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on surfactant
metabolism
Department of Internal Medicine and the Department of Veterans Affairs Medical Center, University of Iowa College of Medicine, Iowa City, Iowa 52242
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Tumor necrosis
factor-
(TNF-) has been shown to play an integral role in the
pathogenesis of the acute respiratory distress syndrome. This disorder
is characterized by a deficiency of alveolar surfactant, a
surface-active material that is composed of key hydrophobic proteins
and the major lipid disaturated phosphatidylcholine (DSPC). We
investigated how TNF- might alter DSPC content in rat lungs by
instilling the cytokine (2.5 µg) intratracheally for 10 min and then
assaying parameters of DSPC synthesis and degradation in alveolar type
II epithelial cells, which produce surfactant. Cells isolated from rats
given TNF- had 26% lower levels of phosphatidylcholine compared
with control. TNF- treatment also decreased the ability of these
cells to incorporate [3H]choline into DSPC by
45% compared with control isolates. There were no significant
differences in the levels of choline substrate or choline transport
between the groups. However, TNF- produced a 64% decrease in the
activity of cytidylyltransferase, the rate-regulatory enzyme required
for DSPC synthesis. TNF- administration in vivo also tended to
stimulate phospholipase A2 activity, but it did not alter
other parameters for DSPC degradation such as activities for
phosphatidylcholine-specific phospholipase C or phospholipase D. These
observations indicate that TNF- decreases the levels of surfactant
lipid by decreasing the activity of a key enzyme involved in surfactant
lipid synthesis. The results do not exclude stimulatory effects of the
cytokine on phosphatidylcholine breakdown.
alveolar type II epithelial cells; cytidylyltransferase respiratory
distress syndrome; tumor necrosis factor-
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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PULMONARY SURFACTANT IS A heterogenous material consisting of key hydrophobic proteins and lipids that line the alveolar surface and prevent alveolar collapse (26). Disaturated phosphatidylcholine (DSPC) is the major surface-active lipid component of surfactant that is produced by the alveolar type II epithelial cell (26). Deficiency of DSPC is an important feature of the neonatal respiratory distress syndrome (RDS), leading to widespread atelectasis, ventilatory impairment, and gas-exchange abnormalities. In RDS, surfactant deficiency is primarily the result of lung immaturity, as insufficient surfactant is synthesized and secreted into the alveolar lumen by the type II cell (26). Surfactant deficiency also occurs in the acute respiratory distress syndrome (ARDS), a condition that commonly occurs secondary to sepsis (10, 16). In sepsis-induced ARDS, surfactant deficiency appears to result from several injurious factors that might inhibit surfactant production or alter its functional properties (16).
Tumor necrosis factor- (TNF-) is a small polypeptide cytokine
released by alveolar macrophages and other cell types. It has diverse
biological effects, including leukocyte activation, induction of fever,
apoptosis, and cell lysis (3). In sepsis-induced ARDS, TNF- has been
implicated as a major factor for inducing acute lung injury (29).
TNF- appears to have inhibitory effects on parameters of surfactant
metabolism. For example, in vitro, TNF- inhibits the production of
the key surfactant-associated proteins, such as SP-A and SP-B (33). In
ARDS patients, elevated levels of TNF- may also be primarily
responsible for decreasing the levels of surfactant phospholipid. One
major mechanism by which TNF- might decrease surfactant phospholipid
is by stimulating the activity of enzymes involved in
phosphatidylcholine breakdown (13, 16, 17, 23, 27, 35).
In addition to phosphatidylcholine degradation, the mass of this lipid is also tightly governed in cells by biosynthesis. The sequential steps required for phosphatidylcholine synthesis involve cellular uptake of choline, phosphorylation of choline by choline kinase (CK, EC 2.7.1.32), conversion of cholinephosphate to CDP-choline by cytidylyltransferase (CT, EC 2.7.7.15), and finally, generation of phosphatidylcholine by cholinephosphotransferase (CPT, EC 2.7.8.2).
