Department of Molecular Biophysics and Physiology, Rush Presbyterian St. Luke's Medical Center, Chicago, Illinois 60612
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ABSTRACT |
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Although alveolar epithelial cells were the first
mammalian cells in which voltage-gated
H+ currents were recorded, no
specific function has yet been proposed. Here we consider whether
H+ channels contribute to one of
the main functions of the lung: CO2 elimination. This idea builds
on several observations: 1) some
cell membranes have low CO2
permeability, 2) carbonic anhydrase is present in alveolar epithelium and contributes to
CO2 extrusion by facilitating
diffusion, 3) the transepithelial
potential difference favors selective activation of
H+ channels in apical membranes,
and 4) the properties of
H+ channels are ideally suited to
the proposed role. H+
channels open only when the electrochemical gradient for
H+ is outward, imparting
directionality to the diffusion process. Unlike previous facilitated
diffusion models, HCO3 and
H+ recombine to form
CO2 in the alveolar subphase.
Rough quantitative considerations indicate that the proposed mechanism
is plausible and indicate a significant capacity for
CO2 elimination by the lung by
this route. Fully activated alveolar
H+ channels extrude acid
equivalents at three times the resting rate of
CO2 production.
pH; acid-base regulation; proton; pulmonary gas diffusion
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INTRODUCTION |
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VOLTAGE-GATED
H+-selective ion channels are
present in a number of cells, including snail neurons, most mammalian
phagocytes, and rat alveolar epithelial cells. Voltage-gated
H+ currents were discovered in
1982 in snail neurons by Roger Thomas and Robert Meech (92). The first
direct measurement of H+ currents
in mammalian cells was in rat alveolar epithelial cells (13), where the
H+ current density is as large as
that of voltage-gated K+ currents.
Specific functions for H+ currents
have been proposed in several cells (see PROPERTIES OF
H+ channels), but none has yet been
proposed in pulmonary epithelium. The properties of
H+ channels appear ideally suited
to extruding acid from cells, and a major function of the lung is to
eliminate metabolically produced acid from the body, in the form of
CO2. It seems obvious that a
possible function of H+ channels
in alveolar epithelium might be to help extrude acid into the alveolar
subphase (the extracellular liquid lining the alveolar surface). Yet,
until now this idea has not been proposed explicitly, largely because
several objections could immediately be raised.
1) It is well known that acid is
extruded by the lung in the form of
CO2, and thus the need for an
additional acid extrusion mechanism is not obvious.
2) To produce outward
H+ current requires that the
electrochemical gradient for H+ be
outward. If the extracellular pH
(pHo) is 7.4 and the
intracellular pH (pHi) is 7.2 [reported values in alveolar epithelial cells range from 7.07 to
7.5 (67, 75)], then the Nernst potential for
H+,
EH is 12
mV. If the resting membrane potential, measured in primary culture, is
40 mV [reported values range from
27 to
63
mV (6, 32)] then ~30-mV depolarization would be required to
produce an outward electrochemical gradient for
H+.
3) Finally, according to the
traditional belief that small, uncharged molecules such as water and
CO2 are freely and rapidly permeant through cell membranes, there would be no need for another mechanism of CO2 extrusion. On the
other hand, alveolar epithelial cells express
H+ channels at a very high
density, and we do not like to imagine Nature doing things for no good
reason. Several factors suggest that it is time to evaluate the
possibility that some part of normal acid extrusion by the lung is
mediated by H+ channels. In brief,
these are: 1)
CO2 is less membrane permeant than
has been assumed traditionally. 2)
Carbonic anhydrase II (CA II) is present in alveolar
epithelial cells. Theoretical and experimental evidence suggests that
carbonic anhydrase facilitates CO2
extrusion by the lung ("facilitated diffusion") and that its deficiency results in respiratory acidosis.
