Departments of 1 Cellular and Molecular Physiology, 2 Pediatrics, and 3 Medicine, Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033
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ABSTRACT |
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Surfactant
protein A (SP-A) plays a role in host defense and inflammation in
the lung. In the present study, we investigated the hypothesis that
SP-A is involved in bleomycin-induced pulmonary fibrosis. We studied
the effects of human SP-A on bleomycin-induced cytokine production and
mRNA expression in THP-1 macrophage-like cells and obtained the
following results. 1) Bleomycin-treated THP-1 cells
increased tumor necrosis factor (TNF)-, interleukin (IL)-8, and
IL-1
production in dose- and time-dependent patterns, as we have
observed with SP-A. TNF-
levels were unaffected by treatment with
cytosine arabinoside. 2) The combined bleomycin-SP-A effect
on cytokine production is additive by RNase protection assay and
synergistic by enzyme-linked immunosorbent assay. 3) Although the bleomycin effect on cytokine production was not
significantly affected by the presence of surfactant lipid, the
additive and synergistic effect of SP-A-bleomycin on cytokine
production was significantly reduced. We speculate that the elevated
cytokine levels resulting from the bleomycin-SP-A synergism are
responsible for bleomycin-induced pulmonary fibrosis and that
surfactant lipids can help ameliorate pulmonary complications observed
during bleomycin chemotherapy.
chemotherapeutic agent; enzyme-linked immunosorbent assay; synergistic effect; ribonuclease protection assay; surfactant protein A
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INTRODUCTION |
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BLEOMYCIN IS A GROUP
of glycopeptides isolated from Streptomyces verticillus.
Although bleomycin is an effective antineoplastic agent,
bleomycin-induced pulmonary fibrosis sometimes becomes fatal and limits
the usefulness of the drug (34, 39). The histological
features of pulmonary fibrosis in human and animal studies include
inflammatory cell recruitment, fibroblast proliferation, and collagen
synthesis (5). A number of studies concerning the
pathogenesis of pulmonary fibrosis have focused on the role of
inflammatory cells, especially alveolar macrophages, in the fibrotic
process. Bleomycin induces inflammatory cells from human and animal
lung to secrete multifunctional cytokines, such as tumor necrosis
factor (TNF)-, interleukin (IL)-1
, IL-8, and transforming growth
factor (TGF)-
(8, 9, 13, 33, 48). In a clinical study,
TNF-
has been shown to be significantly increased after bleomycin
infusion (35).
The mechanism of bleomycin-induced cytokine production is not well
understood. The cytotoxic effect of bleomycin is believed to be related
to DNA damage that is characterized by the appearance of DNA
damage-inducible proteins (25) and apoptosis
(29). There is also increased activity of nuclear factor
(NF)-B, which may result from the increase of reactive oxygen
species by bleomycin (26). NF-
B is a transcriptional
factor that regulates the expression of many cytokine genes
(50). Among these, TGF-
is considered to be an
important cytokine related to fibroblast proliferation and collagen
synthesis (13, 48), and TNF-
is considered to be a
central mediator in bleomycin-induced pulmonary fibrosis (27, 28,
49). TNF-
receptor knockout mice have been shown to be
protected from lung injury after exposure to bleomycin (27, 28).
Pulmonary surfactant is essential for normal lung function. Surfactant
protein (SP) A, in addition to surfactant-related function (10), plays a role in local host defense and regulation of
inflammatory processes (3, 6). SP-A is a collagenous
C-type lectin or collectin (24), and its carbohydrate
recognition domain (CRD) is involved in binding SP-A to pathogens and
promoting phagocytosis of these pathogens by the macrophages (42,
43). In the macrophage-like THP-1 cell line, human SP-A
stimulates production of TNF-, IL-1
, IL-8, and IL-6 in a dose-
and time-dependent manner (19, 36, 45). Similar effects
are seen in other cells of monocytic origin from both rats and humans
(16, 19). SP-A-enhanced TNF-
production appears to
involve NF-
B activation (14). SP-A also enhances immune
cell proliferation (18) and increases expression of some cell surface proteins (17). In addition, SP-A knockout
mice show an increased susceptibility to infection (21). A
recent in vivo study suggests a role for SP-A in neutrophil recruitment in the lungs of preterm lambs (15). There have also been
reports with other systems in which an anti-inflammatory role has been attributed to SP-A (2, 4).