To date, prior studies have not directly evaluated whether TNF-
alters surfactant lipid synthesis in vivo or in vitro. Recent studies
showing that TNF- suppresses [14C]glucose
incorporation into DSPC in human adult type II cells led us to
hypothesize that the inhibitory actions of TNF- on surfactant
phospholipid metabolism are mediated by inhibition of
phosphatidylcholine synthesis (1, 2, 32). Studies using incorporation
of radiolabeled precursors such as [14C]glucose
or choline into surfactant lipids are limited, because differences in
incorporation rates could be regulated at several steps, such as
cellular transport of these labeled substrates, limitations of
substrate pool sizes, and enzymatic sites within the biosynthetic
pathway. Interpretation of studies using
[14C]glucose incorporation into
phosphatidylcholine are also difficult because glucose transport at the
cell surface, interestingly, is also regulated by TNF- (6). Thus, to
test our hypothesis, we administered TNF- intratracheally into rats
and measured the sequential metabolic steps involved in surfactant
synthesis and degradation in primary alveolar type II epithelial cells.
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MATERIALS AND METHODS |
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Materials.
The phospholipids, choline, cholinephosphate, and the lactic
dehydrogenase kit were purchased from Sigma Chemical (St. Louis, MO). Human tumor necrosis factor- (1 µg = 1.1 × 105 activity units) was obtained from Endogen
(Minneapolis, MN). All solvents were of Optima grade (Fisher Chemical).
Silica LK5D (250 mm × 20 × 20 cm) TLC plates were purchased
from Whatman International (Maidstone, UK). DMEM and choline-free
medium were obtained from the University of Iowa Tissue Culture and
Hybridoma Facility (Iowa City, IA). All radiochemicals were purchased
from DuPont-New England Nuclear Chemicals (Boston, MA). Cell numbers
were determined using a Coulter Z1 dual particle counter (Coulter,
Miami, FL).
Animals and tissue preparation.
Adult male Sprague-Dawley rats weighing 250-300 g were obtained
from Sasco (Boston, MA). Rats were anesthetized with phenobarbital sodium (75 mg ip). Each experiment consisted of two control and two
TNF--treated animals. The trachea was intubated with a 20-gauge plastic catheter, and animals immediately received either 0.5 ml of
diluent or 2.5 µg of TNF- intratracheally. Ten minutes after
cytokine treatment, the animals were killed and the lungs were lavaged
by instilling eight aliquots each of 8 ml normal saline. Lung tissue
was enzymatically digested, and adult type II alveolar epithelial cells
were isolated by cell filtration and differential adherance ~4 h
later as described previously (18). Purity of the type II cells was
>90% as assessed by using tannic acid staining. Cells were sonicated
briefly in buffer A (150 mM NaCl, 50 mM Tris, 1.0 mM EDTA, 2 mM
dithiothreitol, 0.025% sodium azide, 1 mM
phenylmethylsulfonyl fluoride, pH 7.4) at 4°C before enzyme
analysis. In separate studies, alveolar type II epithelial cells were
cultured in DMEM with the inclusion of 10% FCS for 24 h.
Lung measurements. Dry lung weight was measured by heating tissue at 80°C under 4 mmHg for 24 h by using a vacuum oven (29). Wet lung weight was also determined to assess for pulmonary edema.
Cell viability. As an overall measure of cell death, the release of lactic dehydrogenase was measured in lavage fluid. Alveolar type II cell viability was further assessed by Trypan blue exclusion. Cells were also pulsed with 1 µCi of [methyl-3H]thymidine to assess metabolic uptake of the nucleotide. After a 24-h pulse, the medium was removed, and 1 ml of cold 5% tricloroacetic acid was added to the cells for 30 min on ice. The cells were rinsed three times with water, and 1 ml of 0.33 N NaOH was added. The cells were scraped from the dishes and spun to pellet the crude membrane and debris, and an aliquot of supernatant was taken for scintillation counting.