3) The transepithelial potential
difference favors selective activation of
H+ channels in the apical membrane
rather than the basolateral membranes. 4)
H+ channels are expressed at a
high level in mammalian alveolar epithelial cells. Their properties are
ideally suited to the proposed role in
CO2 extrusion by the lung.
In essence, the present hypothesis extends the idea of
facilitated diffusion by proposing that recombination of
HCO3 and
H+ occurs in the alveolar subphase
rather than inside the epithelial cell (which would necessitate
CO2 diffusing across the apical membrane). The purpose of this paper is to consider the possibility that H+ channels are expressed at
high levels in alveolar epithelial cells for the purpose of
facilitating CO2 extrusion by the
lung. Final confirmation or refutation of this hypothesis will require further study, but it is hoped that this suggestion will stimulate and
focus research into this question.
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CO2 PERMEABILITY OF CELL MEMBRANES IS NOT AS HIGH AS WE USED TO THINK |
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All of the acid extruded via the lungs is in the form of
CO2. Because of the traditional
assumption that small neutral molecules such as
CO2 and
H2O permeate cell membranes freely
and rapidly, involvement of H+
channels seems superfluous. Recent observations indicate that this
assumption needs to be reexamined. Nakhoul et al. (Ref. 71 and see also
Refs. 10 and 81) found that the
CO2 permeability of
Xenopus oocytes is increased
significantly by the expression of the water channel aquaporin-1 and
was substantially higher than the
CO2 permeability of
lecithin-cholesterol bilayers (40). If the presence of water channels
increases CO2 flux, then the intrinsic membrane permeability of
CO2 clearly must be limited. These
studies reinforce other evidence that the membrane permeability to
CO2, in certain cells at least, is
exceedingly low (95). In tracer studies under a variety of conditions,
the flux of CO2 across the
alveolar/capillary barrier displayed evidence of diffusion limitation
at pH > 8 but not at pH 7.4 (27). It seems a priori logical that it
is in the best interests of the mammal to have a high
CO2 permeability in alveolar
epithelium. However, limited CO2
permeability coupled with CO2
extrusion in the form of H+ via
H+ channels (together with
HCO3 extrusion) would impart strong
outward rectification to the diffusion process. The voltage-gating
mechanism of H+ channels is
tightly regulated by pHo and
pHi, with the result that the
channels open only when there is an outward electrochemical gradient
for H+, and hence only outward
H+ currents are activated under
physiological conditions (5, 8, 16, 18, 55, 68, 91).
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FACILITATED DIFFUSION OF CO2 |
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It has been known for some time that carbonic anhydrase is present in
lung tissue. Some early studies reported localization in alveolar
capillary endothelial cells (43, 63), but further study revealed that
alveolar epithelial cells also express carbonic anhydrase (31, 37, 88).
Several types of evidence indicate that facilitated diffusion of
CO2 occurs in intact lung tissue (reviewed in Ref. 37). Inhibiting carbonic anhydrase reduces the
diffusion of CO2 in vitro and in
the lung (26, 57, 58). Interpreting these studies requires determining
which effects are due to inhibition of carbonic anhydrase in red blood
cells, where it plays a central role in the well-known
"Cl shift" (e.g.,
Ref. 83). In addition, it is necessary to distinguish between effects
on capillary endothelial cells, which express high levels of carbonic
anhydrase, and extravascular spaces, which include epithelial cells.
Enns and Hill (30) demonstrated that intracellular carbonic anhydrase
is present in the lung and plays a role in facilitated
CO2 diffusion. By use of
selectively permeable inhibitors, Heming et al. (44) determined that
diffusion of CO2 was inhibited
only by extravascular carbonic anhydrase inhibition. It has been shown
recently by Northern blot and immunohistochemistry that of four
isozymes of carbonic anhydrase in the lung, the soluble enzyme CA II is
present unambiguously in rat type II cells, both in situ and in vitro
(31). Expression in type I epithelial cells could not be ruled out in
light of their small cytoplasmic volume; furthermore, type II cells in
culture continued to express CA II after differentiation into
type-I-like cells (31). This localization is compatible with a role in
facilitated elimination of CO2 by the lung. Presence in type I cells would provide teleological support
to the present proposal, because although the diffusion distance
through type I cells is short, 0.1-0.5 µm (86), intracellular conversion of CO2 to
HCO
3 and
H+ would obviate the need for
CO2 extrusion through the apical membrane.
