1 Cardiovascular Research Institute, University of California, San Francisco, California 94143-0130; 2 Department of Anesthesiology, Physiology, and Biophysics, University of Alabama, Birmingham, Alabama 35223; and 3 Department of Biological Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel
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ABSTRACT |
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Because tumor
necrosis factor (TNF)- can upregulate alveolar fluid clearance (AFC)
in pneumonia or septic peritonitis, the mechanisms responsible for the
TNF-
-mediated increase in epithelial fluid transport were studied.
In rats, 5 µg of TNF-
in the alveolar instillate increased AFC by
67%. This increase was inhibited by amiloride but not by propranolol.
We also tested a triple-mutant TNF-
that is deficient in the
lectinlike tip portion of the molecule responsible for its membrane
conductance effect; the mutant also has decreased binding affinity to
both TNF-
receptors. The triple-mutant TNF-
did not increase AFC.
Perfusion of human A549 cells, patched in the whole cell mode, with
TNF-
(120 ng/ml) resulted in a sustained increase in Na+
currents from 82 ± 9 to 549 ± 146 pA (P < 0.005; n = 6). The TNF-
-elicited Na+
current was inhibited by amiloride, and there was no change when A549
cells were perfused with the triple-mutant TNF-
or after preincubation with blocking antibodies to the two TNF-
receptors before perfusion with TNF-
. In conclusion, although TNF-
can initiate acute inflammation and edema formation in the lung, TNF-
can also increase AFC by an amiloride-sensitive, cAMP-independent mechanism that enhances the resolution of alveolar edema in
pathological conditions by either binding to its receptors or
activating Na+ channels by means of its lectinlike domain.
tumor necrosis factor-; tumor necrosis factor receptor; patch
clamp; alveolar epithelial cell; acute lung injury; pulmonary edema; pneumonia
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INTRODUCTION |
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ALVEOLAR EPITHELIAL
FLUID transport is a fundamental mechanism for the resolution of
alveolar edema (7, 12, 14, 35, 37, 38, 41, 42). Because of
their location, alveolar epithelial cells are often exposed to
increased intracellular and extracellular concentrations of reactive
oxygen and nitrogen species and inflammatory cytokines such as tumor
necrosis factor (TNF)-. Several studies (8, 45, 46, 48,
52, 55) have demonstrated that TNF-
may have either a
deleterious or a protective effect during the inflammatory response
after infection (53, 54). Rezaiguia et al.
(44) reported that acute Pseudomonas
aeruginosa pneumonia resulted in a marked upregulation of the rate
of net alveolar epithelial Na+ and fluid clearance in rats,
an effect that depended on TNF-
stimulation of alveolar fluid
transport. A recent study (10) also reported that TNF-
mediates upregulated alveolar fluid clearance (AFC) in rats with septic
peritonitis. TNF-
may also upregulate nitric oxide production by
inflammatory cells (1, 22, 28, 50), an effect that could
have several effects on ion transport (15, 16, 23).
To investigate the mechanisms by which TNF- upregulates AFC, we
carried out both in vivo and isolated cell studies. First, using intact
rats, we determined whether intratracheal instillation of TNF-
increased AFC by amiloride-sensitive mechanisms in rats and whether the
TNF-
effect in rats was inhibited by a
-antagonist or accelerated
by a
-agonist. Also, to gain insight into how TNF-
may upregulate
AFC, we carried out experiments in rats with a triple-mutant TNF-
that lacks the lectinlike region of the molecule that is responsible
for the membrane conductance-activating effect of the molecule
(26, 33); the triple mutant also has a modest decrease in
binding to the two known TNF-
receptors TNFRI and TNFRII
(32). To elucidate the mechanisms of TNF-
action, we
measured Na+ currents across A549 cells, a human
alveolar epithelial cell line that possesses many characteristics
of type II cells, including Na+-selective
amiloride-sensitive channels (31), patched in the whole
mode. These measurements were performed before and after perfusion of
A549 cells with TNF-
, TNF-
plus amiloride, or the triple-mutant
TNF-
and across A549 cells preincubated with blocking antibodies to
TNFRI and TNFRII before perfusion with TNF-
.
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MATERIALS AND METHODS |
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Male Sprague-Dawley rats (n = 46; 250-350 g) were used for all animal experiments. The rats were housed in air-filtered, temperature-controlled units with food and water. All procedures were approved by the University of California, San Francisco Committee on Animal Research.
