Cystic Fibrosis/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248
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ABSTRACT |
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We have investigated the role in vivo of mineralocorticoid and glucocorticoid hormones in regulating the rate of electrogenic amiloride-sensitive Na+ absorption across murine airway tissue studied in vivo (nasal potential difference) and in vitro (Ussing chambers). We found that elevating the plasma aldosterone concentration 10-fold (low-Na+ diet) had no significant effect on amiloride-sensitive Na+ absorption across tracheal or nasal epithelia. High doses of dexamethasone for 1 wk likewise did not change the rate of amiloride-sensitive Na+ absorption across airway epithelia. In contrast, both hormonal manipulations elevated the rate of colonic Na+ absorption. Furthermore, adrenalectomy (both normal and cystic fibrosis mice) also failed to alter Na+ absorption across airway epithelia. We conclude that, in vivo, neither the mineralocorticoid nor the glucocorticoid hormones significantly regulate the rates of amiloride-sensitive electrogenic Na+ absorption across airway epithelia in the adult mouse.
aldosterone; dexamethasone; adrenalectomy; mouse; cystic fibrosis
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INTRODUCTION |
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DESPITE THE LIKELIHOOD THAT the volume and composition of airway surface liquid (ASL) is important for mucociliary clearance and airways defense, little is known about the chronic regulation of this liquid layer. The depth and composition of ASL are thought to be regulated by the rates of ion transport and the linked osmotic volume flow. In most airway epithelia, the amiloride-sensitive epithelial Na+ channel is an important element that regulates the rate of absorptive volume flow and the ionic composition of ASL.
Little is known about the physiological regulation of the epithelial Na+ channel (ENaC) in airway epithelia. In the genetic disease cystic fibrosis (CF), the rate of Na+ absorption is markedly upregulated in vivo and in vitro across airway epithelia in both human (20, 21, 23) and mouse proximal airways (15). It has been shown that the product of the normal CF gene [cystic fibrosis transmembrane conductance regulator (CFTR)] tonically inhibits amiloride-sensitive Na+ absorption across airway epithelia (31), and, in CF, absent or defective CFTR is associated with an elevated rate of Na+ absorption (31).
In the renal distal tubules and colonic epithelia, both mineralocorticoid (aldosterone) and glucocorticoid hormones [dexamethasone (DMS)] markedly stimulate amiloride-sensitive Na+ absorption (see Ref. 11 for a review) in a variety of species, including mice (13) and humans (19, 29). In times of Na+ deficit, epithelial Na+ channels in both the kidney and colonic epithelia are recruited under the influence of aldosterone to scavenge Na+ that may otherwise be excreted from the body. In contrast, the ASL functions to maintain an environment optimized for ciliary function and airway defense. Thus the amiloride-sensitive Na+ channel might be expected to be regulated differently in airway epithelia.
Although it has been demonstrated that both the glucocorticoid and mineralocorticoid hormones upregulate amiloride-sensitive Na+ absorption in cultured airway epithelia (7, 8, 24, 26), almost no data are available on the in vivo effect of these hormones on Na+ absorption across airway epithelia. Therefore, the purpose of this investigation was to determine the in vivo effect of mineralocorticoid (raised by low-Na+ diet) and glucocorticoid (DMS subcutaneous injection) hormones on the amiloride-sensitive Na+ absorption across nasal and tracheal epithelia of normal mice studied in vivo and in vitro. The effect of adrenalectomy (resulting in very low levels of adrenocortical hormones) on amiloride-sensitive Na+ absorption across the airway epithelia of both normal and CF mice was also determined in Ussing chamber airway preparations.
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MATERIALS AND METHODS |
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Both CF (cftrtm1unc) and normal littermates (heterozygous for CFTR) were studied (8 wk and older, both sexes). All mice were hybrids of four strains: BAL/c, DBA/2, C57BL/6, and 129/SvEv. Details of mouse care have previously been published (12). Mice were euthanized with 100% CO2, and the nasal, tracheal, and distal colonic epithelia were removed as previously described (13-15).
