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Cardiovascular Research Institute and Departments of Medicine and Physiology, University of California, San Francisco, CA 94143
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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increased EGFR tyrosine phosphorylation and subsequent
activation of p44/42mapk and up-regulated the expression of
MUC5AC at both mRNA and protein levels in NCI-H292 cells. These effects
were blocked by selective EGFR tyrosine kinase inhibitors (AG1478,
BIBX1522) and by a selective MEK inhibitor (PD98059), whereas a
selective platelet-derived growth factor receptor tyrosine kinase
inhibitor (AG1295), a selective p38 MAPK inhibitor (SB203580), and a
negative compound of tyrosine kinase inhibitors (A1) were without
effect. Neutrophil supernatant-induced EGFR tyrosine phosphorylation,
activation of p44/42mapk, and MUC5AC synthesis were
inhibited by antioxidants
(N-acetyl-L-cysteine, DMSO, dimethyl
thiourea, or superoxide dismutase); neutralizing Abs to EGFR ligands
(EGF and TGF-) were without effect, and no TGF- protein was found
in the neutrophil supernatant. In contrast, the EGFR ligand, TGF-,
increased EGFR tyrosine phosphorylation, activation of
p44/42mapk, and subsequent MUC5AC synthesis, but these
effects were not inhibited by antioxidants. These results implicate
oxidative stress in stimulating mucin synthesis in airways and provide
new therapeutic approaches in airway hypersecretory
diseases. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hypersecretory diseases of airways are associated with abnormal cell growth and differentiation in mucus-synthesizing cells including submucosal gland hypertrophy and goblet cell hyperplasia. Recently, mucin synthesis in airways has been reported to be regulated by the EGFR system (18); activation of EGFR tyrosine kinase by its ligands leads to the synthesis of mucin MUC5AC, a major mucin in airways (19, 20), at both mRNA and protein levels, resulting in goblet cell hyperplasia in rats. However, the mechanisms of EGFR activation in airways are unknown. In airways, EGFR activation may be caused by oxidative stress that is induced by activated neutrophils, and this activation of EGFR may result in stimulation of mucin synthesis in airways. To test this hypothesis, we examined whether exogenous or neutrophil-derived oxidative stress causes mucin MUC5AC synthesis, and, if so, whether EGFR activation is involved. Here we show that oxidative stress induces mucin synthesis in airway epithelial cells via ligand-independent EGFR activation that leads to activation of the MAPK kinase (MEK)-p44/42mapk signal transduction pathway. Thus, neutrophils may play important roles in the overproduction of mucins in airway diseases via an EGFR cascade.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human neutrophils were purified from peripheral blood obtained from healthy human donors. Neutrophil isolation was performed by standard techniques of Ficoll-Hypaque gradient separation, dextran sedimentation, and hypotonic lysis of erythrocytes. Cells were routinely >95% viable by trypan blue dye exclusion. To prevent endotoxin contamination, all solutions were passed through a 0.1-µm filter.
Cell culture
NCI-H292 cells, a human pulmonary mucoepidermoid carcinoma cell
line, were grown in RPMI 1640 medium containing 10% FBS, penicillin
(100 U/ml), streptomycin (100 µg/ml), and HEPES (25 mM) at 37°C in
a humidified 5% CO2 water-jacketed incubator.
When confluent, cells were incubated for 1 h with neutrophils
(106 cells/ml) alone, TNF- alone (human
rTNF-, 5–20 ng/ml; Genzyme, Cambridge, MA), IL-8 (human rIL-8,
10-9–10-7 M; Genzyme)
alone, FMLP (10-9–10-7
M; Sigma, St. Louis, MO) alone, TNF- plus neutrophils, IL-8 plus
neutrophils, FMLP plus neutrophils,
H2O2 (10–400 µM), or
TGF- (human rTGF-, 0.1–25 ng/ml; Calbiochem, San Diego, CA). The
cells were then washed and incubated with fresh medium alone.
Experiments were terminated at preselected times (for mRNA, 6 h
and 12 h; for protein, 24 h). As controls, cells were
incubated with medium alone for the same time periods. In other studies
with neutrophils, TNF- was chosen as the stimulus because
preliminary studies showed that TNF- had the most potent effect on
MUC5AC synthesis. To further analyze the mechanism by which neutrophils
induce MUC5AC synthesis, neutrophils were incubated with TNF- (20
ng/ml) for 1 h in the same medium that was used for the incubation
of NCI-H292 cells. After 1 h incubation, the medium (supernatant)
was separated from the neutrophils. A medium that was on top of
NCI-H292 cells was aspirated and replaced immediately with either the
same volume of supernatant or of the activated neutrophils that were
washed with sterile PBS to avoid contamination with the supernatant
(e.g., molecules released from neutrophils), and resuspended with the
same volume of fresh medium. In inhibition studies with tyrosine kinase
inhibitors, NCI-H292 cells were pretreated with BIBX1522 (a selective
inhibitor of EGFR tyrosine kinase, 10 µM; generously provided by
Boehringer Ingelheim, Ingelheim, Germany), tyrphostin AG1478 (selective
inhibitor of EGFR tyrosine kinase, 10 µM), tyrphostin AG1295 (a
selective inhibitor of PDGFR tyrosine kinase, 100 µM), tyrphostin A1
(a negative control for tyrphostins, 100 µM), PD98059 (a selective
MEK inhibitor, 30 µM), and SB203580 (a specific inhibitor of p38
MAPK, 2 µM) 30 min before adding a stimulus. All tyrosine kinase
inhibitors were purchased from Calbiochem. In inhibition studies with
blocking Abs to EGFR ligands, the supernatants were pretreated with
anti-TGF- Ab (Ab-3, 2 µg/ml; Calbiochem) or anti-EGF Ab
(Ab-3, 2 µg/ml; Calbiochem) for 30 min and then added to NCI-H292
cells. The role of oxygen free radicals was examined using
N-acetyl-L-cysteine (20 mM), oxygen
free radical scavengers (DMSO (1%, Sigma) or 1,3-dimethyl-2-thiourea
(DMTU, 50 mM, Sigma)), or superoxide dismutase (SOD, 300 U/ml, Sigma).
