previously
(12). The perfusate bathed the cell basolateral surface.
The cell mucosal surface containing the ASL faced upward. The chamber
was maintained at 37°C using a PDMI-2 microincubator (Harvard
Apparatus) positioned on the stage of an upright epifluorescence
microscope and enclosed in a 100% humidified air-5% CO2
tent maintained at 37°C. For pH measurements, the ASL was stained
with the dual-excitation wavelength pH indicator 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF)
conjugated to dextran (40 kDa, Molecular Probes), dispersed in a low
boiling point perfluorocarbon (Fluorinert FC-72, boiling point 56°C,
3M Company).
Measurement protocols.
The pH sensitivity of BCECF-dextran in the ASL was calibrated by
incubating the cell culture inserts with high-K+ perfusates
(120 mM KCl, 20 mM NaCl, 1 mM CaCl2, 1 mM
MgSO4, and 20 mM HEPES) containing nigericin (10 µM),
valinomycin (10 µM), carbonyl cyanide
m-chlorophenylhydrazone (5 µM), and forskolin (10 µM). Perfusates were titrated to specified pH (6.5-8.0) and equilibrated with cells for 4 h to set ASL pH, a time at which pH
equilibration was found to be complete. For experiments involving HCO by gluconate. In
experiments involving recovery from acute ASL acidification or
alkalization, 20-50 µl of a perfluorocarbon suspension of
HCl/NaOH (prepared by brief sonication) was added onto the ASL to
change pH by 0.4-0.5 pH units. In some experiments, transport
inhibitors were added to the perfusate or to both the perfusate and the
ASL as described in RESULTS.
Measurements in mouse trachea in vivo. Mice (25-35 g body wt) were anesthetized with ketamine (60 mg/kg body wt) and xylazine (8 mg/kg) 15 min after pretreatment with atropine (1 mg/kg intraperitoneal) to prevent secretions as discussed previously (12). A midline incision was made in the neck to expose the trachea for measurement of fluorescence through the translucent tracheal wall. Unless otherwise indicated, the ASL was stained by instillation of 5 µl of the BCECF-dextran suspension in perfluorocarbon using a microcatheter passed through a feeding needle that was introduced via the mouth. The mouse was positioned on the microscope stage for fluorescence measurements as described below. Arterial blood (0.2-0.3 ml) was sampled through a PE-10 catheter inserted into the carotid artery, and blood pH and PCO2 were measured using a blood gas analyzer (Ciba Corning Diagnostic). After completion of the measurements, mice were euthanized by an overdose of pentobarbital (150 mg/kg). Animal protocols were approved by the University of California San Francisco Committee on Animal Research.
In some experiments, amiloride (10 mg/kg of 1 mM solution) was injected intraperitoneally 30 min before anesthesia, and 2.7 µg of amiloride (dispersed in perfluorocarbon) was instilled into trachea together with BCECF-dextran. ASL pH was measured 10 min after the perfluorocarbon instillation. Mice were treated with glibenclamide by intraperitoneal injection of 0.3 ml of a 1 mM glibenclamide solution and intratracheal instillation of 4.9 µg of glibenclamide in perfluorocarbon. To create acute metabolic acidosis or alkalosis, HCl (0.5 meq H+) or NaHCO3 (0.3 meq) were injected intraperitoneally. ASL pH was measured after 20 min. To create respiratory acidosis or alkalosis, the upper trachea of anesthetized, paralyzed (pancuronium, 1 mg/kg intraperitoneal) mice was cannulated with PE-90 tubing, and mice were mechanically ventilated with room air (tidal volume 8 ml/kg, respiratory rate 90 respirations/min) using a mouse constant volume ventilator (Harvard Apparatus). Acute hyperventilation was produced by increasing the respiratory rate to 140 respirations/min for 10 min before ASL pH measurements and arterial blood gas analysis. Acute hypoventilation/hypercarbia was produced by decreasing respiratory rate to 90 respirations/min and addition of 5% CO2 (95% O2, to prevent hypoxia) to the inspired gas.Fluorescence microscopy. The chamber containing the cultured cells or the mouse was positioned on the stage of a Leitz upright fluorescence microscope with a Technical Instruments coaxial-confocal attachment. Fluorescence was detected using a Nikon ×50 extra-long working distance air objective (numerical aperture 0.55, working distance 8 mm) for ratiometric measurement of pH at 440- and 490-nm excitation wavelengths and a 535-nm emission wavelength. Background fluorescence (unstained cells or trachea) was <1% of total fluorescence.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Cell culture experiments.