Several additional lines of evidence suggest that human CA II plays a
role in CO2 extrusion by the lung.
Hereditary CA II deficiency in humans results in severe acidosis, with
both a renal component (87) and a respiratory component (78). Recent
studies using genetic knockout to selectively eliminate CA II support this picture. Lien and Lai (61) demonstrated respiratory acidosis in
mice genetically deficient in CA II, which they attributed to CA II
deficiency of both red blood cells and alveolar type II epithelial
cells. These authors proposed that CA II facilitates CO2 extrusion by the lung by
accelerating the recombination of HCO3
and H+ to form
CO2 within alveolar epithelial
cells. The resulting CO2 then
diffuses out through the apical membrane. Despite this suggestion by
the authors, their data do not distinguish whether
CO2 recombination occurs within
the alveolar epithelium or in the subphase. In any case, the results
make it clear that simple diffusion of
CO2 down its partial pressure
gradient does not eliminate CO2
fast enough to avoid respiratory acidosis.
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PROPERTIES OF H+ CHANNELS |
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Voltage-gated H+ channels are
extremely selective for H+ (21),
are activated by membrane depolarization, and have a miniscule single-channel conductance, ~10 fS (14), roughly 1,000 times smaller
than ordinary ion channels. Given the large macroscopic H+ current (8, 13), each cell must
express 105 to
106
H+ channels.
H+ channels are opened by membrane
depolarization, but the threshold voltage at which the
H+ conductance is first activated
(Vthreshold)
depends strongly and linearly on the pH gradient (pH = pHo
pHi) across the membrane (18).
Decreasing pHi or increasing
pHo by one unit shifts
Vthreshold by 40 mV (8, 18). In fact
Vthreshold can be
predicted from (8)
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(1) |
Several of the properties of H+ channels in alveolar epithelium make them ideally suited to the proposed role in facilitating CO2 extrusion. 1) They appear to be present in the apical membrane. 2) They are opened by cytoplasmic acidification. 3) Their gating is controlled locally, so that the critical factors are local pH and the voltage across the apical membrane. 4) Related to 3, the transepithelial potential is oriented in the direction to enhance H+ channel opening in the apical membrane but not in the basolateral membranes. 5) Finally, there is no energetic cost to the cell of allowing H+ efflux down its electrochemical gradient through H+ channels. Of course the cell must first synthesize the H+ channels and insert them into the apical membrane. In contrast, H+ efflux via the H+-ATPase consumes ATP directly, and H+ efflux via the Na+/H+-antiporter indirectly consumes energy by dissipating the Na+ gradient, which must be restored by the Na+ pump.
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HYPOTHESIS |
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Figure 1 illustrates the
essential features of a hypothetical mechanism in which
H+ channels contribute to the
elimination of CO2 by the lung.
Once CO2 enters the alveolar
epithelial cell, it is converted to
H+ and
HCO3 by carbonic anhydrase.