Surfactant lipids (Surfactant TA) can modulate adherence and superoxide production of neutrophils (37). Surfactant lipids inhibit several SP-A-regulated immune cell functions, including stimulation of macrophages (41). Surfactant lipids and SP-A may be counterregulatory, and changes in the relative amounts of surfactant lipids to SP-A may be important in determining the immune status of the lung. Although most SP-A in the normal alveolar space is thought to be lipid-associated, "lipid-free" SP-A could increase if the balance between SP-A and surfactant lipid were altered under certain conditions (31). There is evidence that bleomycin-induced lung injury in animal models is accompanied by qualitative and quantitative changes of surfactant lipids (30, 38). Increased SP-A contents in rats has been reported after intratracheal treatment of bleomycin (32, 44).
We hypothesized that lipid-free SP-A, the result of an imbalance of SP-A and surfactant lipids after bleomycin treatment, enhances the effects of bleomycin on proinflammatory cytokine production and may be partly responsible for bleomycin-induced pulmonary fibrosis. In the present study, we examined the effects of SP-A on bleomycin-induced cytokine production and mRNA expression in THP-1 cells.
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MATERIALS AND METHODS |
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Cell culture.
The THP-1 cell line was obtained from the American Type Culture
Collection (Manassas, VA). Cells were grown in RPMI 1640 medium (Sigma,
St. Louis, MO) with 0.05 mM 2-mercaptoethanol containing 10% FCS
(Summit Biotechnology, Ft. Collins, CO) at 37°C in an atmosphere of
5% CO2. The cells were split periodically and used at
passages 8-15 in the various experiments. After
differentiation with 108 M vitamin D3 for
72 h, cells were pelleted and washed with cold PBS. The cell
pellet was then resuspended in complete RPMI 1640 medium with 10% FCS
at a density of 2 × 106 cells/ml in 24-well culture
plates and exposed to bleomycin and SP-A. Cell viability was determined
by trypan blue exclusion. Under the conditions employed in this study,
neither bleomycin nor SP-A appeared to have any effect on the viability
of THP-1 cells. Incubations were terminated by pelleting the cells.
Supernatants and/or cell pellets were stored at
80°C until assayed.
Bleomycin and native human SP-A. Bleomycin (Blenoxane; Bristol-Myers Squibb, Princeton, NJ) solutions were prepared immediately before use with endotoxin-free saline (American Pharmaceutical Partners, Los Angeles, CA). Lipopolysaccharide (LPS) was not detected in the stock solution of bleomycin at a bleomycin concentration of 5 U/ml (1 unit = 1 mg) using the method described below.
SP-A was purified from bronchoalveolar lavage of alveolar proteinosis patients with 1-butanol extraction (12). After extraction of whole surfactant with butanol, the pellet was completely dried with a flux of nitrogen gas and then homogenized two times in a freshly prepared buffer (20 mM n-octylStimulation of THP-1 cells with SP-A and bleomycin.
After differentiation with 108 M vitamin D3
for 72 h, THP-1 cells were pelleted and washed as described above.
Cells at a density of 2 × 106 cells/ml were incubated
in 24-well culture plates. For dose-response study, cells were
stimulated with bleomycin at concentrations ranging from 0 to 100 mU/ml. Time-dependent secretion of cytokines after bleomycin treatment
was studied from 0 to 24 h with 5 and 50 mU/ml bleomycin. In
experiments in which the combined effects of SP-A and bleomycin were
examined, SP-A (10 µg/ml) and bleomycin (5 or 50 mU/ml) were added to
cells simultaneously, unless otherwise noted. After treatment, the
culture medium was collected at 4 or 6 h for the enzyme-linked
immunosorbent assay (ELISA) assay of cytokine production, and cells
were harvested for 2 or 4 h for cytokine mRNA analysis.
