 1 Release from Human Epithelial Alveolar Cells through
Two Different Mechanisms
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Abstract |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Transforming growth factor (TGF)-
1 is a growth factor involved in the mechanisms of lung repair and fibrosis that follow inflammatory processes. We sought to examine the link between the generation of reactive oxygen intermediates (ROI) or reactive nitrogen intermediates (RNI) by inflammatory cells and the
expression of TGF-1 by alveolar epithelial cells. Exposure of the A549 lung epithelial cell line to either
an ROI generating system (xanthine and xanthine oxidase) or an RNI donor (S-nitroso-N-acetyl-penicillamine [SNAP]) promoted a time- and dose-dependent increase in TGF-1 release, as measured by a specific enzyme-linked immunosorbent assay. At the peak, the levels of TGF-1 were twice the control values. The induction of TGF-1 release by ROI was blunted by catalase and unaffected by superoxide
dismutase, indicating the involvement of hydrogen peroxide. The response was also blunted by 5,6-dichloro-1--D-ribofuranosyl benzimidazole (DRB), a specific RNA polymerase II inhibitor, and accompanied by a corresponding increase in TGF-1 messenger RNA, as measured by quantitative/competitive reverse transcription polymerase chain reaction, suggesting the involvement of transcriptional mechanisms
and possibly other downstream mechanisms. In contrast, RNI-induced TGF-1 release was unaffected by
DRB and blunted by the protein synthesis inhibitor cycloheximide, suggesting the involvement of translational and post-translational mechanisms. This response required cyclic guanosine monophosphate (cGMP)-
mediated processes because (1) immunoreactive cGMP accumulated in the culture medium of SNAP-treated cells; (2) SNAP-induced TGF-1 release was blunted by KT 5823, an inhibitor of cGMP-dependent protein kinase; and (3) similar increase in TGF-1 release was obtained by cell exposure to membrane-permeable dibutyryl-cGMP or to atrial natriuretic factor, a known agonist of particulate guanylate
cyclase. These data suggest that in vitro exposure of human alveolar epithelial cells to ROI and RNI enhances TGF-1 release through different mechanisms. In vivo, this control may constitute a molecular link
between inflammatory and fibrotic processes.
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Introduction |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Pulmonary fibrosis represents an excess of the normal repair process that follows infectious or noninfectious inflammation (1). The lesions are characterized by the proliferation of fibroblasts in the alveolar interstitium, where
these cells deposit extracellular matrix components (2). The
mechanisms responsible for both lung repair and fibrosis
involve the expression of cytokines and growth factors, of
which transforming growth factor (TGF)- appears to be
one of the most important (3). Indeed, TGF-1, -2, and
-3, the three main mammalian isoforms of TGF-, have been shown to play a role in the regulation of macrophage
deactivation (4) and fibroblast proliferation/differentiation
(3), as well as in the production and maintenance of extracellular matrices (5). Each isoform is produced in a biologically latent form that consists of the mature TGF- bound
to its propeptide, the latency associated peptide (LAP) (6).
After secretion, this form is proteolytically cleaved to the
mature form in particular by plasmin, a serine protease.
TGF-1 is present at sites of fibrosis in human pulmonary
fibrosis (7) and in bleomycin-induced pulmonary fibrosis
in rats (8). In the early stages of the disease, TGF-1 expression is associated with infiltrating macrophages and
then with epithelial cells and extracellular matrices (11).
The in vivo stimulus for TGF-1 production by epithelial cells is not fully elucidated, but the close proximity of
epithelial cells and inflammatory cells suggests that inflammatory cell-derived products might be involved. They
include reactive oxygen intermediates (ROI), such as superoxide anion (O2
), hydrogen peroxide (H2O2), hydroxyl radical (OH·), and hypochlorous acid, as well as reactive nitrogen intermediates (RNI), such as nitric oxide
(NO), that mediate early inflammatory processes preceding repair and fibrosis (12). In support of this concept, the
importance of ROI and RNI to control the synthesis of cytokines and growth factors has been demonstrated in several in vitro models (13). For instance, ROI and RNI have
been shown to modulate the expression and/or release of
monocyte chemoattractant protein-1 (14, 15), tumor necrosis factor-
, or interleukin (IL)-1 (16, 17), IL-8 (18, 19),
and platelet-derived growth factor (20, 21). However, it is
not known whether ROI and RNI affect TGF-1 synthesis
as well. We therefore investigated the effect of exogenously administered ROI and RNI on TGF-1 expression in cultured alveolar epithelial cells. We demonstrate that
both ROI and RNI enhance TGF-1 expression in these
cells, but through distinct molecular mechanisms.