H+, after combining with mobile
buffer, and HCO
3 diffuse across the
cell to the apical membrane (upper pathway in Fig. 1). This
facilitation of CO2 diffusion
within alveolar epithelium by carbonic anhydrase has been proposed
previously (30, 44, 61). However, it is not essential to the present proposal. Conceivably, the main function of carbonic anhydrase in
alveolar epithelium is to convert
CO2 to
HCO
3 and
H+ just inside the apical
membrane, providing a local gradient to drive both
HCO
3 and
H+ extrusion (lower pathway in
Fig. 1). In either case, at the apical membrane
H+ is extruded through
voltage-gated H+ channels, and
HCO
3 exits passively through anion
channels or perhaps via
Cl
/HCO
3
exchange (56, 76). If
Cl
/HCO
3
exchange were the preferred mechanism, the
Cl
in the alveolar subphase
would be replenished by Cl
efflux through anion channels. One attractive feature of the proposed
extrusion of HCO
3 together with
H+ is that the simple act of
extruding HCO
3 would acidify the
subcompartment just inside the apical membrane. Lowering local
pHi would enhance the outward
pH and promote activation of the
H+ conductance. The coextrusion of
HCO
3 and
H+ are thus cooperative.
Furthermore, their coextrusion would be electroneutral. Once
HCO
3 and
H+ arrive in the alveolar aqueous
subphase, the layer of liquid lining the epithelial surface, they
spontaneously recombine to form
CO2, which enters the alveolar gas
phase. The H2O formed at the same
time would be reabsorbed osmotically. In the rest of this paper the
plausibility of the required elements of this hypothesis are evaluated.
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EVALUATION OF THE HYPOTHESIS |
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Can H+ Channels Handle the Job?
Fully activated, the H+ conductance of alveolar epithelial cells extrudes acid ~100 times faster than any other membrane transporter, including Na+/H+ antiport, ClThe magnitude of H+ channel
expression in rat alveolar epithelial cells is impressive. The
H+ current density during a large
depolarization is 20-30 pA/pF (8, 13), which amounts to several
hundred pA in the whole cell membrane.
H+ currents are comparable in size
to voltage-gated K+ currents in
these cells (23, 62, 80), although the intracellular concentration of
H+ is
~107 M, one million times
smaller than that of K+,
~10
1 M. Because the
single-channel current is ~1,000 times smaller for
H+ channels than for
K+ channels, there are evidently
~1,000 times more H+ channels in
the cell membrane.
Are H+ Channels Present in the Apical Membrane?
The hypothesis requires that H+ channels are present in the apical membrane of alveolar epithelial cells. Assuming that alveolar epithelial cells cultured on glass are polarized with their apical side up, this requirement is fulfilled because cell-attached patches and excised patches of this exposed membrane consistently express H+ currents (17). Evidence supporting this intuitively logical orientation of cultured alveolar epithelial cells (basolateral membrane adhering to substrate, apical membrane facing the culture media) is that dome formation has been observed in confluent monolayers (33, 34, 69). These domes reflect fluid accumulation under the monolayer as a result of the fluid-absorptive function of adult alveolar epithelium. Further support for this orientation of the monolayer is that transepithelial potentials have the "correct" apical-negative bias (11, 69). In addition, the apical surface exhibits microvilli (24), characteristic of type II cells in situ.It should be cautioned that most studies of alveolar epithelial cells in culture have been performed on type II cells, in part because isolating type I cells has been an intractable problem. Type II cells differentiate into type I cells in vivo after alveolar epithelial injury, and a process like this takes place in vitro. Thus it seems reasonable to consider that a confluent monolayer of type II cells provides the best available model for transepithelial transport in the alveolus.
Is the Electrochemical Gradient for H+ Ever Outward?
At "normal" pH and resting membrane potential, the electrochemical gradient for H+ is inward, and H+ channels are closed. This is generally desirable, because if H+ channels opened whenH+ Channel Gating is Controlled Locally
The cooperative regulation of H+ channel gating by pHo, pHi, and membrane potential requires only that an outward electrochemical gradient exist in the immediate vicinity of the channel. The sensitivity of H+ channels in excised patches of membrane to both pHo and pHi was the same as in whole cell measurements (17). In addition, H+ channel gating reflected local pH changes due to Na+/H+ antiport (15). Therefore, acidification of the cytoplasm just inside the apical surface due to HCOTransepithelial Potentials Favor Apical H+ Extrusion
Although alveolar epithelial cells studied in vitro are usually patch clamped when they are roughly spherical and unconnected to neighboring cells (conditions which provide for optimal electrical recording), the cells exist in vivo in tight monolayers. Like other epithelia, alveolar epithelia generate a transepithelial potential, with the apical surface negative to the basolateral surface. As a result, the transmembrane potential in an epithelial cell is not uniform but differs at the apical and basolateral surfaces. This is in the correct direction for promoting H+ extrusion selectively across the apical membrane. A key factor is that each H+ channel can sense only the potential across the membrane in which it is located and can sense only the localIs the Transepithelial Potential Large Enough to Activate H+ Extrusion Through Channels?
