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to Rat Lung Induces Severe Pulmonary Inflammation and Patchy Interstitial Fibrogenesis with Induction of Transforming Growth Factor-ß1 and Myofibroblasts
From the Rayne Laboratory,*
Respiratory Medicine Unit,
University of Edinburgh, Edinburgh, Scotland, and Departments of
Biology
and
Pathology,
McMaster University, Hamilton,
Ontario, Canada
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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is up-regulated in a variety of different
human immune-inflammatory and fibrotic pulmonary pathologies.
However, its precise role in these pathologies and, in
particular, the mechanism(s) by which it may induce
fibrogenesis are not yet elucidated. Using a replication-deficient
adenovirus to transfer the cDNA of tumor necrosis factor- to rat
lung, we have been able to study the effect of transient but
prolonged (7 to 10 days) overexpression of tumor necrosis factor- in
normal adult pulmonary tissue. We have demonstrated that local
overexpression resulted in severe pulmonary inflammation with
significant increases in neutrophils, macrophages, and
lymphocytes and, to a lesser extent,
eosinophils, with a peak at day 7. By day 14, the
inflammatory cell accumulation had declined, and fibrogenesis
became evident, with fibroblast accumulation and deposition of
extracellular matrix proteins. Fibrotic changes were patchy but
persisted to beyond day 64. To elucidate the mechanism underlying this
fibrogenesis, we examined bronchoalveolar fluids for the
presence of the fibrogenic cytokine transforming growth factor-ß1 and
tissues for induction of -smooth muscle actin-rich myofibroblasts.
Transforming growth factor-ß1 was transiently elevated from day 7
(peak at day 14) immediately preceding the onset of fibrogenesis.
Furthermore, there was a striking accumulation of
myofibroblasts from day 7, with the most extensive and intense
immunostaining at day 14, ie, coincident with the
up-regulation of transforming growth factor-ß1 and onset of
fibrogenesis. Thus, we have provided a model of tumor necrosis
factor--mediated pulmonary inflammation and fibrosis in normal adult
lung, and we suggest that the fibrogenesis may be mediated by
the secondary up-regulation of transforming growth factor-ß1 and
induction of pulmonary myofibroblasts.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF-)
is a pleiotropic cytokine. It has been detected in a variety of human
pulmonary diseases, but its role in these pathologies is not well
understood. Based on its in vitro effects on leukocyte
activation, adhesion molecule expression, and endothelial cell biology,
it is also likely to have proinflammatory activities in
vivo.1
In addition, it may have fibrogenic potential,
given that it is both mitogenic and chemotactic for
fibroblasts,2
although its effects on collagen gene
expression are inhibitory.3
Clearly, however, up-regulation
of TNF- in vivo does not always result in the same
biological outcome. In particular, TNF- is detected in many
inflammatory and immune diseases that resolve without tissue
fibrosis,1,4
yet in other pathologies TNF- up-regulation
is associated with fibrotic sequelae.5,6
Whether these
outcomes depend directly on TNF- or indirectly on induction of other
bioactive molecules, particularly the cytokines and growth factors,
from both immune-inflammatory and structural cells remains unclear.
To investigate the functional activities of local pulmonary
overexpression of TNF- in lung, we have chosen to exploit a
transient gene transfer approach using a replication-deficient
recombinant adenovirus vector to transfer the cDNA of murine TNF- to
the respiratory epithelium. Using similar cytokine-expressing
adenovectors under control of high-efficiency constitutive promoters,
we and others have shown that after intratracheal administration, the
vectors infect respiratory epithelium and result in local and
transient, but sustained, production of their transgene protein in the
background of a normally developed adult lung.7-9
This is likely to mimic the type of cytokine up-regulation seen in
human immune and inflammatory pulmonary pathologies.