Infasurf inhibition of cytokine production. Infasurf (Forest Pharmaceuticals, St. Louis, MO), an extract of natural surfactant from calf lung, was used as a source of surfactant lipid. Infasurf was supplied by the manufacturer as a suspension containing 35 mg phospholipids/ml sterile saline. Infasurf is predominately phosphatidylcholine and contains ~2% wt/wt protein that includes SP-B and SP-C, but no SP-A. Infasurf in concentrations ranging from 100 to 800 µg/ml was used in the experiments for ELISA assay of cytokine production, but only a single dose (400 µg/ml) of Infasurf was used in the experiment for mRNA analysis. Infasurf was preincubated separately with SP-A (10 µg/ml), bleomycin (5 mU/ml), and SP-A plus bleomycin for 15 min at 37°C before addition to the THP-1 cells. Cells were incubated for 4 h after the treatment. Culture medium and cell pellets were then collected for ELISA assay and mRNA analysis, respectively.
ELISA assay.
The ELISA assays for TNF-, IL-8, and IL-1
(OptEIA Human ELISA
Sets; Pharmingen, San Diego, CA) were performed according to the
instructions recommended by the manufacturer. The ELISA kits were
capable of measuring levels of 7.8-500 pg/ml for TNF-
, 6.2-400 pg/ml for IL-8, and 20-1000 pg/ml for IL-1
. A
reference curve for each of these cytokines was obtained by plotting
the concentration of several dilutions of standard protein vs. the corresponding absorbance.
Analysis of cytokine mRNA.
Total RNA was isolated from THP-1 cells at 2 or 4 h after
treatment by using RNeasy Mini Kits (QIAGEN, Valencia, CA) according to
the protocol of the RNeasy Mini Handbook. Cytokine mRNA
quantification was performed by RNase protection assay (RPA). RiboQuant
Ribonuclease RPA Starter Package and a Customized Human Template Set
(Pharmingen) were used to analyze TNF-, IL-1
, and IL-8 mRNA in
one assay. The customized template set contains DNA templates that can
be used for T7 RNA polymerase-directed synthesis of
[
-32P]UTP-labeled antisense RNA probes. These can be
hybridized to TNF-
, IL-1
, and IL-8 mRNA. Templates for the L32
and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) housekeeping genes
were also included to allow for normalization of sampling or technical
error. Aliquots of 2 µg of total RNA were hybridized with
radiolabeled probes at 56°C for 16 h. RNase treatment followed,
resulting in degradation of single-stranded RNA and free probes. After
inactivation and precipitation, protected probes were resolved by a 5%
polyacrylamide-urea sequence gel electrophoresis and visualized by
autoradiography. Densities of the protected bands were quantified by
soft laser densitometry. The mRNA level is expressed as the ratio of
the densitometric value of each cytokine mRNA to that of the L32 or GAPDH mRNA.
Statistics. Values are presented as means ± SE. Data were analyzed using SigmaStat statistical software. For each experiment, statistical treatment included a one-way ANOVA followed by a Student-Newman-Keuls test for pairwise comparison and was judged to be significantly different at P < 0.05.
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RESULTS |
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Dose-response and time course studies of bleomycin effects on
stimulation of cytokine production by THP-1 cells.
To study the response of THP-1 cells to bleomycin stimulation, we first
performed a dose response and a time course of bleomycin effects on
TNF-, IL-8, and IL-1
levels. The concentrations of bleomycin for
the dose-response study ranged from 0 to 100 mU/ml, which spans a
relevant pharmacological dose (33). As shown in Fig.
1, a bleomycin concentration as low as
0.5 mU/ml increased both TNF-
and IL-8 levels (Fig. 1, A
and B), but a higher concentration of bleomycin (50 mU/ml)
was needed to increase the IL-1
level significantly (Fig.
1C). Cytokine production continued to increase as the
bleomycin dose was increased to 100 mU/ml. In contrast, the TNF-
level after Ara-C treatment did not differ from that of the control
(Fig. 1D).
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Combined effect of SP-A and bleomycin on cytokine production and
mRNA expression by THP-1 cells.