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Materials and Methods |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Reagents
Xanthine, xanthine oxidase (grade III), glucose oxidase
(1,000 U/ml), catalase (3,000 to 6,000 U/mg protein), superoxide dismutase (SOD) (3,000 U/mg), 5,6-dichloro-1--D-ribofuranosyl benzimidazole (DRB), actinomycin D,
cycloheximide, and N
-nitro-L-arginine methyl ester (L-NAME) were obtained from Sigma Chemical Co. (St.
Louis, MO). S-nitroso-N-acetyl-penicillamine (SNAP) and
KT 5823 were purchased from ICN Pharmaceuticals (Orsay, France). Rat atrial natriuretic factor (ANF) was from
Peninsula Laboratories (Merseyside, UK). Cyclic guanosine monophosphate (cGMP) and [125I]cGMP were from
the Radiochemical Centre (Amersham, UK). Rabbit anti-ANF and anti-cGMP antibodies were obtained from Institut Pasteur (Marnes la Coquette, France). TGF-1 enzyme-linked immunosorbent assay (ELISA) Predicta was
from Genzyme (Cergy St. Christophe, France).
SOD and catalase were heat-inactivated by steam autoclaving for 30 min and by boiling for 30 min, respectively.
Cell Culture
The A549 human lung alveolar epithelial cells were obtained
from the American Type Culture Collection (Rockville,
MD). The cells were grown in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum
(FBS), L-glutamine (2 mM), penicillin (100 U/ml), and streptomycin (100 µg/ml), and were maintained at 37°C in a humidified incubator (95% air and 5% CO2). In assays in which
TGF-1 levels were measured, cells were seeded at 250,000 cells per 500 µl in 12-well plates. Supernatant was then replaced by culture medium without FBS for 2 d before cells
were exposed to ROI and RNI generating systems. Generation of ROI (O2, H2O2, and OH·) was initiated by the addition of xanthine (0.1 mM) and increasing concentrations
of xanthine oxidase (0.1 to 2 mU/ml) (22). Generation of
RNI (NO) was initiated by the addition of SNAP (23).
ELISA and Radioimmunoassay
TGF-1 in cell culture supernatant was quantitated by
specific ELISA as recommended by the manufacturer.
This assay is sensitive to 0.05 ng/ml TGF-1, detecting the
active form of the molecule. All supernatant samples were
thus assayed after acid activation (pH 2.0 for 1 h) to determine the amount of both active and latent TGF-1. When
supernatant samples were exposed to ROI or RNI generating system, TGF-1 measurements gave unchanged values. Thus, ROI and RNI did not affect TGF-1 ELISA.
Total cGMP content in cell-culture supernatant was determined by radioimmunoassay after acetylation of the samples and standards, as previously described (24).
Results were expressed as picograms per milliliter and
femtomoles per milliliter of cell-culture supernatant for
TGF-1 and cGMP concentrations, respectively.
RNA Extraction and Quantitation
Total RNA was isolated from cultured cells using TRIzol reagent (GIBCO BRL, Cergy Pontoise, France) supplemented with glycogen (Boehringer Mannheim, Meylan, France). The concentration and purity of RNA were evaluated by spectrophotometry at 260 and 280 nm. Alternatively, after agarose gel electrophoresis, 28S and 18S RNA bands were visualized with ethidium bromide staining and quantified by densitometry.
