Department of Pharmacology and Toxicology, Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada K7L 3N6
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ABSTRACT |
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Amiodarone (AM) is an
antidysrhythmic agent with a propensity to cause pulmonary toxicity,
including potentially fatal fibrosis. In the present study, the
potential roles of c-Jun and transforming growth factor (TGF)-1 in
AM-induced inflammation and fibrogenesis were examined after
intratracheal administration of AM (1.83 µmol/day on days
0 and 2) or an equivalent volume (0.4 ml) of distilled water to male Fischer 344 rats. Northern and immunoblot analyses demonstrated that lung TGF-
1 (mRNA and protein) expression was increased 1.5- to 1.8-fold relative to control during the early inflammation period and 1 day, 1 wk, and 2 wk post-AM treatment. Lung
c-Jun protein expression was increased concomitantly with evidence of
AM-induced fibrosis; at 5 wk post-AM treatment, c-Jun protein was
increased 3.3-fold relative to control. The results indicate a role for
induction of c-jun and TGF-
1 expression in the
development of AM-induced pulmonary fibrosis in the Fischer 344 rat and
provide potential targets for therapeutic intervention.
pulmonary toxicity; intratracheal treatment; gene expression; transforming growth factor-1
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INTRODUCTION |
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AMIODARONE (AM), an iodinated benzofuran derivative, is an effective antidysrhythmic agent. However, AM use has been associated with a variety of adverse effects (17), the most serious of which is AM-induced pulmonary toxicity (AIPT), which can progress to potentially fatal pulmonary fibrosis (17, 39). Although numerous mechanisms of AIPT have been proposed (reviewed in Refs. 33 and 46), its etiology remains to be defined. With AM use gaining favor as a first-line therapy for the treatment of acute ventricular tachycardia and fibrillation (13) and with numerous clinical trials demonstrating the benefits of prophylactic AM use in postcoronary bypass surgery (19) and postmyocardial infarction (23), understanding the etiology of AIPT is of considerable clinical value.
It is well known that the recruitment and activation of inflammatory cells leads to the release of inflammatory mediators that play an important role in the stimulation and proliferation of cells involved in fibrotic processes (11). Macrophage activation and subsequent cytokine/growth factor production are important factors in other models of pulmonary toxicity (40, 42). With in vitro evidence that AM induces release of various mediators and chemotactic factors involved in inflammation and fibrosis (47, 62), it stands to reason that altered mediator release is important in the pathogenesis of AIPT.
c-Jun is a nuclear transcription factor that belongs to the activator
protein-1 (AP-1) family of inducible nuclear proteins. As a homo- or
heterodimer (with other Jun or Fos proteins), c-Jun binds to the AP-1
binding site located in the promoter regions of several genes and
causes trans-activation (1). Numerous studies
have examined the role of c-Jun in controlling cellular proliferation,
indicating that aberrant c-jun expression may lead to
malformation or disease (25). c-jun mRNA is
highly expressed in lung tissue (52), and studies
implicating c-Jun in pulmonary inflammation and fibrosis suggest
involvement in the downstream signaling pathways of mediators such as
interleukin-1 (IL-1; see Ref. 36), tumor necrosis
factor- (TNF-
; see Ref. 56), reactive oxygen species
(27), platelet-derived growth factor (PDGF; see Ref.
51), and transforming growth factor (TGF)-
(6). Because c-jun overexpression can induce
expression of genes involved in fibrotic tissue remodeling, such as
collagen (2, 10) and collagenase (18, 34),
and the pulmonary fibrogenicity of asbestos has been associated with
increases in c-jun expression both in vitro
(58) and in vivo (44), we hypothesized that
c-Jun may play a role in the development of AIPT.
TGF-1 belongs to the TGF-
polypeptide superfamily, a group
composed of TGF-
isoforms, activins, and morphogenic proteins. There
are five distinct TGF-
isoforms known to exist, three of which,
TGF-
1, -
2, and -
3, are expressed in mammalian
species. The different isoforms appear to have distinct effects and/or potencies, at least in vitro (9). TGF-
1 may play a role
in normal immune defense as suggested by its expression in activated human macrophages (3) and constitutive expression in
normal human lung (54). With mounting evidence
demonstrating that TGF-
1 plays a role in accumulation of
extracellular matrix macromolecules (14, 30, 35, 38, 50),
this growth factor has been implicated in the pathogenesis of various
models of pulmonary fibrosis.