After testing the effects of bleomycin treatment on TNF-, IL-1
,
and IL-8 production by THP-1 cells, we examined the combined effects of
SP-A and bleomycin on cytokine production. A dose of 10 µg/ml SP-A
was chosen rather than the dose of 50 µg/ml we have used in previous
experiments (19, 45), since the low dose may better
identify synergistic or additive effects of the two substances. As
shown in Fig. 3A, TNF-
values induced by SP-A (10 µg/ml) alone and bleomycin (5 mU/ml) alone
were 86.6 ± 11.5 and 45.9 ± 10.6 pg/ml, respectively, but
the combined treatment increased the level to 201.7 ± 34.3 pg/ml.
A high concentration of bleomycin (50 mU/ml) alone induced a TNF-
level of 82.1 ± 17.3 pg/ml, whereas the value of the combined
effect was 416 ± 61.9 pg/ml. There was a similar response pattern
for IL-8 when the combined effects of SP-A and bleomycin were examined
(Fig. 3B). Because IL-1
reached a maximum value at a
later time point than TNF-
and IL-8 did, we measured its level
6 h after treatment. The means of IL-1
levels (Fig.
3C) induced by the combined treatment were greater than the
sum of the separate means by SP-A or bleomycin alone as we saw with
TNF-
and IL-8. SP-A and bleomycin appear to have synergistic effects
on TNF-
, IL-1
, and IL-8 production by THP-1 cells.
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Inhibitory effect of Infasurf on SP-A and bleomycin-induced
cytokine production and mRNA expression.
We examined the ability of surfactant lipids to modulate the cytokine
level. As shown in Fig. 6, Infasurf had
no effect on the TNF- level in the absence of SP-A and bleomycin.
The SP-A-induced TNF-
level was significantly reduced by Infasurf at
100 µg/ml and was totally inhibited with a higher dose of Infasurf.
In contrast, the bleomycin effect was not significantly reduced by
Infasurf, even at 800 µg/ml. Infasurf decreased the TNF-
level
induced by SP-A plus bleomycin in a dose-dependent pattern. The TNF-
level was significantly decreased from 226.8 ± 35.7 pg/ml in the absence of Infasurf to 109 ± 19.3 and 41.5 ± 0.7 pg/ml at
200 and 800 µg/ml Infasurf, respectively.
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DISCUSSION |
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In the present study, we investigated whether SP-A plays a role in bleomycin-induced inflammation and whether surfactant lipids modulate this process. With the macrophage-like THP-1 cell line, we used RPA and ELISA and observed the following: bleomycin (as has been shown for SP-A) enhances proinflammatory cytokine production by THP-1 cells. The combined bleomycin-SP-A effect on cytokine production is additive by RPA and synergistic by ELISA. No effect on cytokine production is observed by Ara-C, a chemotherapeutic agent that has not been associated with lung inflammation and fibrosis, suggesting that the effect is specific to bleomycin and/or to agents associated with lung inflammation and fibrosis. The surfactant lipids significantly suppress the additive or synergistic effect on cytokine production observed in the presence of both SP-A and bleomycin. These data indicate that surfactant lipids may be useful in the suppression of inflammatory processes induced by SP-A and bleomycin in the lung. This in turn could prevent lung fibrosis, a serious complication of chemotherapeutic agents such as bleomycin.
Bleomycin stimulates THP-1 cells to secrete cytokines in dose- and
time-dependent patterns in the present study, as we have observed
previously in these cells after treatment with SP-A (19, 45). THP-1 cells are of a monocytic origin that, upon vitamin D3 differentiation (as described in MATERIALS AND
METHODS), acquire a macrophage-like phenotype. Undifferentiated
THP-1 cells, on the other hand, respond minimally to SP-A
(19) and to bleomycin (data not shown). The response
pattern of the TNF- time course observed in this study is similar
but not identical to that of clinical observations about the
circulating TNF-
level after bleomycin treatment (35).
In THP-1 cells, the TNF-
response is transient, whereas in vivo
(35), although it decreases with time, it does not return
to basal levels. This may reflect the simple nature of the THP-1 system
compared with that in the intact organism. The transient (4-8 h)
response of TNF-
is also seen with SP-A and LPS, although other
proinflammatory cytokines (IL-1
and IL-8) show a sustained increase
(19). Because some differences between the THP-1 cell line
and alveolar macrophage were apparent in the kinetics and the level of
TNF-
and IL-1
induced by bleomycin treatment (33),
it is possible that the THP-1 cell response may not entirely reflect
that of alveolar macrophages. However, the data presented in this
report demonstrate the usefulness of the THP-1 cell line as a model
system for the study of bleomycin-induced cytokine production.