Quantitative/Competitive Reverse Transcription
Polymerase Chain Reaction of TGF-1
Messenger RNA
A quantitative/competitive reverse transcription polymerase chain reaction (RT-PCR) analysis of TGF-1 messenger RNA (mRNA) was established by developing a mutated complementary DNA (cDNA) template of TGF-1
cDNA that would compete with test cDNA on an equimolar basis (25). This mutant template was created by deletion of 47 base pairs (bp) within a region of the human
TGF-1 gene delimited by specific PCR primers. The resulting 246-bp cDNA was cloned into the pGEM5Z transcription vector and corresponding RNA was synthesized
using an RNA transcription kit. The concentration of mutant transcripts was measured by spectrophotometry at 260 and 280 nm after digestion of plasmid with deoxyribonuclease. Five serial dilutions of template RNA were reverse
transcripted and amplified together with a fixed amount of
total cellular RNA. RT was carried out for 45 min at 37°C
with random hexamers (0.3 U/ml; Promega, Madison, WI)
and Moloney murine leukemia virus reverse transcriptase
(GIBCO BRL) in a final volume of 10 µl followed by inactivation of the enzyme by heating for 5 min at 94°C. In controls, reverse transcriptase was omitted. A total of 40 µl of PCR buffer (10 mM Tris-HCl [pH 8.3], 50 mM KCl, and
1.5 mM MgCl2, final concentrations) containing 0.2 mM
each of deoxynucleotide triphosphate (Promega), 0.5 µM
specific sense and antisense oligonucleotides, and 1.25 U
Taq DNA polymerase (Promega) were added to each sample. The cDNA was denatured for 4 min at 94°C, and the
amplification was achieved in a temperature cycler (Hybaid
Omnigen, Teddington, UK) by 32 cycles of temperature
(94°C for 30 s, 56°C for 1 min, and 72°C for 1 min) followed
by a 5-min final extension at 72°C. A total of 10 µl of each
PCR sample was loaded on a 2.5% agarose gel stained with
ethidium bromide. The relative fluorescence of PCR products was analyzed by densitometry. The densitometric values of the test and the mutant bands were calculated, and
their ratio was plotted as a function of the amount of mutant template added. The amount of TGF-1 cDNA in the
test sample was calculated from the equivalence point (ratio = 1) by regression analysis assuming that this amount
was equal to the amount of mutated cDNA template added.
The sense and antisense oligonucleotides used to amplify the TGF-1 gene fragment were 5'-GAAACCCACAACGAAATCTATG-3' and 5'-CCTCCACGGCTCAACCAC-3', respectively.
Statistical Analysis
The data are expressed as means ± standard error of the
mean (SEM). The significance of differences in TGF-1
concentration between control and individual experimental groups was determined by the Mann-Whitney U test.
In time-course studies, the areas under curve of control
and individual experimental groups were compared by using the Mann-Whitney U test. Statistical significance was
defined as P 
0.05.
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Results |
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Abstract
Introduction
Materials and Methods
Results
Discussion
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TGF-1 Release from A549 Cells upon
Exposure to ROI or RNI
Unstimulated A549 cells released immunoreactive TGF-1 that was first detected at 3 h and increased over the first
24 h (Figures 1A and 1B). To determine the effect of exogenous ROI and RNI on TGF-1 release, we used the ROI
generating system xanthine-xanthine oxidase and the NO-donating compound SNAP, respectively. Cell exposure to
either agent enhanced the time-dependent release of TGF-1. Increases in TGF-1 levels appeared after 3 h of
exposure, peaked at 6 h, and remained almost unchanged
at all later time points. To study the concentration dependence of TGF-1 synthesis and release, A549 cells were
treated with increasing concentrations of ROI or RNI generating agents, and samples of the cell supernatants were
collected at 6 h (Figures 1C and 1D). Either agent caused a
dose-dependent increase in TGF-1 release. Maximal release of TGF-1 (2-fold increase when compared with controls) was seen at a xanthine oxidase dose of 1 to 2 mU/ml
and at a SNAP dose of 5 µM. At these concentrations,
ROI/RNI generating agents did not induce cell necrosis
and cell apoptosis, as assessed by measuring the trypan
blue exclusion and the surface exposure of phosphatidylserine, respectively (data not shown).We next determined whether ROI and RNI increased TGF-1 release
by eliciting distinct molecular responses.