Phosphatidylcholine and DSPC analysis. Lipids were extracted from equal amounts of protein from cells by using the method of Bligh and Dyer (5). The lipids were dried under nitrogen gas, applied in 50 µl of chloroform-methanol (2:1) to silica LK5D plates, and developed in chloroform-methanol-petroleum ether-acetic acid-boric acid [40:20:30:10:1.8, vol/vol, (21)]. After each plate was dried in a fume hood, the sample lanes and phospholipid standard lanes were briefly exposed to iodine vapors. Samples that comigrated with phosphatidylcholine standard were scraped from the silica gel and quantitatively assayed for phosphorus content (18). In other studies, the phosphatidylcholine samples were reacted with osmium tetroxide and run in the second dimension (21). The levels of DSPC were then quantitated by using scintillation counting or the phosphorus assay (18).
Choline transport and choline pool sizes. Choline transport was assessed by rinsing cells in choline-free medium and preincubating the cells in this medium overnight. Cells were then pulsed for 4 h with 1 µCi [methyl-3H]choline chloride at 37°C, after which the medium was discarded, cells rinsed thrice, and 0.1 N NaOH was applied to the cell monolayers (7). Cells were scraped into 15-ml plastic tubes, centrifuged, and the cell pellet resuspended and sonicated briefly in buffer A. An aliquot was then taken for scintillation counting.
Choline mass was assayed as a modification of the enzymatic procedure described by Post et al. (24). Each reaction contained 250 µg of protein residue, 100 mM glycylglycine (pH 9.2), 4 mM MgCl2, 6 mM ATP, 4 µCi [
-32P]ATP, and 0.1 units
CK in a final volume of 200 µl. The reaction was terminated with the
addition of 200 µl of cold ethanol after 1 h at 37°C, and the
mixture was added to a 1 × 6-cm column prefilled with AG1-X8
resin. The choline phosphate product was eluted with three 1-ml volumes
of 0.1 M ammonium bicarbonate and the resulting effluent taken for
scintillation counting. The radioactivity of choline phosphate was
compared with a standard curve of choline to determine choline mass.
Enzymes of phosphatidylcholine synthesis. The activity of CK was assayed as described (11). The reaction mixture (0.1 ml volume) contained 100 mM Tris · HCl buffer (pH 8.0), 10 mM magnesium acetate, 0.016 mM [14C]choline (specific activity ~7,000 dpm/nmol), 10 mM ATP, and 50-100 µg of cell sample. After a 1-h incubation at 37°C, the reaction was terminated with 0.02 ml of cold 50% trichloroacetic acid. Twenty-microliter aliquots of the mixture were spotted on Whatman 3MM paper, and choline metabolites were resolved by using paper chromatography as described (11). The spots that comigrated with the radiolabeled standard, choline phosphate, were cut and used for scintillation counting.
The activity of CT was determined by measuring the rate of incorporation of [methyl-14C]phosphocholine into CDP-choline by using a charcoal extraction method (21). All assays were performed without the inclusion of a lipid activator in the reaction mixture. Enzyme-specific activity is expressed as picomoles per minute per milligram of protein. One picomole per minute of activity represents 1 pmol of the product, CDP-choline, synthesized per minute and is equivalent to 1 microunit of enzyme activity. The activity of CPT was assayed as described (22). Each reaction mixture contained 50 mM Tris · HCl buffer (pH 8.2), 0.1 mg/ml Tween 20, 1 mM 1,2-dioleoylglycerol, 0.8 mM phosphatidylglycerol, 0.5 mM [14C]CDP-choline (specific activity 1,110 dpm/nmol), 5 mM dithiothreitol, 5 mM EDTA, 10 mM MgCl2, and 30-40 µg of sample. The lipid substrate was prepared by combining appropriate amounts of 1,2-dioleoylglycerol (1 mM) and phosphatidylglycerol (0.8 mM) in a test tube, drying under nitrogen gas, and brief sonication before addition to the assay mixture to achieve the final desired concentration. The reaction proceeded for 1 h at 37°C and terminated with 4 ml of methanol-chloroform-water (2:1:7, vol/vol). The remainder of the assay was performed exactly as described (22).Enzymes of phosphatidylcholine hydrolysis. Direct exogenous assays for the acidic, calcium-independent phospholipase A2 (PLA2) and phosphatidylcholine-specific phospholipase C (PC-PLC) were conducted (8). The reactions were linear up to 500 µg of protein in the reaction mixture. Phospholipase D (PLD) activity was also measured exactly as described (15).