In vitro tissue study. The airway
tissues were mounted on small-aperture Ussing chambers (0.025 cm2), and distal colonic
epithelia were mounted on chambers having an aperture surface area of
0.25 cm2. Tissues were bathed
bilaterally in Krebs-Ringer bicarbonate buffer having the following
composition (in mM): 140 Na+, 120 Cl, 5.2 K+, 1.2 Mg2+, 1.2 Ca2+, 2.4 HPO2
4, 0.4 H2PO
4, and 25 HCO
3. Some tissues were studied in
bilateral Cl
-free Ringer
solution (see Ref. 12 for details). All tissues were allowed to
equilibrate for 30 min after mounting before basal bioelectric
measurements were taken. The tissues were studied under short-circuit
current (Isc)
conditions for the duration of the experiment. A constant voltage pulse
(1 mV, 1 s duration) was applied to the tissue every minute. Potential
difference (PD) and resistance were calculated by Ohm's law from the
changes in Isc in
response to the voltage pulse. After the basal bioelectric measurements
were made, amiloride (10
4
M) was added to the luminal bath. Inhibition of the
Isc by amiloride was used as an index of the magnitude of electrogenic
Na+ absorption (see
RESULTS). Unless otherwise indicated, all
drugs and chemicals were purchased from Sigma (St. Louis, MO).
Nasal PD. Mice were anesthetized with Avertin for the nasal electrical PD measurements, as previously described (15). Mice used for nasal PD measurements were allowed to recover for 1 day before euthanasia and tissue removal for Ussing chamber studies.
Elevated hormone levels. To elevate serum aldosterone levels, mice (normal mice only) were placed on a low-Na+ diet (Purina Mills, Richmond, IN) for 14 days as previously described (13). To elevate glucocorticoid levels, a group of mice were injected subcutaneously with the synthetic glucocorticoid hormone DMS (Elkins-Sinn, Cherry Hill, NJ) (600 µg/100 g twice per day) for 7-8 days before study.
Adrenalectomy. Mice, both normal and CF, were anesthetized with Avertin (15) and were shaved, and a small incision was made just behind the ribs through the cutaneous and muscle layer. A small retractor was inserted to hold the muscle layers open to aid in the visualization of the adrenal gland. The vessels supplying the adrenal gland were crushed, the gland was removed, muscle layers were sutured with 5-0 silk, and the skin incision was closed with wound clips. The procedure was then repeated on the opposite side. All mice tolerated the procedure well. After adrenalectomy (ADX), the mice drank Colyte (13) (0.75% Na+) to which 2.5% glucose was added.
Because levels of adrenocortical hormones were still measurable in many of these mice 7 days following ADX (see Table 1), additional mice were adrenalectomized and then treated with aminoglutethimide (50 mg/kg twice per day for 3 days and then 100 mg/kg twice per day for an additional 4 days before study). This drug inhibits the synthesis of steroid hormones and reduces residual corticosteroid secretion following ADX.
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Hormone assay. Blood was collected by cardiac puncture in heparinized syringes immediately after euthanasia. Plasma was separated by centrifugation for both the aldosterone and corticosterone assays. Corticosterone was determined using an RIA kit (I125; ICN Biomedical, Costa Mesa, CA). Although the detection limit of the kit is reported to be 10 ng/ml, we found that we could reproducibly measure the hormone to 5 ng/ml. Aldosterone was also determined using a I125 RIA kit (detection limit 6 pg/ml; Biodata, Cortland Manor, NY). All assays were run in duplicate and the results averaged.
Statistics. Results are shown as means ± SE, with the number of mice studied shown (n). If only two groups were being compared, a Student's t-test was used. If more than two groups were compared, an ANOVA was used, and a Student-Newman-Keuls test was used for multiple comparison testing among groups. In the event of nonhomogeneity of variance, a Kruskal-Wallis one-way ANOVA on ranks was used where indicated.