Using this gene transfer approach we have been able to demonstrate that
transient local overexpression of high levels of TNF- in adult rat
lung results in intense pulmonary accumulation of neutrophils,
macrophages, and lymphocytes and, to a lesser extent, eosinophils over
2 to 10 days without gross distortion of the lung architecture. This is
followed by the development of patchy interstitial fibrogenesis,
associated with significant increases in transforming growth
factor-ß1 (TGF-ß1) protein and accumulation of myofibroblasts.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A replication-deficient recombinant adenovirus expressing
full-length murine TNF- cDNA under control of an efficient murine
cytomegalovirus promoter and with the interferon-
-secretory leader
sequence was used to locally overexpress TNF- in the lung. Its
construction and demonstration of release of the secreted form of
TNF- have been previously described.10
This vector or a
control vector with identical deletions (AdDL70-3)11
at a dose of 109
plaque-forming units in 300 µl of
phosphate-buffered saline was instilled intratracheally to anesthetized
Sprague Dawley rats weighing 220 to 280 g. All animal experiments
were approved by the McMaster University Animal Ethics Committee. Rats
were provided with food and water ad libitum and were
examined at 1, 3, 7, 14, 21, 28, or 64 days. Blood was taken from the
abdominal aorta, and bronchoalveolar lavage (BAL) was performed as
previously described.8
BAL total cell counts were
determined using a hematocytometer. Differential cell counts were
performed on cytospins stained with Diff-Quik (Baxter, McGaw Park, IL)
by randomly counting 500 cells/cytospin. Three to five animals per
group were evaluated. BAL fluid and sera were stored at -20°C until
TGF-ß1 and TNF- levels were determined in BAL fluid and
serum as described below.
TNF- and TGF-ß Measurements
Concentrations of TNF- in BAL fluid and serum were determined
using a commercial enzyme-linked immunosorbent assay (ELISA) kit
specific for murine and rat TNF- (R&D Systems, Minneapolis, MN) with
a sensitivity of 5 pg/ml. TGF-ß1 in BAL fluid was measured using a
commercial human TGF-ß1 ELISA kit that efficiently detects rat
TGF-ß1 protein due to the high homology of TGF-ß1 across species
(R&D Systems). The assay detects only the active form of TGF-ß1, and
samples were activated before measurement according to the
manufacturer's instructions. The sensitivity of this kit is 5 pg/ml.
Analysis was performed on samples from three to six animals per group.
Lung Fixation and Histological Examination
Lungs were removed and fixed by perfusion with neutral buffered formaldehyde before routine processing and paraffin embedding. Multiple sections from each lobe were stained with hematoxylin and eosin or Elastic van Gieson, a specific histochemical stain for collagen and elastin. Lungs from three to six rats per time point were examined.
Immunohistochemical Staining for -Smooth Muscle Actin
Lung tissue sections were deparaffinized, and endogenous
peroxidase was blocked. Sections were then treated with blocking goat
serum for 30 minutes and were incubated for 16 hours with a monoclonal
anti--smooth muscle actin (-SMA) antibody (Sigma Chemical Co.,
St. Louis, MO) at a dilution of 1:100. Control sections were treated
with control mouse immunoglobulin G. Sections were then incubated for
15 minutes with biotinylated goat anti-mouse immunoglobulin
(Histostain-SPTM Bulk Kit; Zymed Labororatories, Inc., San Francisco,
CA) and treated for 10 minutes in streptavadin-peroxidase conjugate.
Finally, they were placed in a substrate chromogen mixture, and color
was allowed to develop for 15 minutes before counterstaining with
Mayer's hematoxylin.
Data Analysis
Data are expressed as means ± standard error of the mean (SEM). Statistical analysis was performed using an unpaired t-test. The difference was considered statistically significant when P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Protein Expression in Vivo after TNF-
Gene Transfer to the Lung
To assess the effects of local overexpression of TNF- in lung
tissue, AdTNF- or control virus AdDL70-3 was injected
intratracheally into rat lung. TNF- protein expression in lung was
then examined at various time points by assaying BAL fluid by ELISA. In
rats infected with AdTNF-, TNF- protein expression was high
between days 1 and 7, peaked at day 3 (154.9 ± 45.3 ng/ml), and
rapidly declined by day 14 (Figure 1)
. In
comparison, levels of TNF- induced by the control virus were very
low, with a peak also at day 3 (0.14 ± 0.12 ng/ml) (data not
shown). These differences between AdTNF-- and AdDL70-3-infected rats
were highly significant P < 0.0001 at day 3 and
P = 0.0062 at day 7. To confirm that the transgene
product was largely compartmentalized in the lung, sera were taken at
various time points and assayed by ELISA for TNF- protein. TNF-
was not detected in sera of any rats infected with control virus. In
rats infected with AdTNF-, TNF- protein was detected in animals
only at days 1 and 3, and levels were about 100- to 300-fold lower
than in the BAL fluid, ie, 0.21 ± 0.051 ng/ml at day 1 and
0.53 ± 0.06 ng/ml at day 3.