The concentrations were determined from previous studies (17, 21, 22, 23, 24).
Immunoblotting for activated p44/42mapk and activated EGFR
Cells were serum-starved for 24 h and then stimulated with
H2O2, with the supernatant
of activated neutrophils, or with TGF- for 15, 30, and 60 min. After
stimulation, cells were lysed with lysis buffer (20 mM sodium
phosphate, pH 7.8, 150 mM NaCl, 5 mM EDTA, 50 mM HEPES, 1% Triton
X-100, 50 mM NaF, 1 mM sodium orthovanadate, 5 mM PMSF, and 10 µg/ml
each of leupeptin and aprotinin) and incubated for 30 min at 4°C. To
remove insoluble materials, cell lysates were centrifuged at 14,000 rpm
for 5 min at 4°C. Aliquots of supernatants containing equal amounts
of protein were suspended in SDS sample buffer and boiled for 5 min.
Proteins were separated by SDS-PAGE in 4–15% acrylamide gel. The
resulting gel was equilibrated in the transfer buffer: 25 mM Tris-HCl,
192 mM glycine, 20% (v/v) methanol, pH 8.3. The proteins were then
transferred electrophoretically to nitrocellulose membranes, which were
incubated with 5% fat-free skimmed milk in PBS containing 0.05% Tween
20 for 1 h and then incubated with anti-phospho-specific EGFR
mAb (2 µg/ml; Calbiochem) or
anti-phospho-p44/42mapk mAb (2 µg/ml; New
England Biolabs, Beverly, MA) overnight. Bound Ab was visualized
according to a standard protocol for the avidin-biotin-alkaline
phosphatase complex method (ABC kit; Vector Laboratories,
Burlingame, CA).
Visualization of mucous glycoconjugates and MUC5AC protein in NCI-H292 cells
At the end of each experiment, the cells grown on 8-chamber slides were fixed with 4% paraformaldehyde for 1 h and then either stained with Alcian blue/periodic acid-Schiff (PAS) to visualize mucous glycoconjugates or used for immunocytochemistry of MUC5AC. For immunocytochemistry of MUC5AC, PBS containing 0.05% Tween 20, 2% normal goat serum, and levamisol (2 mM) was used as diluent for the Ab. Cells were incubated with a mouse mAb to MUC5AC (clone 45 M1, 1:200; Neo Markers, Fremont, CA) for 1 h at room temperature, and then washed three times with PBS to remove excess primary Ab. Cells were then incubated with biotinylated horse anti-mouse IgG (Vector Laboratories) at 1:200 dilution for 1 h at room temperature. Bound Ab was visualized according to a standard protocol for the avidin-biotin-alkaline phosphatase complex method.
In situ hybridization for human MUC5AC gene
A 298-bp cDNA fragment of human MUC5AC (generously provided by Dr. Carol Basbaum, University of California, San Francisco) was inserted into TA cloning vector (Invitrogen, San Diego, CA). The preparation of RNA probes and in situ hybridization were performed as described previously (25).
Immunoassay of MUC5AC protein
MUC5AC protein was measured as described previously (18). In brief, cell lysates were prepared with PBS at multiple dilutions, and 50 µl of each sample was incubated with bicarbonate-carbonate buffer (50 µl) at 40°C in a 96-well plate (Maxisorp Nunc, Fisher Scientific, Santa Clara, CA), until dry. Plates were washed three times with PBS and blocked with 2% BSA, fraction V (Sigma) for 1 h at room temperature. Plates were again washed three times with PBS and then incubated with 50 µl of MUC5AC mAb (1:100) that was diluted with PBS containing 0.05% Tween 20. After 1 h, the wells were washed three times with PBS, and 100 µl HRP-goat anti-mouse lgG conjugate (1:10,000) was dispensed into each well. After 1 h, plates were washed three times with PBS. Color reaction was developed with 3,3',5,5'-tetramethylbenzidine peroxidase solution (Kirkegaard & Perry Laboratories, Gaithersburg, MD) and stopped with 2 N H2SO4. Absorbance was read at 450 nm.
Quantitative analysis of TGF- protein
TGF- protein was measured using a commercially available kit
for ELISA (Calbiochem), following the manufacturer’s instructions.
Supernatant taken after incubation of neutrophils plus TNF- (20
ng/ml) for 1 h was mixed with the lysis buffer PBS containing 1%
Triton X-100, 1% sodium deoxycholate, and several protease inhibitors
(Complete Mini; Boehringer Mannheim, Mannheim, Germany), and then used
to measure TGF-.
Statistics
All data are expressed as mean ± SEM. One-way ANOVA was used to determine statistically significant differences between groups. Scheffe’s F test was used to correct for multiple comparisons when statistical significances were identified in the ANOVA. A probability of <0.05 for the null hypothesis was accepted as indicating a statistically significant difference.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has been reported that NCI-H292 cells express MUC5AC protein in
the resting condition (18). Addition of
H2O2 to the cells increased
MUC5AC protein synthesis in a dose-dependent fashion; the maximum
synthesis of MUC5AC protein occurred at 200 µM of
H2O2 (Fig. 1
).