The purpose of this study was to investigate the involvement of c-Jun
and TGF-1 as potential mediators involved in the pathogenesis of
AIPT in a rat model. Although we have previously shown that intratracheal administration of AM to hamsters can reliably produce pulmonary fibrosis similar to clinical AIPT (8, 12, 31), a
Fischer 344 rat model, demonstrated by others to produce pulmonary fibrosis after intratracheal administration of AM (49,
57), was employed in the current study. This allowed us to use
available cDNA probes and antibodies for the rat versions of
c-jun and TGF-
1.
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MATERIALS AND METHODS |
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Chemical sources.
Chemicals were obtained as follows:
N-chloro-p-toluenesulfonamide sodium salt
(chloramine T), p-dimethylaminobenzaldehyde (Ehrlich's
reagent), sodium thiosulfate, DL-alanine, 10% neutral buffered formalin solution, Triton X-100, sodium deoxycholate, dithiothreitol (DTT), phenylmethylsulfonyl fluoride (PMSF), pepsin, leupeptin, aprotinin, and
2-N-butyl-3(4'-diethylaminoethoxy)-3',5'-diiodobenzoyl benzofuran (AM HCl) were from Sigma Chemical (St. Louis, MO); 20×
saline-sodium citrate buffer and BamHI were from GIBCO BRL, Life Technologies (Burlington, ON); [-32P]dCTP was
from Amersham Pharmacia Biotech (Oakville, ON); Tween 20, agarose, and
Permount medium were from Fisher Scientific (Nepean, ON); Harris'
hematoxylin and eosin were from BDH Chemicals (Toronto, ON); 40%
acrylamide, 2% bisacrylamide, and Bio-Rad (Bradford) protein reagent
were from Bio-Rad (Mississauga, ON);
-mercaptoethanol and ammonium
persulfate were from ICN Biomedicals (Montreal, PQ); trans-4-hydroxy-L-proline was from Aldrich
Chemical (Oakville, ON); pentobarbital sodium (Somnotol) was from MTC
Pharmaceuticals (Cambridge, ON); fluanisone/fentanyl citrate (Hypnorm)
was from Janssen Pharmaceutica (Beerse, Belgium); midazolam (Versed)
was from Hoffmann-La Roche (Mississauga, ON); and 2% xylocaine jelly was from Astra Pharma (Mississauga, ON). All other chemicals were of
reagent grade or better and were obtained from common commercial sources.
AM treatment. Animals were cared for in accordance with the principles and guidelines of the Canadian Council on Animal Care. Male Fischer 344 rats (175-200 g; Charles River Canada, St. Constant, PQ) were housed in group plastic cages containing hardwood shavings. They were maintained on a 12:12-h light-dark cycle and were fed Purina laboratory rat chow and water ad libitum. Rats were allowed to acclimate in the Queen's University Animal Care facility for at least 1 wk before treatment.
AM was dissolved in distilled water (dH2O) at 65°C and allowed to cool to room temperature before instillation. Rats were anesthetized by intraperitoneal administration of Hypnorm and Versed (1:1:10 of Hypnorm-Versed-dH2O, 2 ml/kg), followed by a dose of AM (1.83 µmol, 0.4 ml of 3.125 mg/ml AM solution) or an equivalent volume of vehicle (0.4 ml of dH2O) by transoral intratracheal instillation with a 22-gauge stainless steel catheter fitted with a piece of polyethylene tubing, essentially as described by Daniels et al. (12) for hamsters and Taylor et al. (57) for rats. The instillation of drug or vehicle was followed by rapid intratracheal injection of 0.5 ml of air to facilitate deposition of drug or vehicle into the lungs. Except for rats killed on day 1 after receiving a single dose of 1.83 µmol of AM, rats treated on day 0 were allowed to recover for 48 h and then were dosed again on day 2. In preliminary tests to verify that the treatment protocol resulted in distribution of the drug or vehicle in both left and right lobes of the lung, 0.4 ml of 0.1% trypan blue solution followed by 0.5 ml of air was instilled intratracheally into the lungs in the manner described above. After thoracotomy, the presence of blue dye throughout both left and right lobes validated the protocol.Preparation of lung tissue for biochemical and histological
analyses.