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RESULTS |
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Low-Na+ diet. To determine the effects of elevating the serum aldosterone concentration on the rate of electrogenic Na+ absorption across nasal and tracheal airway epithelia, normal mice were placed on a low-Na+ diet for 2 wk before study. This protocol elevated the serum aldosterone levels 10-fold (Table 1). However, neither the basal bioelectric properties (Table 2) nor the amiloride-sensitive Isc (Fig 1, A and B) were significantly altered across the tracheal or nasal epithelia in response to raised serum aldosterone levels. Although the high aldosterone levels did not appear to influence the amiloride-sensitive Na+ absorption across airway epithelia, we have previously shown that mice on a low-Na+ diet exhibit a significantly enhanced amiloride-sensitive Isc across the distal colonic epithelia compared with mice on a normal diet (13).
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DISCUSSION |
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Electrogenic Na+ absorption appears to be the major ion actively transported across human (4, 23) airway epithelia and murine nasal (15) and bronchial (unpublished observations) epithelia. In addition, in a variety of other species, electrogenic Na+ absorption appears to be the major ion actively absorbed across all airway epithelia (3, 25, 32). Therefore, regulation of airway Na+ transport is predicted to be important in homeostasis of ASL.
In both gut and airway tissue, the amiloride-sensitive
Na+ channel has been shown to be
comprised of three subunits (,
,
) (5, 6). Direct evidence for
the role of the subunits in amiloride-sensitive
Na+ transport across airway
epithelia comes from the finding that mice in which the
-ENaC gene
(codes for
-subunit) has been disrupted by gene targeting
[
-ENaC(
/
)] lose all amiloride-sensitive
Isc across
tracheal epithelia (18). The importance of electrogenic Na+ absorption in clearance of
lung liquid at birth was demonstrated when
-ENaC(
/
)
mice were found to die in the early postnatal period due in part to a
failure to clear lung liquid (18). There is evidence that the
mineralocorticoid and glucocorticoid hormones regulate ENaC subunit
expression in colonic epithelia (27), but evidence for hormonal
regulation of ENaC expression and function in pulmonary epithelia of
the adult is conflicting (24, 27).
In cultured airway epithelia (adult human, canine, bovine),
glucocorticoid and mineralocorticoid hormones have been shown to
elevate electrogenic Na+
absorption (7, 8, 26, 33). In cultured human nasal and bronchial
epithelia, a 24-h exposure to aldosterone, hydrocortisone, or DMS
increased the amiloride-sensitive
Na+ absorption two- to fourfold
(7). This study also revealed that cultured human airway epithelia had
a greater sensitivity to aldosterone
(ED50 = 0.1 µM) than to the
other two hormones (ED50 = 25 µM
for hydrocortisone and 50 µM for DMS). Another recent report also noted that aldosterone significantly increased
amiloride-sensitive Na+ absorption
across cultured human airway epithelia (33). In cultured canine
tracheal epithelia (primarily a
Cl secretory tissue), a
2-day exposure to aldosterone increased the baseline
Isc by 55% and
the amiloride-sensitive
Isc similarly (8). In cultured bovine tracheal epithelia, DMS, but not aldosterone exposure (18 h to 8 days) significantly increased the
amiloride-sensitive Isc (26).
When native airway epithelia were studied in Ussing chambers, however, exogenous corticosteroid hormones failed to alter the basal or amiloride-sensitive Isc of these airway preparations. Addition of exogenous aldosterone to native rabbit tracheal preparations failed to alter the basal or amiloride-sensitive Isc when tissues were studied 4 h after hormonal addition (2). In contrast, when aldosterone was exogenously added to rabbit colonic preparations in vitro, an increase in the basal and amiloride-sensitive Isc was detectable within 2 h (10). In another Ussing chamber study, a 6-h DMS exposure failed to alter the basal Isc or PD of canine and feline native tissue tracheal preparations (30).
There are few reported studies investigating the in vivo administration of either glucocorticoid or mineralocorticoid hormones on electrogenic Na+ absorption across airway epithelia. When adult rats were placed on a low-Na+ diet for 15 days (to elevate aldosterone) or given DMS exogenously (2 days) and tissue removed, there was no increase in either mRNA or protein expression for any of the three Na+ channel subunits in the airway epithelia (27). However, if the rats were adrenalectomized and tissue studied 7 days after the surgery, there was a significant decrease both at the mRNA and protein levels of all three subunits in the airways (27).