Surgical Preparation for AFC Measurements
Rats were anesthetized with pentobarbital sodium (50-100 mg/kg ip). A tracheostomy was done, and a 0.2-mm-internal diameter endotracheal tube (PE-240, Clay Adams, Becton Dickinson, Parsippany, NJ) was inserted. The rats were maintained in the right decubitus position and ventilated (Harvard Apparatus, Millis, MA) with 100% O2, peak airway pressure of 12-15 cmH2O, and positive end-expiratory pressure of 3 cmH2O. The respiratory rate was adjusted to maintain arterial PCO2 between 35 and 45 mmHg. A catheter was inserted into the right carotid artery to monitor systemic blood pressure and obtain blood samples. Body temperature was always kept constant at 38°C by placing the animals on a thermostatically controlled pad. This protocol was according to previous studies by Jayr et al. (27) and Rezaiguia et al. (44).Preparation of the Instillate
A 5% isosmolar bovine serum albumin (BSA; Sigma, St. Louis, MO) solution with Ringer lactate was prepared according to previous reports (24, 30, 49). We added 1 mg of anhydrous Evans blue dye and 0.5 µCi of 125I-labeled human serum albumin (Merck-Frosst, Montreal, PQ) to the instillate. In some studies, 10TNF-
General Protocol
A 1-h baseline period of stable blood pressure and heart rate was required before alveolar fluid instillation. 131I-labeled albumin (3 µCi) was injected intravenously as a vascular tracer 15 min before instillation. The vascular tracer was used to calculate the flux of plasma protein into the airspaces (27). Blood samples were obtained every 30 min during the experiment for 131I-albumin and 125I-albumin radioactivity and arterial blood gas determinations. We instilled 6 ml/kg of isosmolar fluid into both lungs. At the end of studies (60 min), the rats were exsanguinated and the lungs were removed through a midline sternotomy. An alveolar fluid sample (0.1-0.2 ml) was aspirated with a 3-ml syringe and Silastic tubing that was passed into a wedged position in both lungs. Total protein and radioactivity of the alveolar fluid sample were measured. The lungs were homogenized for extravascular lung water measurements and radioactivity counts.Specific Protocols: Rat Studies
Basal alveolar fluid clearance was determined in group 1 (n = 4 rats). The effects of TNF-Measurement of AFC
According to prior studies by our laboratory (7, 18, 27, 37, 41, 44), AFC was estimated by measuring the increase in the final concentration of the alveolar protein tracer compared with the initial instilled tracer protein concentrations. We subtracted the dry weight of the added protein in the lung water calculation from the final alveolar sample.Patch Clamp
Cell line and culture methods. A549 cells were purchased from American Type Culture Collection (Manassas, VA) in the 76th passage. They were suspended in DMEM-F-12 medium (Cellgro) supplemented with 1% penicillin-streptomycin and 10% fetal calf serum, plated on plastic tissue culture flasks (Corning Glass Works, Corning, NY), and placed in an incubator in 21% O2, 5% CO2, and balance N2 at 37°C and 100% humidity. All experiments were carried out on cells between the 78th and the 97th passages.
Electrophysiology, patch-clamp recording, and analysis. Macroscopic currents were recorded from A549 cells in the whole cell recording mode of the patch-clamp technique (23).