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Because neutrophils are known to cause oxidative stress when they
are activated by stimuli that activate neutrophils (9, 26, 27, 28, 29, 30), the effect of activated neutrophils on MUC5AC synthesis
was tested in NCI-H292 cells. Neutrophils plus activating stimuli
(IL-8, FMLP, TNF-) incubated with NCI-H292 cells for 1 h caused
increased MUC5AC protein synthesis within 24 h in a dose-dependent
manner, whereas nonactivated neutrophils
(106/ml), IL-8 alone, or FMLP alone had no
effect; incubation with TNF- alone caused a small, insignificant
increase in MUC5AC synthesis (Fig. 2).
When neutrophils were preincubated for 1 h with TNF- and then
the neutrophils and their supernatant were separated, subsequent
incubation of the supernatant for 1 h with NCI-H292 cells
increased MUC5AC protein synthesis significantly; neutrophils separated
from the supernatant after incubation were without effect (Fig. 2). We
conclude that activated neutrophils rapidly secrete an active product,
which causes MUC5AC synthesis.
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Resting neutrophils showed only a weak cytoplasmic staining with
both Alcian blue/PAS and anti-MUC5AC Ab. Addition of
H2O2 or supernatant of
activated neutrophils to the cells increased the cytoplasmic staining
for MUC5AC protein in a pattern similar to Alcian blue/PAS staining
(Fig. 3). The staining pattern with both
Alcian blue/PAS and anti-MUC5AC Ab showed a patchy distribution
(similar to the pattern of MUC5AC mRNA, Fig. 4) when
H2O2 or supernatant of
activated neutrophils was added, although all of cells showed increased
staining in their cytoplasm.
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Resting NCI-H292 cells showed little expression of
MUC5AC mRNA at both 6 and 12 h. Addition of
H2O2 or supernatant of
activated neutrophils to the cells up-regulated MUC5AC mRNA
expression within 6 h and accentuated at 12 h (Fig. 4
). The
intense expression of MUC5AC mRNA was found in certain cells
and thus showed a patchy distribution of the expression. The sense
probe of MUC5AC showed no expression (Fig. 4).
Activation of p44/42mapk and EGFR tyrosine kinase by H2O2 and by supernatant of activated neutrophils
Because EGFR tyrosine kinase activation causes MUC5AC synthesis,
activation of EGFR tyrosine kinase was examined. The EGFR ligand,
TGF-, increased EGFR-specific tyrosine phosphorylation in NCI-H292
cells. H2O2 and supernatant
of activated neutrophils also increased EGFR-specific tyrosine
phosphorylation, but to a lesser extent (Fig. 5). EGFR tyrosine phosphorylation induced
by H2O2 or by supernatant
of activated neutrophils was approximately one-third of that induced by
TGF-. Because activation of MAPK plays an important role in gene
transcription of many mammalian cells and is known to be downstream of
the EGFR signaling pathway, we tested whether
p44/42mapk was phosphorylated in this system.
Similar to EGFR phosphorylation, TGF- increased
p44/42mapk phosphorylation in NCI-H292 cells.
Both H2O2 and supernatant
of activated neutrophils also increased
p44/42mapk phosphorylation. The peak of
phosphorylation of p44/42mapk induced by
H2O2 and by supernatant of
activated neutrophils was slower than phosphorylation induced by
TGF- (data not shown). Pretreatment of NCI-H292 cells with BIBX1522
inhibited both EGFR tyrosine phosphorylation and
p44/42mapk phosphorylation (Fig. 5B),
whereas PD98059 had no effect on EGFR tyrosine phosphorylation, but it
inhibited p44/42mapk phosphorylation induced by
H2O2, by supernatant of
activated neutrophils, and by TGF- (Fig. 5A).
N-acetyl-L-cysteine inhibited EGFR
tyrosine phosphorylation induced by
H2O2 and by supernatant of
activated neutrophils but had no effect on TGF--induced EGFR
tyrosine phosphorylation (Fig. 5C).
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Because both H2O2 and
supernatant of activated neutrophils increased EGFR tyrosine
phosphorylation and p44/42mapk phosphorylation,
the effects of inhibitors of EGFR tyrosine phosphorylation and of MEK
were tested on MUC5AC synthesis. Pretreatment of NCI-H292 cells with
selective EGFR tyrosine kinase inhibitors (BIBX1522, AG1478) or a MEK
inhibitor (PD98059) prevented the MUC5AC synthesis at both mRNA (Fig. 4) and protein levels (Fig. 6) that were
usually induced by H2O2 and
by supernatant of activated neutrophils. A selective tyrosine kinase
inhibitor of PDGFR (AG1295), a selective inhibitor of p38 MAPK,
SB203580, and a negative control for tyrphostins (A1) were without
effect (Fig. 6).
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To determine whether activation of EGFR tyrosine kinase is
dependent on EGFR ligands (EGF and TGF-), we preincubated the
supernatant of activated neutrophils with neutralizing Abs to EGFR
ligands. Pretreatment of the supernatant with either an
anti-TGF- Ab or with an anti-EGF Ab did not inhibit MUC5AC
synthesis induced by the supernatant of activated neutrophils (Fig. 7). Furthermore, TGF- was not detected
in the supernatant (data not shown). Thus, EGFR tyrosine
phosphorylation caused by the supernatant of activated neutrophils was
induced by a mechanism independent of the EGFR ligands, EGF and
TGF-.