Moreover, the THP-1 cells have the advantage of providing a homogeneous
cell population for study, whereas primary alveolar macrophages, even
from a single subject, vary significantly from one another depending on
what they have been exposed to in vivo and the length of time they have
been in the alveolus. Ara-C, another chemotherapeutic agent, can also
cause pulmonary complications, but this is typically noncardiogenic pulmonary edema (11) rather than inflammation and
fibrosis. No effect of Ara-C on cytokine production was observed in
THP-1 cells, confirming the specificity of the effect of bleomycin on cytokine production by THP-1 cells and pulmonary toxicity.
It has been previously reported that native human SP-A can stimulate cytokine production in macrophage-like THP-1 cells and that this effect of SP-A can be inhibited by surfactant lipids (17, 36). There have also been reports that SP-A can inhibit LPS-induced cytokine production (4). These disparate results have led to a controversy as to whether SP-A is proinflammatory or anti-inflammatory. In several animal models, there are increases in SP-A early in inflammatory processes. These models include neonatal hyperoxia (7), sepsis (23), and preterm ventilated sheep (15). On the other hand, in the SP-A knockout mouse (21) and in a very premature baboon (2) the lack of SP-A appears to cause increased inflammation. In both of these models, there is a significant delay in pathogen clearance, which is likely to prolong the proinflammatory stimulus provided by the pathogen. However, in the presence of SP-A, pathogen clearance is enhanced, and this may result in reduced inflammation because of removal of the proinflammatory stimulus provided by the pathogen.
Although SP-A clearly enhances many aspects of host defense function,
these different lines of evidence prevent it from being easily
classified as proinflammatory or anti-inflammatory. It is possible that
its role changes at different stages of the inflammatory response, as
has been proposed recently for NF-B (20).
In the present study, we showed that SP-A in a low dose (10 µg/ml)
significantly increased cytokines at both the protein and mRNA levels.
LPS (0.1 ng/ml) was used as a positive control in the present study. A
striking difference in IL-1 mRNA expression between LPS- and
SP-A-treated cells was observed, especially at 2 h after treatment
(Fig. 4A). The relative intensity of IL-1
mRNA induced by
LPS was 18-fold greater than that induced by SP-A (0.92 ± 0.23 vs. 0.05 ± 0.02), whereas the differences between LPS and SP-A in
TNF-
or IL-8 mRNA are only around twofold. These data may provide
additional evidence that the regulation of proinflammatory cytokine
production by SP-A in THP-1 cells occurs by a different pathway than
that utilized by LPS (36).
Under normal physiological conditions, most of the SP-A in the alveoli
is combined with surfactant lipids in the form of a surfactant
lipoprotein complex. Our data suggest that these SP-A-lipid complexes
do not affect cytokine production, perhaps because the complexed SP-A
is unable to interact directly with immune cells (36).
Therefore, it is possible that, if the lipids are reduced in quantity
or quality, the stimulatory influence of SP-A could be enhanced. In
fact, in bleomycin-induced pulmonary fibrosis, changes in surfactant
composition and function have been revealed in animal models (30,
38). Studies in rat indicate that there is a significant
increase of SP-A but not of surfactant phospholipids in response to
bleomycin treatment (32, 44). We showed that, although
surfactant lipids by themselves had no effect on cytokine production,
Infasurf completely inhibited SP-A proinflammatory function observed in
both ELISA and RPA assays of cytokine protein and mRNA, respectively.