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Gene Transfer to
the Lung
To assess the cellular responses after overexpression of TNF-
in the lung, total and differential cell counts in BAL fluid were
quantitated at a variety of time points. Infection with the control
vector resulted in low levels of neutrophilia at day 1 and,
subsequently, a small increase in the number of macrophages and
lymphocytes at day 7 (Figure 2A
/B). In
contrast, infection with AdTNF- resulted in a dramatic accumulation
of neutrophils, macrophages (Figure 2A)
, and lymphocytes in the BAL
fluid (Figure 2B)
. Cell accumulation was evident from day 3 but was
most significant at day 7, when, compared with control vector-treated
rats, AdTNF--treated rats demonstrated a 39-fold increase in
neutrophils, a 6-fold increase in macrophages, and a 17-fold increase
in lymphocytes. There was also a small increase in eosinophils. The
cellular accumulation resolved thereafter. Neutrophil and macrophage
numbers returned toward those observed in rats infected with control
virus by day 14, and lymphocytes numbers returned to control levels by
day 21.
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Gene Transfer to the Lung
Rats infected with control virus appeared healthy, and microscopic
examination showed some minor inflammatory changes with a few
neutrophils and mononuclear cells in the perivascular and peribronchial
areas at days 1, 3, and 7. These inflammatory changes did not extend
into the alveolar spaces or septae beyond, and they rapidly cleared
with no evidence of tissue remodeling or fibrosis, similar to the
minimal changes seen with a second control vector expressing the marker
gene ß-galactosidase.8
In contrast, rats receiving
AdTNF- lost weight and appeared lethargic. Macroscopically, areas of
consolidation were evident at early time points. Microscopic
examination of their lungs revealed widespread and severe inflammatory
changes beginning 24 hours after infection, when there was accumulation
of neutrophils in the alveolar spaces and of neutrophils and
mononuclear cells in the interstitium, particularly in perivascular and
peribronchial areas (data not shown). These changes were much more
severe than in control vector-treated rats. By day 3, accumulation of
inflammatory cells was more pronounced (Figure 3A)
, and by day 7, in keeping with the
kinetics of cell accumulation in the BAL fluid, there was intense
tissue inflammation with dramatic accumulation of neutrophils and
mononuclear cells, particularly in perivascular and peribronchial
areas, but extending widely throughout the parenchyma right up to the
pleural surface (Figure 3B)
. The alveolar septae were expanded by
infiltrated inflammatory cells, but the general tissue architecture was
maintained. Only a few eosinophils were observed. By day 14, the tissue
neutrophilia had resolved while there was still accumulation of
perivascular and peribronchial mononuclear cells, although this was
much less severe than at day 7. However, at this time point, there was
thickening of some alveolar walls and emergence of areas of
interstitial fibrosis with accumulation of fibroblasts and destruction
of normal tissue architecture (Figure 3C)
. Deposition of disorganized
collagen and elastic fibers was evident on Elastic van Gieson staining
(Figure 3D)
. Inflammation had greatly declined by day 21, but some
patchy fibrotic changes persisted, with areas of fibrosis scattered
throughout the parenchyma, sometimes reaching the pleural surface.
These fibrotic changes persisted up to day 64 (Figure 3E)
, when there
was deposition of more organized collagen and elastin fibers.