Statistical analysis. The data are expressed as means ± SE. Statistical analysis was performed by using Student's t-test or the ANOVA with a Bonferroni adjustment for multiple comparisons.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Cell viability.
TNF- can induce cell death by apoptosis, and high doses (>75 µg)
of cytokine can also induce cell necrosis (31). Thus we assayed
parameters of cellular viability (Table 1).
Recent studies demonstrate that low doses of intratracheal TNF- (5 µg) do not induce alveolar type II epithelial cell apoptosis (20).
Cell viability in the present studies was 87 ± 2 and 86 ± 3% in the control and TNF--treated groups, respectively, as
determined by Trypan blue exclusion immediately after cell isolation.
Preliminary studies demonstrated no histological evidence of lung cell
injury (data not shown). Finally, because TNF- has also been shown
to alter cell proliferation, we assayed tritiated thymidine uptake as
an overall measure of DNA synthesis and metabolic activity (Table 1).
Indeed, no significant differences were observed for thymidine uptake,
and the yield of type II cells was also comparable between the two
groups.
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Lavage analysis.
Total lavage cell counts and levels of lactic dehydrogenase tended to
be higher in the group of animals given TNF- compared with controls;
however, these values were not significantly different (Table
2). No significant differences in lavage
protein concentration, total protein recovery, or lung weights were
observed between the two groups. However, TNF- administration
decreased DSPC levels by 35% relative to control (Table 2, n = 3, P 
0.05). Thus these results suggest that low doses of
TNF- decrease surfactant lipid content in vivo without significantly
inducing alveolar inflammation.
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Phosphatidylcholine and DSPC analysis.
Intratracheal instillation of TNF- significantly decreased the mass
of phosphatidylcholine (Fig. 1A).
After TNF- instillation, the content of phosphatidylcholine in type
II cells decreased from 30.7 ± 1.5 nmol/mg protein (control) to 22.7 ± 2.5 nmol/mg protein (TNF-, P < 0.05). To determine
whether the decrease in phosphatidylcholine mass was due to a decrease
in phospholipid synthesis, type II cells were pulsed with
[methyl-3H]choline and incorporation
into DSPC, a more specific marker of surfactant lipid, was assessed.
TNF- significantly decreased incorporation of the label into DSPC by
45% (P = 0.001, Fig. 1B). These results suggest that
TNF- substantially reduces the biosynthesis of surfactant lipid in
the lung by primary type II cells.
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Choline transport and choline pool sizes.
Differences in choline incorporation into DSPC observed between the two
groups could be attributed to a decrease in choline transport or
greater intracellular pools of unlabeled substrates for DSPC, such as
choline, in TNF- cells compared with controls (24, 30). To address
these possibilities, we first cultured the cells in the presence of
choline-free medium overnight and then pulsed the cells with
[3H]choline in the same medium for 4 h.
Cellular uptake of [3H]choline was then
measured. Consistent with prior studies (6), TNF--treated cells
analyzed shortly after isolation exhibited a 30% lower activity for
[3H]choline transport relative to control
cells, but these differences were not statistically significant (data
not shown). To confirm whether there were differences in the pool size
of choline, we directly assayed the concentration of choline in freshly
isolated type II cells. In three separate studies, we did not detect
significant differences between the groups in the mass of choline
[15 ± 2.3 nmol/mg protein (control) vs. 12.5 ± 1.5 nmol/mg
protein (TNF-)].
Enzymes of phosphatidylcholine synthesis.
To confirm whether TNF- inhibits surfactant lipid synthesis, we
assayed the activities of enzymes within the CDP-choline pathway, the
principal pathway for phosphatidylcholine synthesis. There were no
significant effects of the cytokine on CK activity, the first committed
step in the pathway, or on CPT, the terminal enzyme involved in
phosphatidylcholine synthesis. TNF- significantly decreased CT
activity by 64% compared with control in alveolar type II epithelial
cells after 10 min of exposure (Table 3). Additional dose-response studies showed that 0.75-10 µg of
intratracheal TNF- administration were all effective in
significantly reducing CT activity compared with control (Fig.