The ASL of tracheal cells cultured at an air-liquid interface was
stained with the pH indicator BCECF-dextran by addition of microliter
quantities of a low boiling point perfluorocarbon containing the
dispersed indicator. The perfluorocarbon evaporated within a few
seconds, permitting the BCECF microparticles to dissolve rapidly in the
ASL. The cells on the porous support were mounted in a 37°C perfusion
chamber in which the basolateral surface was perfused, and the
apical surface was exposed to a 100% humidified atmosphere.
Figure 1A shows an in
situ calibration of the ratio of BCECF:fluorescence at 490- and
440-nm excitation wavelengths (F490/F440). ASL
pH was set using perfusates containing high K+ and
ionophores. The pKa of BCECF-dextran in the ASL was 7.05, not different from that in saline. Figure 1A also shows the
averaged results from a series of measurements done in cells in the
absence and presence of CO2/HCO
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cm2) and trypan blue dye exclusion. Figure 2B
shows the kinetics of ASL pH following changes in perfusate pH in the
absence and presence of CO2/HCO0.030 ± 0.003 (perfusate pH 6.0) and 0.023 ± 0.005 (pH 8.0) in the absence of
CO2/HCO0.027 ± 0.003 (pH
6.0) and 0.025 ± 0.007 (pH 8.0) in the presence of
CO2/HCO
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cotransporter), omeprazole (K+/H+ exchanger),
or 4,4'-dinitrostilbene-2,2'-disulfonic acid
(Na+/3HCO
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transport by
Na+/H+ exchange is the principal mechanism of
ASL pH equilibration in the absence of
CO2/HCO transporters in the regulation of ASL pH. The
inhibitors included H2DIDS
(Cl/HCO
channel, CFTR), and acetazolamide (carbonic anhydrase), and the CFTR
agonist forskolin was tested. All compounds were added to the
perfusate, and the Cl transport inhibitors (dispersed in
perfluorocarbon) were also added onto the ASL. Figure
5A shows that after a 2-h
incubation, forskolin (20 µM) and glibenclamide (500 µM) had no
significant effect on ASL pH, whereas NPPB (200 µM), DPC (300 µM),
H2DIDS (100 µM), and acetazolamide (100 µM) mildly
acidified the ASL. Also shown is the acidified ASL following incubation
of cells for 2 h with Cl-free perfusate
(gluconate replacing Cl). Kinetic studies
were done in which the time course of ASL alkalization was measured in
response to addition of HCl to the ASL. Figure 5B shows the
slowing of ASL alkalization in the presence of NPPB and
H2DIDS. The averaged rates of ASL pH alkalization are
summarized in Fig. 5C. The significant slowing of ASL pH
recovery by H2DIDS suggests the involvement of
Cl-HCO
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In vivo mouse trachea experiments.
ASL pH was measured in mouse trachea after staining the tracheal lumen
with BCECF-dextran. The perfluorocarbon suspension of BCECF-dextran was
introduced into the trachea using a small feeding needle that was
passed through the mouth and then promptly withdrawn to permit
spontaneous breathing. Fluorescence was detected through the
translucent tracheal wall after surgical exposure of the trachea by a
midline neck incision. Figure 6 shows
images of the trachea at excitation wavelengths of 440 nm
(left) and 490 nm (middle) and the computed ratio
image (right), showing a quite uniform pH distribution. The
average ASL pH in anesthetized, spontaneously breathing mice was
7.14 ± 0.01 (SE, n = 4 mice). Arterial blood gas
analysis in these mice (room air) showed a PO2
of 107 ± 23 mmHg, a PCO2 of 52 ± 9, pH of 7.20 ± 0.04, and a computed HCO
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The purpose of this study was to characterize ASL pH using an
established airway cell culture model and the in vivo mouse trachea.