Measurement of the alveolar transepithelial PD is complicated greatly by tissue geometry. In situ measurements are complicated by the possibility of cross talk with the PD across airway epithelium (79). Tracheal and bronchial PD values differed both from each other and from one mammalian species to another (4). The canine tracheal PD averagedReported values of the resting membrane potential of cultured alveolar
epithelial cells are 27 mV (6) and
63 mV (32). The extent
to which either value reflects the in vivo value is unclear, because
the epithelium is composed mainly of type I rather than type II cells,
and there is a transepithelial PD. The existence of the transepithelial
PD means that the apical and basolateral membranes have different
membrane potentials, and there is no single correct value for the whole
cell membrane. Type II cells in primary culture, both early after
isolation when they retain type-II-like properties, as well as weeks
later when they flatten, lose their lamellar bodies and resemble type I
cells and express depolarization-activated delayed rectifier-type
K+ channels but not inward
rectifier K+ channels (23, 62,
80). In general, cells with only delayed rectifier
K+ channels tend to have more
positive resting membrane potentials than cells expressing inward
rectifier channels (22). To the extent that the resting membrane
potential is set by K+ channels,
it will be near their threshold for activation. The most common variety
of delayed rectifier K+ channel in
rat alveolar epithelial cells, the type
"n" or "low-threshold" K+ channel (probably Kv1.3), has a
threshold at
40 to
30 mV (12, 23, 62, 80). During the
first few days in culture, 21-32% of type II cells express a
different voltage-gated K+ channel
(type "l" or low-threshold, probably Kv3.1), which has a more positive threshold at
10 to
20 mV (23, 80). There may be two populations of alveolar epithelial cells in vivo, with different resting membrane potentials, reflecting their different K+ channels. All things
considered, it appears that any combination of transepithelial PD,
local pH gradients beyond bulk values, or epithelial cell membrane
depolarization approaching ~10-30 mV would suffice to drive
H+ channels to their threshold for opening.
Facilitated Diffusion
The idea that carbonic anhydrase facilitates the diffusion of CO2 by converting it into HCOIn traditional models of facilitated diffusion,
HCO3 recombines with
H+ to form
CO2, which then diffuses through
the membrane. In the present proposal
HCO
3 and
H+ pass through the apical
membrane of alveolar epithelium and recombine to form
CO2 in the alveolar subphase. The
recombination of HCO
3 and
H+ is a very rapid,
diffusion-limited protonation reaction, with a rate constant of 4.7 × 1010
M
1 · s
1
at 25°C (28). However, the slower equilibration between
H2CO3
CO2 + H2O has a time constant of 4.75 s
under conditions in the alveolar subphase, pH 6.92 (74) and 37°C,
calculated according to Eq. 4 and the rate
constants of Gros et al. (37). Would this reaction proceed fast enough
to produce significant CO2? The
fluid in the alveolar subphase contains 11 mM
HCO
3 (73). An early estimate of the
volume of fluid in the alveolar subphase was 10-50 pl/alveolus
(98), but the true volume may have been underestimated due to
dehydration (73). An elegant study using rapid freezing and
low-temperature microscopy gives an average depth of the subphase of
0.2 µm at 80% of total lung capacity (3), which, multiplied by the
total alveolar surface area [75 m2 (97)], gives an aqueous
subphase volume of 15 ml for the entire lung. Using Roughton's (83)
parameter values and the subphase HCO
3
and pH measurements of Nielson and co-workers (73, 74), the forward
rate of uncatalyzed conversion of HCO
3 to CO2 would be:
kv[HCO
3][H+]/Ka = 70 (11 × 10
3)(10
6.92)/(2 × 10