This result was comparable to that reported previously with Survanta
(19). Although both Infasurf and Survanta contain the
hydrophobic surfactant proteins SP-B and SP-C, several studies
comparing these preparations with either protein-free synthetic
surfactant or pure lipids suggest that SP-B and SP-C do not affect
cytokine expression (1, 40, 41, 46, 47). Infasurf could
significantly inhibit the combined effects of SP-A and bleomycin on
cytokines, suggesting involvement of complex mechanisms. This result
may be because of the association of lipid-free SP-A with surfactant
lipids, since the bleomycin effect on cytokines was not significantly
changed by Infasurf, even at the highest dose of 800 µg/ml, further
suggesting that these two agents (SP-A and bleomycin) operate through
different mechanisms. Infasurf appears to significantly inhibit the LPS
and the LPS plus bleomycin effect on TNF- production (data not shown).
The mechanism of bleomycin-induced cytokine production has not been
fully elucidated. It is generally believed to be related to DNA damage
(25), apoptosis (29), and activation
of NF-B (50). It has also been demonstrated that
bleomycin-induced injury is associated with the generation of reactive
oxygen species, particularly superoxide anion (26, 37). We
speculate that this mechanism involves the production of reactive
oxidants by the bleomycin-treated cells, which in turn activate NF-
B
and increase transcription of cytokine genes. Although the mechanism of
action of SP-A is not known either, it is likely that it involves interaction with a cell membrane molecule, possibly the C1q receptor (22), activating intracellular events, including the
eventual activation of NF-
B (14). When SP-A and
bleomycin were added to the cell at the same time, the levels of both
TNF-
and IL-8 were higher than the sum of each cytokine induced by
SP-A or bleomycin alone. Analysis of mRNA showed that the combined
treatment of SP-A and bleomycin exhibited an additive effect on the
expression of TNF-
, IL-1
, and IL-8 mRNA. Although bleomycin
itself did not induce a significant increase of IL-1
mRNA even at
4 h after treatment, it greatly enhanced the level of IL-1
mRNA
after being combined with SP-A. The fact that the combined effect of
SP-A plus bleomycin shown in cytokine protein production was much
greater than that observed in the mRNA level indicates that various
posttranscriptional and posttranslational mechanisms may be involved in
bleomycin-induced proinflammatory cytokine production by THP-1 cells in
response to SP-A. The details of these mechanisms remain to be
determined. The synergistic effect of SP-A and bleomycin on cytokine
production in THP-1 cells raises the possibility that SP-A plays a role
in bleomycin-induced pulmonary fibrosis.
The underlying mechanism of the combined SP-A and bleomycin effect on
cytokine production by THP-1 cells is unclear. The CRD of SP-A may
interact with bleomycin, which is a group of glycopeptides. We
speculate that, in experiments in which SP-A and bleomycin are added to
the cells simultaneously, these agents exert their effect through
different moieties, and the different pathways converge and cause
increased cytokine gene expression. To distinguish whether the
synergistic effect is the result of the binding of SP-A to bleomycin or
an independent action of SP-A and bleomycin, we performed preincubation
experiments. We observed that the TNF- level was decreased after 15 min of preincubation of SP-A with bleomycin before addition to cells.
The reduced effect seen when SP-A and bleomycin are preincubated may be
the result of bleomycin binding to the CRD of SP-A. This may in turn
compromise the binding of one or the other of these agents to THP-1
cells and thus interfere with the stimulatory effects.
In summary, we have demonstrated that both SP-A and bleomycin can stimulate production of inflammatory cytokines by THP-1 cells and that there is a synergistic effect when both agents are used. Surfactant lipids significantly suppress the synergistic SP-A-bleomycin effect on cytokine production. We speculate that the significantly elevated cytokine levels resulting from this synergism are responsible for bleomycin-induced pulmonary fibrosis and that surfactant lipids can help ameliorate pulmonary complications observed during chemotherapy.
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ACKNOWLEDGEMENTS |
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We thank Susan DiAngelo and Todd M. Umstead for expert technical assistance.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants 1R01 ES-09882-01 and R37 HL-34788 and the Julia Cotler Hematology Research Fund.
Address for reprint requests and other correspondence: J. Floros, Dept. of Cellular and Molecular Physiology, H166, Penn State College of Medicine, 500 Univ. Dr., Hershey, PA 17033 (E-mail: jfloros{at}psu.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.
First published February 22, 2002;10.1152/ajplung.00434.2001
Received 7 November 2001; accepted in final form 12 February 2002.
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