2). An overall trend for a dose-response
effect for TNF- was observed; however, no significant differences in
activity were seen between groups of animals receiving 
1 µg of
cytokine (Fig. 2). When TNF- was instilled for longer periods of
time, the cytokine also inhibited enzyme activity. For example, after a
30-min instillation, TNF- decreased CT activity by 46%. Preliminary
studies using similar conditions revealed that another cytokine
elevated in ARDS, interleukin-1
, did not substantially reduce CT
activity after intratracheal administration (data not shown). These
results indicate that the primary effect of TNF- is to block the
conversion of cholinephosphate to CDP-choline at the rate-limiting step
within the phosphatidylcholine biosynthetic pathway.
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Enzymes of phosphatidylcholine hydrolysis.
The above studies showing reduced levels of alveolar and cellular
levels of phosphatidylcholine mass after short-term TNF- exposure
might also suggest concurrent activation of phospholipases. Thus
freshly isolated type II cells were analyzed for the activities of
major phospholipases by using direct exogenous substrate assays. As
shown in Table 4, TNF- tended to
increase PLA2 activity by nearly 41%, although these
effects did not reach statistical significance. Other studies revealed
no effect of the cytokine on either PC-PLC or PLD activities. These
results do not exclude the possibility that stimulation of
PLA2 activity might also contribute to the negative effects
of TNF- on lung DSPC content.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Sepsis-induced ARDS is associated with surfactant deficiency and
remains an important cause of mortality in hospitalized patients (28).
The pathophysiological mechanisms underlying lung injury in ARDS remain
complex. Neutrophils or alveolar macrophages recruited to the lung
actively participate in producing lung edema and injury, in part, by
releasing a variety of inflammatory mediators. Some of these mediators,
including oxygen radicals and phospholipases, have been shown to
decrease the functional pool of surfactant by directly inactivating its
surface activity; these mediators can also decrease surfactant
synthesis by injuring alveolar epithelium (16, 28). Perhaps more
importantly, many of the manifestations of sepsis-induced lung injury
can be reproduced in vivo by infusion of cytokines, such as
TNF- (28). The deleterious effects of TNF- can also be attenuated
in animal models by blocking antibodies to this cytokine (4). We
focused our studies, therefore, on this cytokine because it appears to
be a key participant in sepsis-associated ARDS. To date, prior studies
have not directly investigated effects of TNF- on surfactant lipid
metabolism. In this work, we demonstrate that intratracheal TNF-
decreases surfactant phosphatidylcholine levels. Moreover, a novel
observation from these studies is that the reduced levels of
phospholipid are the result of TNF- inhibiting the activity of the
rate-limiting enzyme required for surfactant phospholipid synthesis,
CT, rather than significant effects of the cytokine on stimulation of
phospholipase activity.
One concern for these studies is that our biochemical observations
might be attributed to significant cellular injury to alveolar epithelium after TNF- treatment. Indeed, there is evidence that intratracheal cytokine administration to the animal model can induce
considerable alveolar inflammation. By using one-fifth the dose of
TNF- used in this study, Ulich et al. (31) showed in rats that a
neutrophilic inflammatory infiltrate persists up to 48 h after
intratracheal cytokine (50 × 105 U)
treatment, and at higher doses (75 µg of TNF-) Fuchs et al. (9)
demonstrated significant bronchovascular edema. Interestingly, neither
of these studies reported that intratracheal TNF- produced alveolar
epithelial cell death. Our results also show that the type II cell
isolates were highly viable and metabolically active after TNF-
exposure (Table 1). In related studies, we have shown that alveolar
type II epithelial cells do not undergo apoptosis after low-dose
intratracheal TNF- administration (20). Collectively, these
observations indicate that potential cytotoxic effects of TNF- on
alveolar epithelium are not a major contributor to the findings in this study.