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MUC5AC synthesis by
H2O2 or by supernatant of
activated neutrophils was inhibited by pretreatment with
N-acetyl-L-cysteine, by free radical
scavengers (DMSO and DMTU), and by SOD, but MUC5AC protein synthesis by
TGF- was unaffected by antioxidants (Fig. 7).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TNF- had the greatest effect, and this is compatible with the potent
release of oxidants from neutrophils by TNF- (9, 26, 27, 28, 29, 30).
To examine whether neutrophils release mediators that cause mucin
synthesis, the supernatant was separated from the neutrophils after
1 h incubation with TNF- and incubated with NCI-H292 cells
separately: the neutrophil supernatant up-regulated mucin
MUC5AC mRNA expression and subsequent MUC5AC protein
synthesis; the time sequence was similar to previous reports of
neutrophil release of ROS (29). In contrast to the
supernatant, the activated neutrophils themselves did not stimulate
MUC5AC synthesis. The reason for the lack of response of activated
neutrophils could be due to the timing of the studies or it could be
due to lack of adhesion of the neutrophils to NCI-H292 cells. Because
previous reports showed that neutrophil adhesion potentiates the
oxidative burst in neutrophils (31), it is possible that
more potent mucin synthesis caused by neutrophil-dependent oxidative
burst might exist when neutrophil-epithelial cell adhesion occurs.
Cigarette smoke is another important source of oxidants and may play a
role in the production of mucins in airways in chronic obstructive
pulmonary disease.
Because EGFR activation by interaction between EGFR with its ligands has been shown to cause MUC5AC synthesis (18), we examined whether activation of EGFR is required in MUC5AC synthesis induced by H2O2 or by supernatant of activated neutrophils. Both H2O2 and supernatant of activated neutrophils induced increased EGFR tyrosine phosphorylation, and selective inhibitors of EGFR tyrosine kinase completely blocked both EGFR tyrosine phosphorylation and MUC5AC synthesis caused by H2O2 and by the supernatant of activated neutrophils; a selective PDGFR tyrosine kinase inhibitor (AG1295) and a negative control for tyrphostins (A1) were without effect. These findings implicate EGFR tyrosine phosphorylation in mucin synthesis induced by H2O2 and supernatant of activated neutrophils.
EGFR tyrosine kinase has been shown to be activated by two distinct
processes. First, the binding of EGFR ligands to EGFR activates the
intrinsic receptor tyrosine kinase and induces tyrosine phosphorylation
(32). Second, there is increasing evidence that tyrosine
phosphorylation of EGFR can be activated by a ligand-independent
mechanism (ìtransactivationî); EGFR transactivation
occurs with various stimuli such as oxidative
(H2O2) (16, 33), ultraviolet (34), and osmotic
(34) stress, stimulation of G-protein coupled-receptor by
endothelin-1, lysophosphatidic acid, and thrombin (35), m1
muscarinic acetylcholine receptor (36), and growth hormone
(37). To analyze further the mechanism by which
supernatants of activated neutrophils induce EGFR tyrosine
phosphorylation, we examined both ligand-dependent and
ligand-independent EGFR pathways. To test the ligand-dependent pathway
of EGFR tyrosine phosphorylation, we used two different approaches.
First, we measured TGF- in the supernatant of activated neutrophils
and found that the supernatant did not contain measurable amounts of
TGF-, a finding compatible with previous reports that showed that
neutrophils only contained low concentrations (2.5
pg/106 cells) of TGF- (38). In
fact, the effect of supernatant from activated neutrophils on MUC5AC
synthesis was as potent as the effect of 1 ng of TGF-, which was
400-fold higher than the amount of TGF- found in neutrophils. There
is still the possibility that other ligands for EGFR such as
heparin-binding EGF-like growth factor, amphiregulin, and betacellulin,
which have not been reported in neutrophils, may affect mucin synthesis
caused by supernatant of activated neutrophils. Second, we performed
blocking studies with neutralizing Abs of EGFR ligands. Pretreatment
with neutralizing Abs to EGF and TGF- failed to inhibit MUC5AC
synthesis caused by the supernatant of activated neutrophils. These
results suggest that neutrophil supernatant-induced MUC5AC synthesis
was not due to the secretion of EGFR ligands (TGF- and EGF) by
neutrophils. Third, we performed inhibition studies with antioxidants,
because ROS are known to be released by neutrophils during activation.
We found that an antioxidant
N-acetyl-L-cysteine, scavengers of
free radicals (DMSO and DMTU), and SOD inhibited MUC5AC synthesis by
the supernatant of activated neutrophils, implicating oxidative stress
in this response. In the present studies, we showed that ligand-induced
EGFR tyrosine phosphorylation and mucin synthesis were not affected by
antioxidants and that MUC5AC synthesis induced by supernatant of
activated neutrophils was inhibited by antioxidants. From these
results, we conclude that MUC5AC synthesis induced by supernatant of
activated neutrophils is oxidant dependent. Although ROS are known to
be produced by activated neutrophils, there is the possibility that the
supernatant of activated neutrophils may contain factors that induce
ROS production by NCI-H292 cells. Interestingly, it has been reported
that an oxidative burst induces fibroblasts to synthesize and release
TGF- during acute inflammatory lung injury in vivo
(39). Thus, neutrophils could induce MUC5AC synthesis via
both ligand-dependent and ligand-independent activation of EGFR in
vivo.
The mechanism by which oxidative stress activates EGFR tyrosine phosphorylation is unknown. However, it has been speculated that inhibition of protein tyrosine phosphatase or the activation of intracellular protein tyrosine kinase such as Src might be involved in oxidative stress-induced EGFR phosphorylation (40).