Inflammatory changes had largely resolved by this point.
|
Gene Transfer to
the Lung
To help address the mechanism of TNF--induced interstitial
fibrosis, we examined the content of TGF-ß1 in BAL fluid by ELISA. We
and others have shown TGF-ß1 to be a key fibrogenic cytokine in the
lung.7,12
Increased levels of TGF-ß1 were evident in
AdTNF--treated rats from day 3 with a peak at day 14
(P = 0.0057, AdTNF- compared with control)
and a decrease back toward control levels by day 64 (Figure 4)
. No such increase in TGF-ß1 was
observed in control vector-infected rats.
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Gene
Transfer to the Lung
The myofibroblast is a fibroblast-like cell characterized by the
expression of -SMA13
and is thought to be important in
fibrogenesis and wound healing.14
To assess whether TNF-
overexpression resulted in the generation of myofibroblasts during the
fibrogenic process, we examined lung tissues for induction of
-SMA-expressing myofibroblasts using a monoclonal antibody directed
against -SMA. In control vector lungs and in lungs of
AdTNF--infected rats, immunostaining of bronchial wall and vascular
smooth muscle was observed as expected. There was no other
immunostaining in control virus-treated animals at any time points. In
AdTNF--treated rats, there was no increase in -SMA immunostaining
above control virus-infected animals at day 3 (Figure 5A)
; however, by day 7, immunostaining of
fibroblastic cells was evident widely throughout the parenchyma (Figure 5B)
. By day 14, when fibrogenesis was evident, there was intense and
extensive immunostaining of fibroblastic cells in fibrotic foci within
the interstitium (Figure 5C)
. Immunostaining within these fibrotic
areas persisted up to day 64, although it was not as extensive or
intense as it had been on day 14 (Figure 5D)
. The fibroblast-like cells
staining for -SMA also immunostained with an antibody directed
against vimentin. This confirmed that these cells were myofibroblasts
and not smooth muscle cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is an "early-wave" alarm-type cytokine. It appears to
be up-regulated soon after injury in a number of tissues including
lung, and increased TNF- expression has certainly been documented in
a wide variety of different human pulmonary diseases and animal models.
However, our understanding of its precise role, particularly in the
process of pulmonary fibrogenesis, is poorly understood. An effective
strategy of assessing the role of any cytokine in vivo is to
locally overexpress it in a tissue-specific manner, and there are
several ways to achieve this. Administration of recombinant cytokines
is one possibility. Using this approach, Ulich et al15
administered recombinant TNF- to rat lung and demonstrated induction
of moderate neutrophilia, which resolved within 48 hours, leaving no
evidence of permanent tissue damage. An alternative strategy is to
develop a tissue-specific transgenic animal model, and using this
approach, Miyazaki et al16
reported their findings in a
transgenic model in which TNF- gene expression was driven from the
lung-specific SP-C promoter. In contrast to the recombinant protein
experiments, these mice developed an early lymphocytic alveolitis,
followed later by a fibrogenic response. Although both of these
approaches provide useful information on the in vivo
biological effects of TNF-, they may not accurately reflect the type
of overexpression seen in adult human disease, in which TNF-
up-regulation is likely to be more prolonged than in experiments using
recombinant proteins, but shorter than the lifelong overexpression of
genetic transgenics. In addition, unlike the permanent transgenic
models in which abnormal lung development can occur as a consequence of
transgene overexpression in utero, most adult lung disease
occurs in the background of a normally developed
lung.16,17
To overcome some of these problems and to
examine the role of TNF- overexpression in normal adult lung, we
chose a transient transgenic approach using a replication-deficient
adenovirus.10
We demonstrated that delivery of the
adenoviral gene transfer vector resulted in high levels of transgene
overexpression with a peak at day 3 and a rapid decline after 7 days.