Data from the present study suggest that, in vivo, electrogenic Na+ absorption across adult murine airway epithelia is not regulated by the corticosteroid hormones. Neither tracheal nor nasal epithelia from normal mice treated exogenously with DMS or placed on a low-Na+ diet to stimulate aldosterone production exhibit any change in amiloride-sensitive Isc (or amiloride-sensitive PD in vivo) as a result of these hormonal manipulations. However, the colonic epithelia of the hormone-treated mice clearly exhibited an increase in electrogenic Na+ absorption. Our data are consistent with a recent study that reported that nasal epithelia from rabbits receiving a low-Na+ diet for 1 wk exhibited bioelectrical properties that were not different from nasal epithelia from rabbits on a control diet (9). These authors concluded that aldosterone is not responsible for long-term regulation of Na+ absorption across rabbit airway epithelia.
Although elevation of aldosterone or DMS failed to alter electrogenic Na+ absorption across the airway epithelia of mice, based on data in rats (27) we had speculated that electrogenic Na+ absorption across airway epithelia may be downregulated by decreasing the endogenous corticosteroid hormones to very low levels. Thus groups of normal and CF mice were adrenalectomized and studied 7 days later. The normal adrenalectomized mice, having nondetectable corticosterone levels, exhibited amiloride-sensitive Na+ absorption that was not significantly different from tissue from control mice. CF mice, which exhibit a significantly elevated rate of electrogenic Na+ absorption across nasal epithelia (15), also showed no change in amiloride-sensitive Na+ absorption following ADX. In the rat, ADX reduces the expression of both the message and protein levels of the three ENaC subunits in airway tissue, but function was not studied (27). We did not measure the ENaC mRNA or protein responses to ADX in murine airway epithelia, but, if changes did occur, our functional data suggest that sufficient subunit protein remains to allow normal rates of Na+ absorption.
Little data are available on the role of in vivo corticosteroids in human airway epithelia. However, there are two recent reports in which the effect of an elevated aldosterone concentration (33) and topical DMS administration (16) were studied in vivo in human nasal epithelia by the PD technique. Patients on a low-Na+ diet (6 days) exhibited a significant increase in the transepithelial amiloride-sensitive PD compared with controls. However, the magnitude of the difference in the amiloride-sensitive PD between controls and low-Na+ subjects was small [2.2 mV (<10%)] (33) compared with the magnitude of the increase in amiloride-sensitive PD across colonic epithelia as a result of aldosterone stimulation [40-60 mV (19)]. In another study, DMS was applied topically to human nasal epithelia every 15 min for 8 h, and nasal PD was measured at hour 8. In this study, while the basal PD was significantly elevated in the treated nasal epithelia, there was no significant effect of DMS treatment on amiloride-sensitive PD (16). Similarly (22), when spironolactone was given to human patients to block the aldosterone receptors, it significantly reduced the rectal PD but failed to alter nasal PD (22), suggesting that electrogenic Na+ absorption was unaltered across airway epithelia. Therefore, as found in the present investigation, these studies suggest that there is little, if any, influence of the corticosteroid hormones on electrogenic Na+ absorption across human airway epithelia in vivo.
In conclusion, we find no evidence in adult murine airway epithelia that in vivo alterations of either the mineralocorticoid or glucocorticoid hormones regulate amiloride-sensitive Na+ absorption across airway epithelia. These data are consistent with the hypothesis that Na+ transport by pulmonary tissue is not involved in the overall salt balance of the organism. We speculate that, if indeed alterations in the rate of transport of this cation are important in ASL homeostasis, rapid regulation of Na+ transport by an as yet unidentified factor is necessary.
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ACKNOWLEDGEMENTS |
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This study was supported by National Heart, Lung, and Blood Institute Specialized Center of Research Grant HL-42384-10 (Project 1A and Core C).
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FOOTNOTES |
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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. §1734 solely to indicate this fact.
Address for reprint requests: B. R. Grubb, Cystic Fibrosis/Pulmonary Research and Treatment Center, 7011 Thurston-Bowles Bldg., CB# 7248, The Univ. of North Carolina, Chapel Hill, NC 27599-7248.
Received 16 January 1998; accepted in final form 8 April 1998.
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