Because the MEK-MAPK transduction pathway is known to be downstream of
EGFR activation and because a selective inhibitor of MEK, PD98059, is
reported to inhibit MUC2 gene expression induced by
Pseudomomas aeruginosa (41), we examined the
involvement of MEK-MAPK transduction pathway in mucin MUC5AC synthesis
induced by both ligand-dependent and ligand-independent activation of
EGFR. Similar to EGFR tyrosine phosphorylation,
H2O2, supernatant of
activated neutrophils, and TGF- induced increased activation of
p44/42mapk, effects that were blocked by PD98059
and by BIBX1522. Furthermore, PD98059 blocked MUC5AC synthesis induced
by H2O2, by supernatant of
activated neutrophils, and by TGF-, without blocking EGFR tyrosine
phosphorylation, implicating MEK-MAPK as downstream of the EGFR
transduction pathway in causing MUC5AC synthesis. Other stimuli (e.g.,
P. aeruginosa) may also cause mucin synthesis via the EGFR
cascade.
Oxidative stress is a central feature in airway inflammatory diseases, and recruited neutrophils are one of the important origins of oxidative stress in airways. Present studies show that recruited neutrophils act as regulators of epithelial cell differentiation via oxidant-dependent, ligand-independent activation of EGFR, up-regulating mucin MUC5AC gene and protein expression in airway epithelial cells. Because MUC5AC has been shown to be an important mucin in airway epithelium (19), which is present in respiratory secretions (20), inhibition of the EGFR signaling pathway and antioxidants are proposed as therapies in hypersecretory airway diseases. Proof of concept in humans will require testing in patients with these diseases.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Jay A. Nadel, Cardiovascular Research Institute, Box 0130, University of California San Francisco, San Francisco, CA 94143-0130. E-mail address:
3 Abbreviations used in this paper: ROS, reactive oxygen species; EGFR, epidermal growth factor receptors; MEK, mitogen-activated protein kinase kinase; MAPK, mitogen-activated protein kinase; PDGFR, platelet-derived growth factor receptor; DMTU, 1, 3-dimethyl-2-thiourea; SOD, superoxide dismutase; PAS, periodic acid-Schiff.
Received for publication August 19, 1999. Accepted for publication November 19, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 J. C. Hogg, F. S. F. Chu, W. C. Tan, D. D. Sin, S. A. Patel, P. D. Pare, F. J. Martinez, R. M. Rogers, B. J. Make, G. J. Criner, et al. Survival after Lung Volume Reduction in Chronic Obstructive Pulmonary Disease: Insights from Small Airway Pathology Am. J. Respir. Crit. Care Med., September 1, 2007; 176(5): 454 - 459. [Abstract] [Full Text] [PDF]
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A. E. Hegab, T. Sakamoto, A. Nomura, Y. Ishii, Y. Morishima, T. Iizuka, T. Kiwamoto, Y. Matsuno, S. Homma, and K. Sekizawa Niflumic Acid and AG-1478 Reduce Cigarette Smoke-Induced Mucin Synthesis: The Role of hCLCA1 Chest, April 1, 2007; 131(4): 1149 - 1156. [Abstract] [Full Text] [PDF]
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S. Pierrou, P. Broberg, R. A. O'Donnell, K. Pawlowski, R. Virtala, E. Lindqvist, A. Richter, S. J. Wilson, G. Angco, S. Moller, et al. Expression of Genes Involved in Oxidative Stress Responses in Airway Epithelial Cells of Smokers with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., March 15, 2007; 175(6): 577 - 586. [Abstract] [Full Text] [PDF]
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D. Yuan-chen Wu, R. Wu, S. P. Reddy, Y. C. Lee, and M. M.-J. Chang Distinctive Epidermal Growth Factor Receptor/Extracellular Regulated Kinase-Independent and -Dependent Signaling Pathways in the Induction of Airway Mucin 5B and Mucin 5AC Expression by Phorbol 12-Myristate 13-Acetate Am. J. Pathol., January 1, 2007; 170(1): 20 - 32. [Abstract] [Full Text] [PDF]
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J. L. Koff, M. X. G. Shao, S. Kim, I. F. Ueki, and J. A. Nadel Pseudomonas Lipopolysaccharide Accelerates Wound Repair via Activation of a Novel Epithelial Cell Signaling Cascade J. Immunol., December 15, 2006; 177(12): 8693 - 8700. [Abstract] [Full Text] [PDF]
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L. Finzi, V. Barbu, P.-R. Burgel, M. Mergey, K. S. Kirkwood, E. C. Wick, J.-Y. Scoazec, F. Peschaud, F. Paye, J. A. Nadel, et al. MUC5AC, a Gel-Forming Mucin Accumulating in Gallstone Disease, Is Overproduced via an Epidermal Growth Factor Receptor Pathway in the Human Gallbladder Am. J. Pathol., December 1, 2006; 169(6): 2031 - 2041. [Abstract] [Full Text] [PDF]
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 J. C. Hogg State of the Art. Bronchiolitis in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, August 1, 2006; 3(6): 489 - 493. [Full Text] [PDF]
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T. K. Baginski, K. Dabbagh, C. Satjawatcharaphong, and D. C. Swinney Cigarette Smoke Synergistically Enhances Respiratory Mucin Induction by Proinflammatory Stimuli Am. J. Respir. Cell Mol. Biol., August 1, 2006; 35(2): 165 - 174. [Abstract] [Full Text] [PDF]