At 1 day and 1-5 wk after initial intratracheal instillation, rats
were killed by a lethal injection of pentobarbital sodium (Somnotol;
~300 mg/kg ip). Thoracotomy was performed, and the trachea of each
rat was exposed and cannulated. The right bronchus was then ligated,
and the right lung was removed, wrapped in aluminum foil, snap-frozen
in liquid nitrogen, and stored at 70°C for later analysis of
hydroxyproline content and for Northern and immunoblot analyses. Via
the trachea, the left lung was inflated in situ with 10% neutral
buffered formalin to a pressure of 20 cmH2O for 1 h.
The trachea was then ligated, and the lung was removed and stored in
formalin for 1 wk before histological analysis.
Histological analysis. A disease index was used to quantitate morphological damage by an established protocol (7, 12) in a blinded manner. The hematoxylin- and eosin-stained lung sections were viewed at a magnification of ×200 with an eyepiece grid consisting of 100 equal-sized squares. A square was deemed diseased if it contained evidence of cellular infiltration of the alveolar space or interstitium, thickening of the interstitium, or fibrosis. Squares were not counted more than one time if they contained more than one contributor to disease. The disease index is expressed as the percentage of tissue area exhibiting damage. The number of squares examined per lung section was 7,136 ± 2,512 (SD), and the total number of squares examined per animal was 21,221 ± 5,509.
Lung hydroxyproline determination. The spectrophotometric method of Lindenschmidt and Witschi (32) was used to determine hydroxyproline content. Briefly, an aliquot of right lung tissue (~100 mg) was pulverized in liquid nitrogen and hydrolyzed in 5.0 ml of 6.0 N HCl at 110°C for 72 h. After neutralization with 2.75 ml of 10 N NaOH and oxidation with 0.6 ml of 0.2 M chloramine T, 0.6 ml of Ehrlich's reagent was used to form a chromagen that was measured at 560 nm. Samples from each digest were measured in triplicate. Lung hydroxyproline was not measured in rats killed on day 1.
Probe preparation.
A c-jun DNA template was provided by ISIS Pharmaceuticals
(Carlsbad, CA), and an 18S rRNA DECA probe template was purchased from
Ambion (Austin, TX). The TGF-1 template was purchased as an
Escherichia coli plasmid insert (American Type Culture
Collection, Manassas, VA). Plasmid DNA was extracted using a QIAprep
Spin miniprep kit and restriction digested with BamHI
restriction enzyme for 1 h at 37°C. Radiolabeling of cDNA probes
was carried out from a 25-ng DNA template using a random primer
labeling kit (GIBCO BRL, Life Technologies) with 100 µCi of
[
-32P]dCTP. Unincorporated radiolabeled dCTP was
removed using Quickspin Sephadex columns (Roche Biomedicals, Laval, PQ).
Northern analysis.
Total RNA was isolated from aliquots of frozen right lung tissue (~50
mg) using a QIAGEN RNeasy mini kit and quantified by spectrophotometric
measurement of ultraviolet absorption at 260 nm. Total RNA (10 µg) in
denaturing buffer was electrophoresed on a 1% (wt/vol)
denaturing agarose gel containing 1.1% (vol/vol) formaldehyde. RNA was
transferred from gels to Hybond nylon membranes overnight (Amersham
Pharmacia Biotech) via capillary blotting. Membranes were prehybridized
for 30 min in 8.0 ml of QuikHyb solution (Stratagene, La Jolla, CA) at
68°C, followed by hybridization with 2.4 × 107
counts/min of radiolabeled cDNA probe for 4 h at 68°C.
Hybridized probe was visualized and quantitated using a STORM 820 PhosphorImager (Molecular Dynamics, Sunnyvale, CA). Membranes were
stripped of bound probe, and the hybridization was repeated with each
of the other probes. mRNA was quantitated as the ratio of
c-jun or TGF-1 band intensities to 18S band intensity.
Because RNA from different time points was analyzed on different
membranes, data are expressed as a percentage of control in the
following manner: mean ± SD was calculated for control and
treatment groups at each time point; the mean value for control at each
time point was assigned a value of 100%; and all other values (control
SD, AM group mean and SD) were adjusted accordingly.