This induced rapid and intense accumulation of neutrophils,
macrophages, and lymphocytes from 24 hours. Inflammation in both BAL
fluid and tissue was maximal at day 7, ie, shortly after the peak of
transgene protein expression. Inflammation thereafter started to
resolve, although inflammatory changes were still evident at days 21
and 28, long after transgenic protein was no longer detectable. The
inflammatory changes were most severe in the peribronchial areas,
likely reflecting the high concentrations of transgene protein in these
areas. However, these changes also spread throughout the parenchyma up
to the pleural surface, either as a result of diffusion of the cytokine
itself, or more likely by TNF--mediated induction of other
inflammatory cytokines such as interleukin-8, granulocyte-macrophage
colony-stimulating factor, or macrophage chemotactic protein-1 from
adjacent cells in a paracrine fashion.18,19
The
neutrophilia in this model was more severe than in either the
recombinant protein or transgenic models, perhaps because of higher
local tissue concentrations of TNF-. Lymphocytic accumulation was a
notable feature in the transgenic model, as in the present study, but
increases in the number of macrophages seem specific to our model. The
mechanisms of this TNF--mediated accumulation of neutrophils,
lymphocytes, macrophages, and eosinophils are likely to involve both
direct effects of TNF- itself on regulation of adhesion molecule
expression and induction of other cytokines and growth factors capable
of mediating leukocyte chemotaxis and survival.1
After the
intense inflammation in the tissue, there was evidence of a fibrogenic
response. This was evident from day 14, when there was
accumulation of fibroblasts and deposition of both collagen and
elastin. The destruction of normal lung architecture and the
persistence of these changes to day 64 likely indicate that this
fibrogenesis is, at least in part, irreversible. Certainly, TNF- has
been shown to be up-regulated in a number of fibrotic human and animal
pulmonary pathologies,5,6,20,21
and there is evidence that
inhibiting early TNF- expression with either anti-TNF- antibodies
or TNF- antagonists inhibits fibrogenesis.22,23
Equally,
however, TNF- up-regulation has been documented in other
inflammatory and immune lung pathologies in which normal lung repair
processes ensue without evidence of fibrotic reactions.1
This raises the question of the precise role of TNF- in
vivo during pulmonary fibrogenesis and whether TNF- may be
acting indirectly through up-regulation of other fibrogenic molecules
during pathological processes with a fibrotic sequela. In particular,
it appears that TGF-ß1 is up-regulated in many of the pathologies in
which TNF- is associated with fibrosis but not in those where
TNF- expression results in immune-inflammatory damage without a
fibrotic outcome.5,24,25
To address this hypothesis, we
examined the AdTNF--infected animals for up-regulation of TGF-ß1
protein and found increased protein synthesis from day 3, with a peak
around day 7 to 14, immediately preceding the onset of fibrogenesis. To
further investigate the mechanism of the fibrogenesis in this
model, we then examined tissue for induction of -SMA-expressing
myofibroblasts. Myofibroblasts have been demonstrated in a variety of
fibrotic and repairing tissues14,26
and have been shown to
be the major cells producing procollagen mRNA in the bleomycin model of
fibrosis.27
In the AdTNF--treated rats, aside from the
expected immunopositive bronchial and vascular smooth muscle, we found
-SMA and vimentin-immunopositive fibroblast-like cells from day 7
scattered widely throughout the parenchyma. By day 14, there was
intense immunostaining within fibroblast-like cells in the fibrotic
foci, and staining persisted to day 64 although, its intensity and
extent were lessened. Interestingly, in the studies of Rubbia-Brandt et
al,28
in which TNF- was administered subcutaneously by
osmotic minipump, fibroblast accumulation occurred, but there was no
evidence of induction of myofibroblasts and minimal collagen
deposition, suggesting that TNF- overexpression alone is
insufficient to generate myofibroblasts.28
In contrast,
overexpression of TGF-ß1 in lung or skin results in induction of many
-SMA-rich myofibroblasts and extensive collagen
deposition.7,29
These data suggest that in the present
model, induction of myofibroblasts may be secondary to the increased
TGF-ß1 protein rather than to a direct effect of TNF-. Certainly,
the temporal association of increased TGF-ß1 and induction of
myofibroblasts at days 7 to 14 would support this concept.