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M. J. Holtzman, J. T. Battaile, and A. C. Patel Immunogenetic Programs for Viral Induction of Mucous Cell Metaplasia Am. J. Respir. Cell Mol. Biol., July 1, 2006; 35(1): 29 - 39. [Full Text] [PDF]
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J. A. Voynow, S. J. Gendler, and M. C. Rose Regulation of Mucin Genes in Chronic Inflammatory Airway Diseases Am. J. Respir. Cell Mol. Biol., June 1, 2006; 34(6): 661 - 665. [Abstract] [Full Text] [PDF]
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S. M. Casalino-Matsuda, M. E. Monzon, and R. M. Forteza Epidermal Growth Factor Receptor Activation by Epidermal Growth Factor Mediates Oxidant-Induced Goblet Cell Metaplasia in Human Airway Epithelium Am. J. Respir. Cell Mol. Biol., May 1, 2006; 34(5): 581 - 591. [Abstract] [Full Text] [PDF]
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 M. C. Rose and J. A. Voynow Respiratory Tract Mucin Genes and Mucin Glycoproteins in Health and Disease Physiol Rev, January 1, 2006; 86(1): 245 - 278. [Abstract] [Full Text] [PDF]
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S. Kim, A. J. Schein, and J. A. Nadel E-cadherin promotes EGFR-mediated cell differentiation and MUC5AC mucin expression in cultured human airway epithelial cells Am J Physiol Lung Cell Mol Physiol, December 1, 2005; 289(6): L1049 - L1060. [Abstract] [Full Text] [PDF]
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K. F. Chung The Role of Airway Smooth Muscle in the Pathogenesis of Airway Wall Remodeling in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2005; 2(4): 347 - 354. [Abstract] [Full Text] [PDF]
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C. A. Owen Proteinases and Oxidants as Targets in the Treatment of Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2005; 2(4): 373 - 385. [Abstract] [Full Text] [PDF]
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J. A. Voynow, B. M. Fischer, B. C. Roberts, and A. D. Proia Basal-like Cells Constitute the Proliferating Cell Population in Cystic Fibrosis Airways Am. J. Respir. Crit. Care Med., October 15, 2005; 172(8): 1013 - 1018. [Abstract] [Full Text] [PDF]
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C. S. Stevenson, K. Coote, R. Webster, H. Johnston, H. C. Atherton, A. Nicholls, J. Giddings, R. Sugar, A. Jackson, N. J. Press, et al. Characterization of cigarette smoke-induced inflammatory and mucus hypersecretory changes in rat lung and the role of CXCR2 ligands in mediating this effect Am J Physiol Lung Cell Mol Physiol, March 1, 2005; 288(3): L514 - L522. [Abstract] [Full Text] [PDF]
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M Mata, B Sarria, A Buenestado, J Cortijo, M Cerda, and E J Morcillo Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells Thorax, February 1, 2005; 60(2): 144 - 152. [Abstract] [Full Text] [PDF]
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R A O'Donnell, A Richter, J Ward, G Angco, A Mehta, K Rousseau, D M Swallow, S T Holgate, R Djukanovic, D E Davies, et al. Expression of ErbB receptors and mucins in the airways of long term current smokers Thorax, December 1, 2004; 59(12): 1032 - 1040. [Abstract] [Full Text] [PDF]
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J. Tamaoki, K. Isono, K. Takeyama, E. Tagaya, J. Nakata, and A. Nagai Ultrafine carbon black particles stimulate proliferation of human airway epithelium via EGF receptor-mediated signaling pathway Am J Physiol Lung Cell Mol Physiol, December 1, 2004; 287(6): L1127 - L1133. [Abstract] [Full Text] [PDF]
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P-R Burgel and J A Nadel Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium Thorax, November 1, 2004; 59(11): 992 - 996. [Abstract] [Full Text] [PDF]
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P-R. Burgel, L.O. Cardell, I.F. Ueki, and J.A. Nadel Intranasal steroids decrease eosinophils but not mucin expression in nasal polyps Eur. Respir. J., October 1, 2004; 24(4): 594 - 600. [Abstract] [Full Text] [PDF]
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J.-H. Kim, K.-H. Jung, J.-H. Han, J.-J. Shim, K.-H. In, K.-H. Kang, and S.-H. Yoo Relation of Epidermal Growth Factor Receptor Expression to Mucus Hypersecretion in Diffuse Panbronchiolitis Chest, September 1, 2004; 126(3): 888 - 895. [Abstract] [Full Text] [PDF]
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A. Almolki, C. Taille, G. F. Martin, P. J. Jose, C. Zedda, M. Conti, J. Megret, D. Henin, M. Aubier, and J. Boczkowski Heme oxygenase attenuates allergen-induced airway inflammation and hyperreactivity in guinea pigs Am J Physiol Lung Cell Mol Physiol, July 1, 2004; 287(1): L26 - L34. [Abstract] [Full Text] [PDF]
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J. H. Kim, S. Y. Lee, S. M. Bak, I. B. Suh, S. Y. Lee, C. Shin, J. J. Shim, K. H. In, K. H. Kang, and S. H. Yoo Effects of matrix metalloproteinase inhibitor on LPS-induced goblet cell metaplasia Am J Physiol Lung Cell Mol Physiol, July 1, 2004; 287(1): L127 - L133. [Abstract] [Full Text] [PDF]