4) = 463 µM/s, which, for a 15-ml subphase volume is 6.9 µmol/s. This is 4%
of the total metabolic rate of CO2
production (186 µmol/s). Independently of whether
H+ channels supply the
H+ necessary for this reaction, it
evidently takes place to some extent and appears to contribute to
CO2 extrusion by the lung. The
absence of non-HCO
3 buffers in the
subphase fluid would tend to accelerate the approach of the
HCO
3 dehydration reaction to
equilibrium (36). If carbonic anhydrase were present in the subphase or
bound to the apical membrane surface, this would speed the
recombination reaction sufficiently to account for most of the
CO2 extruded by the lung. However,
existing data contradict this localization (26, 27). That local
concentrations of the relevant molecular species near the membrane may
differ substantially from bulk values seems quite likely, in light of the large continual flux across the apical membrane of alveolar epithelial cells. For example, the local concentration of
H+ at 1 Å from the
distal mouth of a H+ channel
conducting 2 fA of H+ current
would be ~1.9 × 10
6
M or pH 5.7 (calculated using Eq. 152 of Ref. 2). The rate of spontaneous recombination with
HCO
3 to form CO2 at this pH is 7.2 mM/s or 108 µmol/s for the entire subphase. This latter value is more than
one-half the normal rate of CO2 production by the body. Obviously these calculations involve many uncertainties and arbitrary assumptions, and more direct measurements would be valuable.
HCO3 Extrusion is Required
Alternatively, HCO3 might exit via the
Cl
/HCO
3
exchanger, which is present in adult mammalian alveolar epithelial
cells in vitro (56, 76). However, the Cl
/HCO
3
exchanger appears to be located exclusively in the basolateral
membranes of rat alveolar epithelial cells in monolayers (66). If the
basolateral localization extends to human alveolar epithelium in vivo,
this would preclude participation of the
Cl
/HCO
3
exchanger in the proposed mechanism of CO2 extrusion.
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EXPERIMENTAL TESTS |
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The hypothesis presented here should be evaluated experimentally.
Several specific tests are suggested. The main result of the
exploration of the hypothesis is that the feasibility of
H+ channels eliminating most of
the CO2 produced in the body in the form of H+ is restricted by
the slow rate of CO2 formation
from H+ and
HCO3 in the aqueous subphase. Because
the subphase lacks carbonic anhydrase activity (26, 27), instilling exogenous carbonic anhydrase should enhance
CO2 efflux. In the converse
experiment, exogenous carbonic anhydrase applied into the airways
greatly enhanced CO2 influx across
the lung from alveolar air to perfusate, presumably by converting
HCO
3 to
CO2 (26).
Other elements of the hypothesis should be examined experimentally, as well. It would be useful to determine exactly where H+ channels are located. Are they expressed exclusively in the apical membrane or also in basolateral membranes? Are they present in both type II cells and type I cells? Type I cells comprise 90-95% of the alveolar surface (60) and ought to participate if this mechanism is to play a major role in CO2 elimination. It is thus an important observation that type II cells continue to express CA II in culture even after they differentiate into type-I-like cells (31). Similarly, that type II cells in culture for weeks continue to express high levels of H+ channels (8, 13, 19) suggests that type I cells also express these channels. Because type II cells are precursors of type I cells, e.g., during repair of epithelial damage, it is generally assumed that cultured type II cells are the best available model for alveolar transport processes that in vivo would largely involve type I cells, but this assumption should be tested if possible.