Immunoblot analysis.
Approximately 50 mg of frozen right lung tissue were minced manually
with scissors in 1.5 ml of lysis buffer [20 mM HEPES solution, pH 7.9, 100 mM KCl, 0.1 mM EGTA, 0.1 mM EDTA, 1% (vol/vol) Triton X-100, 0.5%
(wt/vol) sodium deoxycholate, 10 mM DTT, 0.5 mM PMSF, 1 µg/ml leupeptin, and 1 µg/ml aprotinin]. The suspension was
homogenized with a Polytron (Brinkmann Instruments, Westbury, NY) and
centrifuged at 1,000 g for 15 min, and the pellet was discarded. Protein concentration was determined using the Bradford assay (Bio-Rad). Proteins were separated by SDS-PAGE on 10% gels for
c-Jun (40 µg/lane) and 16.5% gels for TGF-1 (20 µg/lane) and
were transferred to polyvinylidene difluoride membranes (Amersham Pharmacia Biotech). Membranes were incubated at room temperature for
1 h with primary antibody against c-Jun (1:1,250; BD Transduction Laboratories, Franklin Lakes, NJ) or TGF-
1 (1:1,000; R&D Systems, Minneapolis, MN), followed by incubation at room temperature for 1 h with secondary antibody (goat anti-mouse IgG conjugated to horseradish peroxidase; Bio-Rad) in a dilution of 1:3,000 (for c-jun) or 1:1,000 (for TGF-
1) in 5%
(wt/vol) skim milk in Tris-buffered saline-Tween.
Immunoreactive bands were visualized by enhanced chemiluminescence
(ECL) using a Lumi-GLO ECL kit (Kirkegaard & Perry Laboratories,
Gaithersburg, MD), and quantitation of bands was performed using a
FluorChem (Alpha Innotech, San Leandro, CA) chemiluminescence imager.
Membranes were stained with Coomassie blue, and a common arbitrary band
(whose linearity with respect to protein content was confirmed) was
quantitated and used to normalize for loading variations in the same
manner as described for the Northern blot procedure.
Immunohistochemistry.
Detection of c-Jun and TGF-1 distribution in lung tissue was
performed with c-Jun/AP-1 polyclonal rabbit IgG (Oncogene Science, Boston, MA) and TGF-
1 polyclonal rabbit IgG (Santa Cruz
Biotechnology, Santa Cruz, CA) antibodies. Lung sections from control
and AM-treated animals at the same time point were processed together
on the same microscope slides. After rehydration, 5-µm lung sections were incubated in 0.3% (vol/vol) hydrogen peroxide in PBS at room temperature to quench endogenous peroxidase activity, followed by a
30-min incubation in 0.1% (wt/vol) pepsin in 0.01 N HCl
at 37°C to permeabilize cell membranes and expose epitopes. Sections were incubated with either c-Jun (1:25) or TGF-
1 (1:500) primary antibodies diluted in 3% (vol/vol) normal goat serum (NGS) and 1%
(wt/vol) BSA overnight at 4°C. Sections were then
incubated for 1 h in secondary antibody (1:200 biotinylated goat
anti-rabbit IgG; Vector Laboratories, Burlington, ON) at room
temperature, followed by incubation for 1 h with an avidin-biotin
complex reagent (Vector Laboratories). Immunoperoxidase staining was
developed using a diaminobenzidine peroxidase substrate kit
(Vector Laboratories). Negative controls were prepared by
replacing the primary antibodies with either nonimmune rabbit IgG or
3% NGS-1% BSA.
Data analysis. Data were analyzed by two-way ANOVA and the Student-Newman-Keuls multiple-comparison post hoc test. In all cases, P < 0.05 was considered statistically significant. All data are expressed as group means ± SD.
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RESULTS |
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Development of AM-induced pulmonary fibrosis in the Fischer 344 rat.
Throughout the first week, AM-treated animals had significantly lower
body weights than did vehicle-treated animals, with decreases ranging
from 5 to 20%. From 2 to 5 wk posttreatment, however, no difference in
body weight was observed between the two treatment groups. Mean right
lung weight of AM-treated animals 1-5 wk postdrug was
significantly higher than that of vehicle-treated animals by ~26, 19, 12, 12, and 13%, respectively. An approximately 30% increase in right
lung hydroxyproline content in AM-treated rats was found 4 and 5 wk
posttreatment (Fig. 1).