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D. H. Kim, H.-S. Chu, J. Y. Lee, S. J. Hwang, S. H. Lee, and H.-M. Lee Up-regulation of MUC5AC and MUC5B Mucin Genes in Chronic Rhinosinusitis Arch Otolaryngol Head Neck Surg, June 1, 2004; 130(6): 747 - 752. [Abstract] [Full Text] [PDF]
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 S. M. Casalino-Matsuda, M. E. Monzon, G. E. Conner, M. Salathe, and R. M. Forteza Role of Hyaluronan and Reactive Oxygen Species in Tissue Kallikrein-mediated Epidermal Growth Factor Receptor Activation in Human Airways J. Biol. Chem., May 14, 2004; 279(20): 21606 - 21616. [Abstract] [Full Text] [PDF]
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B. A. Mercer, N. Kolesnikova, J. Sonett, and J. D'Armiento Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke J. Biol. Chem., April 23, 2004; 279(17): 17690 - 17696. [Abstract] [Full Text] [PDF]
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M. Chokki, S. Yamamura, H. Eguchi, T. Masegi, H. Horiuchi, H. Tanabe, T. Kamimura, and S. Yasuoka Human Airway Trypsin-Like Protease Increases Mucin Gene Expression in Airway Epithelial Cells Am. J. Respir. Cell Mol. Biol., April 1, 2004; 30(4): 470 - 478. [Abstract] [Full Text] [PDF]
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S. Blanchet, K. Ramgolam, A. Baulig, F. Marano, and A. Baeza-Squiban Fine Particulate Matter Induces Amphiregulin Secretion by Bronchial Epithelial Cells Am. J. Respir. Cell Mol. Biol., April 1, 2004; 30(4): 421 - 427. [Abstract] [Full Text] [PDF]
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J. Aarbiou, R. M. Verhoosel, S. van Wetering, W. I. de Boer, J. H. J. M. van Krieken, S. V. Litvinov, K. F. Rabe, and P. S. Hiemstra Neutrophil Defensins Enhance Lung Epithelial Wound Closure and Mucin Gene Expression In Vitro Am. J. Respir. Cell Mol. Biol., February 1, 2004; 30(2): 193 - 201. [Abstract] [Full Text] [PDF]
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M. Mata, A. Ruiz, M. Cerda, M. Martinez-Losa, J. Cortijo, F. Santangelo, A. Serrano-Mollar, A. Llombart-Bosch, and E.J. Morcillo Oral N-acetylcysteine reduces bleomycin-induced lung damage and mucin Muc5ac expression in rats Eur. Respir. J., December 1, 2003; 22(6): 900 - 905. [Abstract] [Full Text] [PDF]
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R. D. Wang, H. Tai, C. Xie, X. Wang, J. L. Wright, and A. Churg Cigarette Smoke Produces Airway Wall Remodeling in Rat Tracheal Explants Am. J. Respir. Crit. Care Med., November 15, 2003; 168(10): 1232 - 1236. [Abstract] [Full Text] [PDF]
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B. B. Vargaftig and M. Singer Leukotrienes mediate part of Ova-induced lung effects in mice via EGFR Am J Physiol Lung Cell Mol Physiol, October 1, 2003; 285(4): L808 - L818. [Abstract] [Full Text] [PDF]
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 M. X. G. Shao, I. F. Ueki, and J. A. Nadel Tumor necrosis factor {alpha}-converting enzyme mediates MUC5AC mucin expression in cultured human airway epithelial cells PNAS, September 30, 2003; 100(20): 11618 - 11623. [Abstract] [Full Text] [PDF]
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K. S. Song, W.-J. Lee, K. C. Chung, J. S. Koo, E. J. Yang, J. Y. Choi, and J.-H. Yoon Interleukin-1{beta} and Tumor Necrosis Factor-{alpha} Induce MUC5AC Overexpression through a Mechanism Involving ERK/p38 Mitogen-activated Protein Kinases-MSK1-CREB Activation in Human Airway Epithelial Cells J. Biol. Chem., June 20, 2003; 278(26): 23243 - 23250. [Abstract] [Full Text] [PDF]
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 W. Sun, X. Wei, K. Kesavan, T. P. Garrington, R. Fan, J. Mei, S. M. Anderson, E. W. Gelfand, and G. L. Johnson MEK Kinase 2 and the Adaptor Protein Lad Regulate Extracellular Signal-Regulated Kinase 5 Activation by Epidermal Growth Factor via Src Mol. Cell. Biol., April 1, 2003; 23(7): 2298 - 2308. [Abstract] [Full Text] [PDF]
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S. Blesa, J. Cortijo, M. Mata, A. Serrano, D. Closa, F. Santangelo, J.M. Estrela, J. Suchankova, and E.J. Morcillo Oral N-acetylcysteine attenuates the rat pulmonary inflammatory response to antigen Eur. Respir. J., March 1, 2003; 21(3): 394 - 400. [Abstract] [Full Text] [PDF]
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X. Chen and M. D. Resh Cholesterol Depletion from the Plasma Membrane Triggers Ligand-independent Activation of the Epidermal Growth Factor Receptor J. Biol. Chem., December 13, 2002; 277(51): 49631 - 49637. [Abstract] [Full Text] [PDF]
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K. Kohri, I.F. Ueki, J-J. Shim, P-R. Burgel, Y-M. Oh, D.C. Tam, T. Dao-Pick, and J.A. Nadel Pseudomonas aeruginosa induces MUC5AC production via epidermal growth factor receptor Eur. Respir. J., November 1, 2002; 20(5): 1263 - 1270. [Abstract] [Full Text] [PDF]
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L. Whittaker, N. Niu, U.-A. Temann, A. Stoddard, R. A. Flavell, A. Ray, R. J. Homer, and L. Cohn Interleukin-13 Mediates a Fundamental Pathway for Airway Epithelial Mucus Induced by CD4 T Cells and Interleukin-9 Am. J. Respir. Cell Mol. Biol., November 1, 2002; 27(5): 593 - 602. [Abstract] [Full Text] [PDF]