An obvious experimental question is whether blocking the
H+ conductance alters
CO2 extrusion by the lung and
secondarily produces respiratory acidosis. Testing this idea is
complicated by the anatomic inaccessibility of the alveoli and by the
absence of selective inhibitors of
H+ channels. The classical
inhibitor is ZnCl2, which inhibits
H+ current at lower concentrations
than K+ channels in alveolar
epithelium (20) but also inhibits most ion channels and binds to many
proteins. If the role of H+
channels requires HCO3 efflux via
Cl
channels, then blocking
these channels should indirectly inhibit CO2 efflux.
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ALTERNATIVE FUNCTIONS |
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If H+ channels do not contribute significantly to normal CO2 extrusion, why are they there? In general, H+ channels contribute to pHi regulation, because they are activated and extrude H+ when there is an outward electrochemical gradient for H+. This role as an acid-relief valve is analogous to the role played by H+ channels in other cells. The H+ conductance is activated during the respiratory burst of phagocytes (22, 46-48) and during recovery from acute acid loads in osteoclasts (77). The importance of pHi homeostasis in alveolar epithelium has been discussed extensively (65). In the lung, H+ channels may be activated during severe acid or CO2 loading of alveolar epithelium, such as exercise, when the rate of CO2 production can increase by more than an order of magnitude.
Although the hypothesis may not be correct, the fact remains that each alveolar epithelial cell expresses several hundred thousand H+ channels. Presumably these channels perform some useful function. This density of H+ channel expression is greater than in any cell besides leukocytes (16), suggesting that alveolar epithelial cells have a greater need for this mechanism of acid dissipation than most other cells. Therefore, several other possible functions will be mentioned.
An advantage to CO2 extrusion via H+ channels is that their tightly regulated gating results in only outward current. They would act as rectifiers, allowing only CO2 efflux. During the normal breathing cycle, the alveolar PCO2 varies by >2 Torr (59), a large range considering the entire PCO2 diffusion gradient from blood to air is, at most, 5-6 Torr. CO2 efflux via H+ channels would prevent backdiffusion of CO2 from air to tissues during early inspiration, when the alveolar PCO2 is highest.
Due to gravity in an erect individual, the
PCO2 in the normal lung varies from
42 Torr at the base to 28 Torr at the apex (99). Because
H+ channel-mediated
CO2 extrusion is apparently
limited by the backreaction of CO2
H+ + HCO
3, then
H+ channels might facilitate
CO2 extrusion at the top of the
lung where the ventilation/perfusion ratio is high and
PCO2 is low. This would maximize
CO2 elimination by tending to
reduce regional variation in PCO2.
Another possibility is that H+ channels regulate the pH of the aqueous subphase, which is more acidic than typical extracellular fluid, and whose pH appears to be tightly regulated (74). Because there is a transepithelial PD, H+ extrusion through H+ channels will lower the pH of the subphase until the chemical gradient balances the apical membrane voltage gradient. If this were the case, then in principle the transepithelial PD could be determined from the alveolar epithelial cell membrane potential and the observed pH gradient.
In summary, the present consideration of the hypothesis that H+ channels contribute to CO2 extrusion by the lung does not establish that this happens in vivo but shows that it is sufficiently feasible to merit exploring.
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ACKNOWLEDGEMENTS |
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I appreciate the constructive comments on the manuscript and the discussion and encouragement from Drs. Vladimir V. Cherny, Richard M. Effros, Elizabeth R. Jacobs, Joel A. Michael, and Allen A. Rovick.
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FOOTNOTES |
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This work was supported in part by National Heart, Lung, and Blood Institute Grant HL-52671. The contents of this paper are solely the responsibility of the author and do not necessarily represent the official views of the National Institutes of Health.
Address for reprint requests and other correspondence: T. E. DeCoursey, Dept. of Molecular Biophysics and Physiology, Rush Presbyterian St. Luke's Medical Center, 1653 West Congress Parkway, Chicago, IL 60612 (E-mail: tdecours{at}rush.edu).
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