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ROI-Induced Increase in TGF-1 Release Is Mediated by
H2O2-Dependent Transcriptional Mechanism
By contrast with xanthine-xanthine oxidase, xanthine oxidase alone had no significant effect on TGF-1 release (Table 1). Thus, the observed effects of xanthine-xanthine oxidase were due to the enzyme acting on its substrate rather
than to contaminating proteases. To identify the oxygen
byproducts responsible for the increase in TGF-1 release
from cells upon exposure to xanthine-xanthine oxidase,
we studied the effects of the two main cell enzymes involved in the metabolism of ROI. SOD, which completely
scavenged O2 as assessed by means of the ferricytochrome
assay (data not shown), had no effect on TGF-1 (Figure
2). Catalase, which metabolizes H2O2, caused a dose-dependent inhibition of the response to xanthine-xanthine oxidase without having a significant effect on the basal values of TGF-1. By contrast, heat-inactivated catalase had no
effect. These results suggest that the production of H2O2
rather than O2 mediated the increase in TGF-1 by xanthine-xanthine oxidase. To further substantiate the role of
H2O2, we examined the effects of glucose-glucose oxidase,
a system known to produce H2O2 directly without generating O2 as an intermediate (26). As with xanthine-xanthine
oxidase, glucose-glucose oxidase caused a dose-dependent
increase in TGF-1 release (Table 1).
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To determine whether altered mRNA transcription
contributed to the ROI-mediated increase in TGF-1, we
analyzed the effect of DRB, a specific RNA polymerase II
inhibitor (27). Cell exposure to DRB had no effect on
basal TGF-1 release but caused a dose-dependent inhibition of the response to xanthine-xanthine oxidase (Figure 3). The effect of ROI on TGF-1 gene transcription was
further analyzed by measuring TGF-1 mRNA levels with
RT-PCR (Figure 4). In a concentration-dependent manner, xanthine-xanthine oxidase increased the TGF-1
steady-state mRNA level after 45 min, with a maximal 1.8-fold increase occuring at a xanthine oxidase dose of 1 mU/ml.
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RNI-Induced Increase in TGF-1 Release Is Mediated by
cGMP-Dependent Post-Transcriptional Mechanism
The involvement of transcriptional mechanism in RNI-
induced increase of TGF-1 release was analyzed as indicated previously. We failed to detect any effect of DRB on
A549 cell response to SNAP (Figure 5A). In addition,
SNAP did not affect the TGF-1 steady-state mRNA level
as assessed by RT-PCR (Figure 5B). These facts support
the view that RNI increase TGF-1 release rather through
a translational or post-translational mechanism. To determine the effect of SNAP on TGF-1 mRNA translation,
we monitored TGF-1 release into the medium after cell
treatment with the protein synthesis inhibitor cycloheximide (1 µg/ml). As shown in Figure 6, this agent did not
affect basal TGF-1 release but totally blunted SNAP-
induced TGF-1 release, suggesting the involvement of
translational and possibly post-translational mechanisms.
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Because the regulation of cell functions by NO frequently involves the stimulation of soluble guanylate cyclase and the increase in cellular cGMP levels, we analyzed the role of cGMP in the response to SNAP. First,
SNAP dose-dependently increased cGMP levels in A549
cells in the absence of cyclic nucleotide phosphodiesterase inhibitor (Figure 7A). The increases in cGMP levels paralleled the increases in TGF-1 release (Figure 1D). Second, KT 5823, an inhibitor of cGMP-dependent kinase
(28), blunted the ability of SNAP to increase TGF-1 release, whereas it did not affect basal TGF-1 release (Figure 7B). Third, exposure of A549 cells to membrane-permeable dibutyryl-cGMP (Figure 7C) or to ANF, a stimulus
for the particulate guanylate cyclase (Figure 7D), dose- dependently increased TGF-1 release. These results suggest that the effect of RNI on TGF-1 release is mediated
by a cGMP-dependent mechanism.
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Finally, because type I and type II NO synthases (NOS)
are constitutively expressed in A549 cells (29, 30), endogenous NO could also control the release of TGF-1 by
these cells. Addition of L-NAME, a competitive inhibitor
of the L-arginine-dependent NOS, dose-dependently reduced basal TGF-1 release (Figure 8A). The effect of 100 µM L-NAME was reversed by the introduction of 100 µM
L-arginine (Figure 8B). These data provide support for the
hypothesis that the endogenous synthesis of NO is involved in the basal release of TGF-1.