The complementary cell culture and in vivo systems were chosen to be
able to test specific transporter agonists and inhibitors, perform ion
substitution maneuvers, and examine the role of
CO2/HCO transporters were found to be involved in the
transient response to imposed pH gradients across the airway
epithelium, ASL pH was not tightly regulated and thus subject to
potentially large variations in response to changes in systemic
acid-base status.
Several lines of evidence have suggested a potentially important role
for HCO
F508, CFTR. These studies suggested that
CFTR might be permeable to HCO-independent,
HCO/HCO
The cell culture studies here showed that although steady-state ASL pH
is determined mainly by perfusate pH, transient responses to sudden
changes in ASL or perfusate pH involved Na+ and
Cl transporters. Ion substitution and inhibitor studies
suggested the involvement of amiloride-sensitive
Na+/H+ exchange and
H2DIDS-sensitive Cl/HCO transport. In the presence of
CO2/HCO replacement and by various
Cl transport inhibitors. Activation of CFTR by forskolin
did not affect ASL pH. Our results are best explained by
Cl/HCO transport in the
presence of HCO transport inhibitors and the complexity of the system.
Assessment of the role of CFTR in HCO
ASL pH in the in vivo mouse trachea was measured using a minimally invasive procedure in which the trachea was exposed by a skin incision in the neck, and the ASL was stained with BCECF-dextran using a blunt feeding needle introduced via the mouth. Measurements were made without direct contact with the tracheal mucosa or invasion of the tracheal wall. We showed previously that measured ASL depth, salt content, and pH remained stable over time (12). Additionally, [Na+] and pH were not different as measured by direct dye addition through a tracheal window or by the less invasive procedure used here of dye addition through a feeding needle and measurement through the intact tracheal wall.
ASL pH in mouse trachea was 7.14 when blood pH was 7.2. The mild
systemic acidosis in control mice is probably related to the
anesthesia, which was maintained at a minimal level using ketamine/xylazine. Mice are quite susceptible to hypoventilation during
anesthesia (22), which probably accounts for the slightly lower ASL pH (6.9-7.0) in our preliminary measurements in mice anesthetized using pentobarbital (12). As summarized in
Fig. 7, acute systemic acid-base disturbances produced substantial changes in ASL pH. Metabolic and respiratory acidosis resulted in
decreased ASL pH. Mild metabolic alkalosis created by
HCO
The pH of ASL has been proposed to be important in the physiology of the cough reflex and airway reactivity. Wong et al. (26) reported that lowering airway pH by citric acid instillation into the human trachea induced cough, possibly by stimulation of stretch/irritant receptors (16). Our data in mouse trachea indicate that ASL pH is affected by serum pH and PCO2 and that ASL pH can change rapidly in response to changes in systemic acid-base status. These findings suggest that substantial changes in ASL pH are produced in clinically relevant situations such as lactic acidosis and acute changes in ventilation. Fine et al. (8) reported evidence of increased airway reactivity and bronchoconstriction after inhalation of buffered HCl or H2SO4. In severe asthma associated with CO2 retention, acute ASL acidosis might be an important exacerbating factor that causes further bronchoconstriction and impairment of ventilation.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institutes of Health Grants HL-60288, HL-59198, DK-35124, and DK-43840 and National Cystic Fibrosis Foundation Research and Development Grant R613.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. S. Verkman, 1246 Health Sciences East Tower, Cardiovascular Research Institute, Univ. of California, San Francisco, San Francisco, CA 94143-0521 (E-mail: verkman{at}itsa.ucsf.edu; http://www.ucsf.edu/verklab).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 23 April 2001; accepted in final form 6 July 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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) and ASL (
) (left). Also
shown is pH measured in the ASL in the absence (
) and
presence (
) of CO2/HCO
) and absence
(