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Analysis of gene expression.
Although lung c-jun mRNA content of AM-treated animals
appeared elevated relative to that in control animals (~1.7-fold) at 5 wk post-AM treatment (Fig. 4), this
increase did not reach the level of statistical significance
(P = 0.08). Nonetheless, lung c-Jun protein was
significantly elevated in AM-treated animals 5 wk posttreatment
~3.3-fold (Fig. 5). Lung TGF-1 mRNA
was upregulated ~1.8-, 1.6-, and 1.8-fold at 1 day, 1 wk, and 2 wk
post-AM treatment, respectively, relative to control values (Fig.
6). TGF-
1 protein was elevated
~1.8-fold at 1 day post-AM treatment and 1.5-fold at both 1 and 2 wk
post-AM treatment (Fig. 7).
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Distribution of c-Jun and TGF-1 protein.
Immunohistochemical analysis revealed that both c-Jun and TGF-
1 were
expressed widely throughout lung tissue. No obvious change in
distribution of immunoreactivity was observed between the lungs of
vehicle and AM-treated animals at the time points when increased gene
expression was found via Northern and immunoblot analyses.
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DISCUSSION |
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In the present study, intratracheal administration of AM to Fischer 344 rats resulted in a patchy interstitial fibrosis that closely resembled that seen in human AIPT and in previously reported rat (48, 49, 57) and hamster (7, 8, 12, 31) models. Particularly at 1 day and up to 3 wk post-AM, lung histology revealed evidence of inflammation, with infiltration of macrophages, neutrophils, monocytes, and some eosinophils into the alveolar spaces accounting for the increase in disease index. The ~30% elevation in lung hydroxyproline content at 4 and 5 wk post-AM treatment is consistent with the increased collagen content found in animal models of AIPT (8, 12, 57). Although the intratracheal instillation of AM does not mimic delivery of the drug to the lung as it occurs clinically during systemic AM therapy, it does produce histopathological changes resembling clinical AIPT in humans (33). Although oral and intravenous administration of AM to experimental animals can produce phospholipidosis in the lung as observed in humans, pulmonary fibrosis does not develop in the animals (4).
The present study indicated an increase in pulmonary c-jun expression that was concurrent with the onset of fibrosis in the AM-treated Fischer 344 rats. The observed elevation in c-Jun protein without a concomitant increase in mRNA at 5 wk post-AM could be attributable to increased c-Jun NH2-terminal kinase (JNK) activity, which would serve to increase the stability of the protein (63). It appears that enhanced c-jun expression does not occur during the early inflammatory phase after AM. This does not necessary preclude a role for c-Jun in AM-induced inflammation, since there is evidence that JNKs contribute to inflammatory processes (45, 61). However, the relevance of these observations to in vivo pulmonary inflammation apparently has not been investigated. Evidence from other animal models suggests that activation of the p38 mitogen-activated protein kinase pathway (37, 59) may also play a role in chemically induced pulmonary inflammation and fibrosis, but its relevance to AIPT has not been investigated.
The co-occurrence of increased c-jun expression with the
onset of AM-induced fibrosis is consistent with observations in a rat
model of crocidolite asbestos-induced pulmonary fibrosis
(44) and implicates c-Jun in the progression of the
fibrotic process, presumably as a component in the signaling pathways
of profibrogenic factors. Relevant factors documented to induce
c-jun (and JNK) activity include IL-1 (28, 36),
TNF- (56), reactive oxygen species (27),
and PDGF (51). Although in vitro incubation of activated
alveolar macrophages with AM has been documented to increase the
release of at least two of these factors, IL-1 (15, 62)
and TNF-
(15, 47), the relevance to in vivo AM exposure
remains unclear. The actions of c-Jun in pulmonary fibrosis are likely
related to its regulation of cellular growth and proliferation
(25, 29) and tissue remodeling related to collagen
turnover, inducing both type I procollagen (2, 10) and
collagenase (18, 34) gene expression via AP-1 promoter binding.