Between 24 and 36 h before any electrophysiological measurements, the A549 cells were lifted from the tissue plates by treatment with 2.5% trypsin-EDTA (Sigma) for 3-6 min at 37°C and then seeded on 12-mm-diameter glass coverslips in DMEM-F-12 medium. The coverslip was rinsed with standard external solution (SES; 310-320 mosM) just before the onset of the measurements. The composition of SES was 145 mM NaCl, 2.7 mM KCl, 1.8 mM CaCl2, 2.0 mM MgCl2, 5.5 mM glucose, and 10 mM HEPES, pH 7.4 (with NaOH). The cells were then transferred to the recording chamber that was mounted on the stage of an inverted microscope (IMT-2, Olympus, Tokyo, Japan) for patch-clamp recordings. The pipettes were made from LG16-type capillary glass (Dagan, Minneapolis, MN) with a vertical puller (model PB-7, Narishige, Japan). The intrapipette solution consisted of 135 mM potassium methylsulfonic acid, 10 mM KCl, 6 mM NaCl, 1.0 mM Mg2ATP, 2.0 mM Na3ATP, 10.0 mM HEPES, and 0.5 mM EGTA, pH 7.2 (with 1 N KOH), at 22°C (standard internal solution; 300 mosM). The pipette resistance varied from 3 to 5 MStatistics
All data are means ± SD unless otherwise noted. AFC data were analyzed by one-way ANOVA followed by Mann-Whitney U-test post hoc. Time-dependent effects were analyzed by repeated-measures ANOVA followed by Student-Newman-Keuls test post hoc. Significance was defined as P < 0.05. ![]() |
RESULTS |
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Effect of Wild-Type TNF- and Amiloride on AFC in Rats
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Effect of -Adrenergic Stimulation and Blockade on AFC During
TNF-
Instillation in Rats
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Effect of Wild-Type TNF- and Triple-Mutant TNF-
on AFC in
Rats
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Patch-Clamp Experiments on A549 Cells With Wild-Type and
Triple-Mutant TNF-
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DISCUSSION |
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The prior study by Rezaiguia et al. (44) indicated
that AFC was upregulated by a TNF--dependent mechanism in acute
bacterial pneumonia in rats. A more recent article (10)
confirmed that TNF-
could augment alveolar epithelial fluid
transport in a model of septic peritonitis in rats. However, the
mechanism by which TNF-
upregulates AFC has not been explored. Our
objective was to study the mechanisms that could account for the
TNF-
-induced upregulation of alveolar fluid transport in both intact
rats and isolated human alveolar A549 epithelial cells. Some
investigators (3, 4, 29, 33) have reported that TNF-
can create ion channels by insertion into the plasma membrane as
reported in human U937 histiocytic lymphoma cells. In those studies,
the effect was enhanced in the presence of a low pH, perhaps because
TNF-
binding to the TNFRs was markedly decreased in a low pH
environment (3, 4). However, van der Goot et al.
(51) reported that membrane insertion is not sufficient
for the membrane conductance activating effect of TNF-
. In the
current study, we used a triple-amino acid mutant that does not contain
the lectinlike domain of TNF-
that is responsible for its membrane
conductance effects; the mutant also has a modest decrease in receptor
binding (32).
The major findings of these studies can be summarized as follows.
1) Wild-type TNF- upregulated AFC in rats, a finding
consistent with the prior study by Rezaiguia et al. (44)
in rats with pneumonia as well as with the recent study of sepsis
(10). 2) Propranolol, a
-adrenergic
antagonist, did not decrease TNF-
-stimulated AFC in rats.
3) No additional upregulation occurred with the
combination of TNF-
and a
-adrenergic agonist. 4)
Amiloride blocked the TNF-
-stimulated AFC in rats. 5) The
triple-mutant TNF-
did not stimulate AFC in rats. 6) In
patch-clamp studies of the human alveolar epithelial A549 cell line,
TNF-
stimulated Na+ influx in A549 cells, an effect that
was inhibited by amiloride. The triple-mutant TNF-
did not induce
Na+ current in the A549 cells, and the TNFR blocking
antibodies abolished the effect of TNF-
.
Because the effect of TNF- occurred within 30 s from the onset
of perfusion in the A549 cells and within 1 h from its
instillation in the distal airspaces of the rat, it is apparent that
the primary mechanism does not depend on a transcriptional effect of
TNF-
. Because the TNF-
effect was inhibitable by amiloride in
both the intact rat lung studies and the isolated human A549 epithelial cells, the primary pathway for augmented fluid transport in lung epithelium depends on Na+ transport. We then tried to
determine whether the TNF-
effect could be mediated by an effect on
membrane conductance by a receptor-independent mechanism. In a prior
study (26), peritoneal macrophages from TNFR
double-knockout mice still showed an increase in ion channel activity
in the presence of wild-type TNF-
, and this activity was amiloride
sensitive. Also, a peptide mimicking the lectinlike domain, with no
binding to the two TNFRs, can still trigger increases in membrane
conductance and also be inhibited by amiloride (33). Because the triple-mutant TNF-
did not stimulate AFC in the rat studies, it seemed plausible that the effect of TNF-
was mediated by
receptor-independent mechanisms in the lung.
But this interpretation could be incomplete, because the TNF- mutant
retains some receptor affinity, although the affinity is decreased
5-fold for TNFR1 and 10-fold for TNFRII (32). Thus the
results of the in vivo studies could be consistent with a receptor-dependent effect, a receptor-independent effect, or both.