Most prior studies in other systems suggest that TNF- lowers
phosphatidylcholine content by increasing phospholipid degradation (13,
16, 17, 23, 27, 35). On the basis of these in vitro data, these effects
of the cytokine are presumably an early event in the setting of
sepsis-induced lung injury (13, 27). In sepsis, bacterial
lipopolysaccharide (LPS) triggers the release of TNF- from alveolar
macrophages and subsequently initiates an inflammatory cascade leading
to diffuse lung injury (16, 28). One event in this cascade is the
activation of phosphatidylcholine-specific phospholipases that appear
to be an important effector mechanism by which LPS and TNF-
stimulate surfactant breakdown. In this study, we observed a trend
toward an increase in PLA2 activity, but we did not detect
substantial increases in the other phospholipases. Nevertheless,
because these enzymes are often activated within seconds to minutes
after TNF- treatment, it is possible that phospholipase activation
was at least partly responsible for decreased alveolar and type II cell
surfactant levels observed in these studies. Thus we suspect that this
pathway is also physiologically relevant in vivo (Table 3).
Unlike surfactant phospholipid catabolism, changes in
phosphatidylcholine biosynthesis usually occur over hours in vivo (34). In this study, we performed analysis of TNF- effects on the
biosynthetic pathway in cells several hours after cytokine
administration. We observed that TNF- exposure produces a
substantial decrease in incorporation of radiolabeled choline precursor
into DSPC in type II cells. Because TNF- produced a modest decrease
in choline transport as described previously in other systems (6, 12), this could partly explain the decrease in choline incorporation into
DSPC. However, a greater effect of TNF- in these studies was to
significantly inhibit the conversion of cholinephosphate to CDP-choline
at the CT step. The fact that TNF- inhibited both choline
incorporation into DSPC and CT activity clearly indicates that the
cytokine downregulates the surfactant lipid biosynthetic pathway. The
mechanisms by which TNF- inhibits CT activity could be attributed to
regulation of protein synthesis, changes in enzyme phosphorylation
state, or induction of lipid inhibitors for the enzyme (14). With
regard to the latter mechanism, we have recently shown that
intratracheal TNF- stimulates the generation of sphingolipids in the
lung (20); some of these lipids have been shown to be elevated in acute
lung injury and inhibit CT function and phosphatidylcholine synthesis
directly (19, 25). Thus, although there was only transient exposure of
the lung to TNF-, it is possible that the cytokine triggered a
series of inflammatory events leading to the generation of these
inhibitory lipids that decrease surfactant production.
In summary, studies to date indicate that TNF- inhibits both
surfactant apoprotein and phospholipid metabolism in alveolar type II
epithelial cells. Effects of the cytokine on lipid metabolism include
rapid acceleration of phosphatidylcholine turnover as supported by data
in prior in vitro studies (27). However, our studies also show that an
important complementary mechanism for TNF- is to negatively impact
overall synthetic capacity of phospholipid in type II cells. The
significance of this latter mechanism on steady-state levels of lung
DSPC content is more likely to be realized long-term after cytokine
exposure; however, these biochemical effects are physiologically
important because inhibitory effects on synthesis would undermine the
ability of these cells to compensate for accelerated surfactant
turnover observed initially. Future studies directed at determining how
phosphatidylcholine production (and specifically CT) are inhibited by
TNF- might lead to new strategies targeted at antagonizing the
cytokine's effect on surfactant synthesis. Such studies might, in
turn, lead to newer therapeutic interventions designed to minimize
sepsis-associated acute lung injury.
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ACKNOWLEDGEMENTS |
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This study was supported by a Merit Review Award from the Office of Research & Development, Department of Veterans Affairs, National Heart, Lung, and Blood Institute Grant RO1HL-55584, and the Children's Miracle Network (to R. K. Mallampalli). R. K. Mallampalli is a recipient of an Established Investigator Award of the American Heart Association.
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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 and other correspondence: R. K. Mallampalli, Pulmonary Division, Dept. of Internal Medicine, Univ. of Iowa College of Medicine, Iowa City, IA 52242 (E-mail: rama-mallampalli{at}uiowa.edu).
Received 17 May 1999; accepted in final form 26 August 1999.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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