The immunohistochemical results from the present study demonstrated no differences in the staining pattern for c-Jun between normal and fibrotic lungs. Thus the increase in c-Jun protein revealed by immunoblotting was likely not a result of novel cell types expressing c-Jun. The observation that c-Jun appears to be most abundant in type II pneumocytes and macrophages is similar to observations of the distribution of lung c-Jun in a rat model of bleomycin-induced pulmonary fibrosis (20).
TGF-1 induction was observed in lung at 1 day, 1 wk, and 2 wk
post-AM treatment, followed by a return to control levels. This adds to
the results of Reinhart and Gairola (48), who noted a
nonsignificant trend toward increased TGF-
1 expression in
bronchoalveolar lavage fluid 1-3 wk post-AM in Fischer 344 rats.
The early induction of TGF-
1 is consistent with data demonstrating
that TGF-
production precedes both total collagen synthesis
(24) and expression of collagen I and III genes in animal
models of pulmonary fibrosis induced by asbestos (5) and
bleomycin (22, 41) and by overexpression of TNF-
(55). However, some investigators have reported that secretion of TGF-
1 from macrophages after lung injury remains elevated throughout the entire fibroproliferative process, suggesting a
positive feedback cycle that increases production of TGF-
1 by
activated cells (53).
Increased TGF-1 expression may account for the increase in IL-1
secretion by AM-exposed macrophages (15), since TGF-
1 has been implicated as a regulator of IL-1
expression in at least some lung cell types (26). Also, the increase in TNF-
secretion observed after AM exposure both in vitro (15,
47) and in vivo (48) may in part be responsible for
the increase in TGF-
1 expression. Numerous investigators have
reported that profibrotic actions of TNF-
require TGF-
1
expression (41, 55).
At sites of lung inflammation and injury, numerous resident and
recruited cell types, including activated macrophages, eosinophils, platelets, epithelial cells, and fibroblasts, release TGF-1
(16, 64). It appears that, in the rat model of AIPT, type
II pneumocytes and macrophages are major sources of TGF-
1, possibly
reflecting roles in recruitment of inflammatory cells and proliferation
of fibroblasts (21, 43, 60) in response to lung injury.
Although both c-jun and TGF-1 have separately been
implicated in the pathogenesis of pulmonary fibrosis, they could work both in concert and independently in the development of AM-induced pulmonary fibrosis. On the basis of results of the present study and
evidence in the literature, the following is a proposed pathogenesis of
AIPT: 1) intratracheal administration of AM produces an
initial cytotoxic insult to the lungs, damaging epithelial cells that subsequently release mediators and chemotactic factors; 2)
inflammatory cells infiltrate the interstitium of lungs and alveolar
spaces from the bloodstream and release TGF-
1 and other cytokines
and chemotactic factors; 3) alveolar macrophages and
epithelial cells release TGF-
1, resulting in proliferation of
fibroblasts and increased production of extracellular matrix components
(fibronectin, elastin, collagen) and inhibition of extracellular matrix
degrading proteases; and 4) c-jun is induced by
factors that require AP-1 DNA binding in their signaling pathways,
leading to proliferation of fibroblasts and induction of both collagen
and collagenase gene expression that initiates tissue remodeling
contributing to pulmonary fibrosis.
In conclusion, the current study demonstrates temporally distinct
induction of the nuclear transcription factor c-Jun and the growth
factor TGF-1 during AM-induced pulmonary fibrosis in Fischer 344 rats. These findings point to a possible direction in the development
of novel therapeutic strategies for prevention or treatment of AIPT via
manipulation of gene expression or gene products.
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ACKNOWLEDGEMENTS |
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We thank ISIS Pharmaceuticals for supplying the rat c-jun cDNA used in probe synthesis and Drs. M. D. Taylor and M. J. Reasor at the University of West Virginia for helpful advice in the establishment of the rat model of amiodarone-induced pulmonary toxicity.
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FOOTNOTES |
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This work was supported by Canadian Institutes of Health Research Operating Grant MT-13257.
Address for reprint requests and other correspondence: T. E. Massey, Dept. of Pharmacology and Toxicology, Rm. 535, Botterell Hall, Queen's Univ., Kingston, ON, Canada K7L 3N6 (E-mail: masseyt{at}post.queensu.ca).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 1 March 2001; accepted in final form 6 July 2001.
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