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 Y.-D. Kim, E.-J. Kwon, D.-W. Park, S.-Y. Song, S.-K. Yoon, and S.-H. Baek Interleukin-1beta Induces MUC2 and MUC5AC Synthesis through Cyclooxygenase-2 in NCI-H292 Cells Mol. Pharmacol., November 1, 2002; 62(5): 1112 - 1118. [Abstract] [Full Text] [PDF]
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J. C. Bonner The epidermal growth factor receptor at the crossroads of airway remodeling Am J Physiol Lung Cell Mol Physiol, September 1, 2002; 283(3): L528 - L530. [Full Text] [PDF]
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K. Kohri, I. F. Ueki, and J. A. Nadel Neutrophil elastase induces mucin production by ligand-dependent epidermal growth factor receptor activation Am J Physiol Lung Cell Mol Physiol, September 1, 2002; 283(3): L531 - L540. [Abstract] [Full Text] [PDF]
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M. Perrais, P. Pigny, M.-C. Copin, J.-P. Aubert, and I. Van Seuningen Induction of MUC2 and MUC5AC Mucins by Factors of the Epidermal Growth Factor (EGF) Family Is Mediated by EGF Receptor/Ras/Raf/Extracellular Signal-regulated Kinase Cascade and Sp1* J. Biol. Chem., August 23, 2002; 277(35): 32258 - 32267. [Abstract] [Full Text] [PDF]
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M. S. Lombardi, A. Kavelaars, P. Penela, E. J. Scholtens, M. Roccio, R. E. Schmidt, M. Schedlowski, F. Mayor Jr., and C. J. Heijnen Oxidative Stress Decreases G Protein-Coupled Receptor Kinase 2 in Lymphocytes via a Calpain-Dependent Mechanism Mol. Pharmacol., August 1, 2002; 62(2): 379 - 388. [Abstract] [Full Text] [PDF]
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A. Richter, R. A. O'Donnell, R. M. Powell, M. W. Sanders, S. T. Holgate, R. Djukanovic', and D. E. Davies Autocrine Ligands for the Epidermal Growth Factor Receptor Mediate Interleukin-8 Release from Bronchial Epithelial Cells in Response to Cigarette Smoke Am. J. Respir. Cell Mol. Biol., July 1, 2002; 27(1): 85 - 90. [Abstract] [Full Text] [PDF]
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 J. Aarbiou, M. Ertmann, S. van Wetering, P. van Noort, D. Rook, K. F. Rabe, S. V. Litvinov, J. H. J. M. van Krieken, W. I. de Boer, and P. S. Hiemstra Human neutrophil defensins induce lung epithelial cell proliferation in vitro J. Leukoc. Biol., July 1, 2002; 72(1): 167 - 174. [Abstract] [Full Text] [PDF]
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J. L. Lordan, F. Bucchieri, A. Richter, A. Konstantinidis, J. W. Holloway, M. Thornber, S. M. Puddicombe, D. Buchanan, S. J. Wilson, R. Djukanovic, et al. Cooperative Effects of Th2 Cytokines and Allergen on Normal and Asthmatic Bronchial Epithelial Cells J. Immunol., July 1, 2002; 169(1): 407 - 414. [Abstract] [Full Text] [PDF]
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R A O'Donnell and A J Frew Is there more than one inflammatory phenotype in asthma? Thorax, July 1, 2002; 57(7): 566 - 568. [Full Text] [PDF]
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S. Kim, J. J. Shim, P.-R. Burgel, I. F. Ueki, T. Dao-Pick, D. C.-W. Tam, and J. A. Nadel IL-13-induced Clara cell secretory protein expression in airway epithelium: role of EGFR signaling pathway Am J Physiol Lung Cell Mol Physiol, July 1, 2002; 283(1): L67 - L75. [Abstract] [Full Text] [PDF]
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P.-R. Burgel, S. C. Lazarus, D. C.-W. Tam, I. F. Ueki, K. Atabai, M. Birch, and J. A. Nadel Human Eosinophils Induce Mucin Production in Airway Epithelial Cells Via Epidermal Growth Factor Receptor Activation J. Immunol., November 15, 2001; 167(10): 5948 - 5954. [Abstract] [Full Text] [PDF]
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Y. Saito, J. Haendeler, Y. Hojo, K. Yamamoto, and B. C. Berk Receptor Heterodimerization: Essential Mechanism for Platelet-Derived Growth Factor-Induced Epidermal Growth Factor Receptor Transactivation Mol. Cell. Biol., October 1, 2001; 21(19): 6387 - 6394. [Abstract] [Full Text] [PDF]
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J. J. Shim, K. Dabbagh, I. F. Ueki, T. Dao-Pick, P.-R. Burgel, K. Takeyama, D. C.-W. Tam, and J. A. Nadel IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils Am J Physiol Lung Cell Mol Physiol, January 1, 2001; 280(1): L134 - L140. [Abstract] [Full Text] [PDF]
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K. Takeyama, B. Jung, J. J. Shim, P.-R. Burgel, T. Dao-Pick, I. F. Ueki, U. Protin, P. Kroschel, and J. A. Nadel Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke Am J Physiol Lung Cell Mol Physiol, January 1, 2001; 280(1): L165 - L172. [Abstract] [Full Text] [PDF]
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K. Chen, J. A. Vita, B. C. Berk, and J. F. Keaney Jr. c-Jun N-terminal Kinase Activation by Hydrogen Peroxide in Endothelial Cells Involves Src-dependent Epidermal Growth Factor Receptor Transactivation J. Biol. Chem., May 4, 2001; 276(19): 16045 - 16050. [Abstract] [Full Text] [PDF]
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, p < 0.05; 