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Discussion |
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Abstract
Introduction
Materials and Methods
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Discussion
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In this study we have demonstrated that both ROI and
RNI increase TGF-1 release from a human epithelial alveolar cell line. The observation is important because ROI
and RNI are of major pathogenetic significance in pulmonary fibrosis. For example, alveolar inflammatory cells
from patients with progressive lung fibrosis have been
shown to release ROI in excess (31), and antioxidant therapy partially blocks experimental lung fibrosis (32, 33). In
addition, strong expression of type II NOS has been seen
in macrophages, neutrophils, and alveolar cells from lungs
of patients with the early to intermediate stages of idiopathic pulmonary fibrosis (34). High expression of type II
NOS is associated with the nitration of proteins by peroxynitrite, which is produced by the rapid reaction of NO
and O2.
In vitro exposure of human epithelial alveolar cells to
ROI or RNI was accompanied by an increase in TGF-1
release, with a maximal effect noted at 6 h, where TGF-1
level in the culture medium reached a value 2-fold greater
than control. That the TGF-1 level remained elevated to
stable level at later time points suggests a transient activity
of reactive species. Alternatively, sustained increase in
TGF-1 release could be blunted by a progressive rise in
TGF-1 degradation or sequestration. Further experimental work will be required to determine these mechanisms.
Different mechanisms have been proposed for the regulation of TGF-1 activity from transcriptional control to
activation following secretion (6). The cell-signaling events
that lead to TGF-1 release from cells exposed to either
ROI or RNI have been analyzed in separate studies.
Treatment of A549 cells with xanthine-xanthine oxidase
led to a rapid increase in TGF-1 mRNA levels (Figure 4).
The resulting increase in TGF-1 release was prevented
by the addition of DRB (Figure 3), supporting the model
that the effects of ROI are mediated through the transcription of TGF-1 gene and possibly other downstream
mechanisms. Because the regulation of gene transcription
by ROI involves mainly two transcription factors, nuclear
factor (NF)-
B and AP-1 (35), their contribution in
ROI-induced TGF-1 upregulation is to be considered.
First, oxidative stress might activate NF-B. However, because no NF-B binding sites are present in the TGF-1
promoter sequence (38), NF-B activation would only
promote the transcription of genes coding for intermediary mediators involved in the regulation of TGF-1 release. Alternatively, an NF-B element acting as a heterodimer with another NF would bind to different specific
sequences present in the promoter of TGF-1 gene (39).
Second, ROI might activate AP-1. Indeed, oxidants such
as H2O2 have been shown to induce AP-1 rather than NF-B in A549 cells (40) and rat lung epithelial cells (41). Further, AP-1 is the major transcription factor involved in the
transcription of the TGF-1 gene in many cell types, including A549 cells (42). This heterodimer is activated in
particular by phorbol ester and TGF-1 itself, and binds to sequences between nucleotides +1 to +271 of the TGF-1
gene (i.e., the second promoter of the TGF-1 gene).
These findings imply that an amplification loop involving
TGF-1 induction of AP-1 may participate in the induction of TGF-1 by ROI.
In addition, ROI might enhance the availability of bioactive TGF-1 by liberating TGF- from storage sites and
by activating latent TGF-1. Indeed, ROI have been
shown to activate latent TGF-1, directly by interacting
with LAP (6) and indirectly by increasing the expression
of the insulin-like growth factor II/mannose-6-phosphate
receptor (43). This receptor is required to localize latent
TGF- to cell surfaces and, hence, in the close proximity
of plasmin activators (44). In turn, plasmin promotes both
the liberation of latent TGF- from matrix and the activation of this molecule (6).
In our studies, TGF-1 release from A549 cells was increased by the NO generating system as well. This response was in striking contrast to that reported previously
(45). In that previous study, exposure of rat mesangial
cells to SNAP slightly reduced both basal and thromboxane-stimulated TGF- release. There are several possible
explanations for why those studies have failed to reveal a
stimulatory role of SNAP on TGF-1 release. First, the response to SNAP might be largely dependent on cell type. Second, a biphasic dose-response relationship between
SNAP concentration and TGF-1 release might occur.