Interestingly, the patch-clamp studies in the A549 cells also
demonstrated a rapid amiloride-inhibitable uptake of Na+ in
the presence of wild-type TNF-, consistent with the data in the
intact rat lung studies. Also, the triple-mutant TNF-
did not
increase Na+ influx in the A549 cells, also consistent with
the results of the rat studies. Therefore, we took advantage of the
availability of specific human TNFRI and TNFRII blocking antibodies to
determine whether the effect of TNF-
in the A549 cells was receptor
mediated. The results provided direct evidence in these cells for a
receptor-dependent effect. Several studies (39, 46-48,
50) have shown that TNFRI is expressed in the lung in airway
epithelium and alveolar epithelium and that both receptors exist in
A549 cells.
However, the mechanism by which TNF- increases
Na+-dependent AFC in vivo may be considerably more
complicated and may involve multiple pathways. TNF-
could stimulate
the release of other mediators in vivo, such as transforming growth
factor-
(9, 52), which has been shown to rapidly
upregulate AFC in rats (17). Furthermore, it is certainly
plausible that receptor-independent effects may occur in vivo in the
lung and that some of the TNF-
effects on enhancing alveolar fluid
reabsorption across the alveolar epithelium could be secondary to
direct effects on the cell membrane.
The combination of TNF- and a
-adrenergic agonist, terbutaline,
did not have an additive effect on increasing AFC in the TNF-
-instilled rats. Also, propranolol, a
-adrenergic antagonist, did not inhibit the TNF-
-induced upregulation of alveolar epithelial fluid transport in rats. These results are similar to the findings after instillation of either endotoxin (21) or bacteria
(44) into rat lungs. Taken together, the data indicate
that TNF-
-induced alveolar epithelial fluid transport is not
mediated by an endogenous release of epinephrine, a finding that is in
agreement with the results of a recent peritonitis study in rats
(10).
Which signaling mechanism mediated the TNF--induced Na+
uptake? TNF-
is known to decrease intracellular cAMP (13,
40), and the recent study by Börjesson et al.
(10) showed that TNF-
upregulation of AFC in rats with
peritonitis was associated with no change in cAMP in the lung.
Therefore, enhanced Na+ and fluid transport from TNF-
probably does not depend on a cAMP-mediated process. Interestingly, G
proteins can mediate several effects of TNF-
(25), and
a G protein has been shown to contribute to Na+ transport
in fetal alveolar type II cells (19, 20, 30, 34). Also,
pertussis toxin can inhibit transepithelial Na+ transport
(2). However, there is no clear evidence for the association of G protein with an immunopurified alveolar type II cell
Na+ transport at this time (6). Thus further
investigation will be needed to elucidate the mechanisms of TNF-
signaling in alveolar epithelial cells.
TNF- has been shown in several studies (11, 49) to
increase lung and systemic vascular permeability. Also, in vitro
studies indicated that TNF-
can alter short-circuit current across
cultured alveolar type II cells (56), and TNF-
decreases surfactant protein B expression (43). Thus
TNF-
can have a deleterious effect on the lung endothelium and the
alveolar epithelium, although the data in this study and other studies
(10, 44) documented a beneficial effect of TNF-
on lung
fluid balance by upregulating alveolar epithelial fluid transport.
In summary, TNF- upregulates alveolar epithelial Na+ and
fluid transport by an amiloride-sensitive, catecholamine-independent mechanism as demonstrated by studies in both intact rats and isolated human A549 alveolar epithelial cells. In the isolated cell studies, the
effect was mediated by a TNFR-dependent process, although the intact
rat studies do not clearly distinguish between receptor-dependent and
-independent effects of TNF-
. Overall, these results provide further
evidence for a beneficial effect of TNF-
on lung fluid balance that
may be germane to clinically important pathological conditions such as
pneumonia (44) or peritonitis (10).
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ACKNOWLEDGEMENTS |
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This study was supported by National Heart, Lung, and Blood Institute Grants HL-51854 and HL-31197.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. A. Matthay, Cardiovascular Research Institute, Univ. of California, 505 Parnassus Ave., HSW-825, San Francisco, CA 94143-0130 (E-mail: mmatt{at}itsa.ucsf.edu).
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 13 April 2000; accepted in final form 18 December 2000.
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