Low concentrations of NO reached in our study with
SNAP concentrations of 1 to 10 µM were stimulatory, whereas high concentrations of NO reached in the study
by Studer and colleagues (45) with a SNAP concentration
of 100 µM were inhibitory. Such ambivalent effects of NO
have been previously described (46).
NO might amplify gene transcription through alteration
of the expression or activity of several transcription factors
(47). However, our data provide evidence that RNI-
induced TGF-1 release is not accompanied by a corresponding increase in TGF-1 mRNA expression (Figure
5). Thus, RNI-induced TGF-1 release may be dependent
on translational mechanisms and possibly other downstream mechanisms. With regard to the post-translational
mechanisms, basic fibroblast growth factor, for instance,
has been shown to increase TGF-1 release from kidney
epithelial cells solely by upregulating the secretion of preformed, stored TGF-1 (48). Such effects of RNI were
mediated, at least to some extent, by the generation of
cGMP because blockade of cGMP-dependent kinase significantly inhibited the SNAP-induced TGF-1 release
(Figure 7). Further, ANF, a stimulus for the particulate
guanylate cyclase, and dibutyryl-cGMP mimicked SNAP
activity (Figure 7). ANF has recently been shown to bind
to specific receptors on alveolar epithelial cells and to decrease sodium influx in these cells (49). Its effect on TGF-1 synthesis has been also observed in cultured mesangial
cells by Wolf and associates (50). The precise mechanisms
whereby cGMP-dependent kinase activity increases TGF-1 translation remain to be further defined. We speculate that cGMP-dependent kinase might affect the phosphorylation status of a transacting factor that binds to specific
sequences within the 5' untranslated region of TGF-1
mRNA. This mechanism has been suggested to regulate
the expression of various proteins at a translational level (51).
Regardless of the mechanisms, our observations suggest that ROI and RNI play an important role in the development of lung fibrosis through the induction of TGF-1.
Indeed, in human idiopathic pulmonary fibrosis, increased
TGF-1 expression has been identified concurrently with
increased extracellular matrix deposits in alveolar epithelial cells, alveolar macrophages, and fibroblasts (7, 52). In
addition to these fibrogenic properties, TGF-1 might exert a feedback mechanism whereby the generation of ROI
and RNI is controlled. Indeed, whereas TGF-1 blunts
ROI and RNI production by activated macrophages (53),
this peptide upregulates H2O2 release from lung endothelial cells and fibroblasts (54).
In summary, the data presented here support the idea
that ROI and RNI generation lead to TGF-1 release. Understanding the control of TGF-1 release from alveolar
epithelial cells yields additional insights into regulation of
the lung fibrotic diseases and possibly provides new rational therapeutic targets.
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Footnotes |
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Abbreviations: atrial natriuretic factor, ANF; complementary DNA, cDNA;
cyclic guanosine monophosphate, cGMP; 5,6-dichloro-1--D-ribofuranosyl
benzimidazole, DRB; enzyme-linked immunosorbent assay, ELISA; hydrogen peroxide, H2O2; N-nitro-L-arginine methyl ester, L-NAME; messenger
RNA, MRNA; nuclear factor, NF; nitric oxide, NO; NO synthases, NOS; superoxide anion, O2; reactive nitrogen intermediates, RNI; reactive oxygen
intermediates, ROI; reverse transcription polymerase chain reaction, RT-
PCR; standard error of the mean, SEM; S-nitroso-N-acetyl-penicillamine,
SNAP; superoxide dismutase, SOD; transforming growth factor, TGF.
(Received in original form March 24, 1998 and in revised form February 25, 1999).
Acknowledgments: This work was supported by the Institut National de la Santé et de la Recherche Médicale, by the Faculté de Médecine Saint-Antoine, by grants (Legs Poix) from Université Pierre et Marie Curie, and by grants (reference 97064) from AP-HP. The authors thank Mrs. N. Ourtirane for secretarial assistance.
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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