Interestingly, in the transgenic study of Miyazaki et al,16
no evidence of TGF-ß gene activation was found, and there was no
induction of myofibroblasts. However, only late time points, after
fibrogenesis was established, were examined. The cellular origin of the
TGF-ß1 in this current model is under investigation. In other
fibrogenic models, macrophages,30,31
eosinophils,32
and tissue structural cells1
have all been shown to be important sources, and it is therefore
noteworthy that macrophage and eosinophil numbers are increased early
in our model. It is interesting to note that based on our own studies
of adenovector-mediated overexpression of other fibrogenic cytokines,
including TGF-ß1,7
granulocyte-macrophage
colony-stimulating factor,33
and now TNF-, there appears
to be a correlation between the levels of TGF-ß1, the extent of
myofibroblast induction, and fibrosis. Specifically, in the TGF-ß1
model, TGF-ß1 levels are very high, myofibroblasts are very numerous,
and fibrosis is severe, but in the TNF- model, levels of TGF-ß1
are lower; myofibroblast induction is less than in the TGF-ß1 model,
especially at later time points; and fibrosis is correspondingly less
severe. The granulocyte-macrophage colony-stimulating factor model lies
intermediately between the other models in all three parameters:
TGF-ß1 induction, myofibroblast presence, and fibrosis.34
In conclusion, our study has provided evidence that in normal adult
lung, transient overexpression of TNF- results in intense but
transient inflammation and patchy interstitial fibrosis associated with
induction of TGF-ß1 and myofibroblasts.
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Acknowledgements |
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Footnotes |
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Supported by the Medical Research Council (Canada) and the Norman Salvesen Emphysema Research Trust (United Kingdom). PJS is a Parker B. Francis Fellow.
Accepted for publication June 26, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Nature 1987, 329:630-632[Medline]
. Gene Ther 1997, 4:1181-1188[Medline]
-smooth muscle actin is transiently expressed by myofibroblasts during experimental wound healing. Lab Invest 1990, 63:21-29[Medline]
transgene in murine lung causes lymphocytic and fibrosing alveolitis: a mouse model of progressive pulmonary fibrosis. J Clin Invest 1995, 96:250-259
, LPS, and IL-1ß. Science 1989, 243:1467-1469 and its mRNA in idiopathic pulmonary fibrosis. Am J Pathol 1993, 143:651-655[Abstract]
and IL-6 in the lungs of pneumoconiosis patients. Am J Respir Crit Care Med 1995, 152:298-306[Abstract]
cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J Exp Med 1989, 170:655-663. Am J Respir Crit Care Med 1995, 152:2163-2169[Abstract]
-smooth muscle actin containing myofibroblasts. Virchows Arch B Cell Pathol 1991, 60:73-82[Medline]
-smooth actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 1993, 122:103-111This article has been cited by other articles:
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J. Gauldie, T. Galt, P. Bonniaud, C. Robbins, M. Kelly, and D. Warburton Transfer of the Active Form of Transforming Growth Factor-{beta}1 Gene to Newborn Rat Lung Induces Changes Consistent with Bronchopulmonary Dysplasia Am. J. Pathol., December 1, 2003; 163(6): 2575 - 2584. [Abstract] [Full Text]
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F. Huaux, T. Liu, B. McGarry, M. Ullenbruch, Z. Xing, and S. H. Phan Eosinophils and T Lymphocytes Possess Distinct Roles in Bleomycin-Induced Lung Injury and Fibrosis J. Immunol., November 15, 2003; 171(10): 5470 - 5481. [Abstract] [Full Text] [PDF]
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S. Tajima, K. Oshikawa, S.-i. Tominaga, and Y. Sugiyama The Increase in Serum Soluble ST2 Protein Upon Acute Exacerbation of Idiopathic Pulmonary Fibrosis Chest, October 1, 2003; 124(4): 1206 - 1214. [Abstract] [Full Text] [PDF]
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N. Kaminski, J. A. Belperio, P. B. Bitterman, L. Chen, S. W. Chensue, A. M.K. Choi, S. Dacic, J. H. Dauber, R. M. du Bois, J. J. Enghild, et al. Idiopathic Pulmonary Fibrosis Am. J. Respir. Cell Mol. Biol., September 1, 2003; 29(3): S1 - 105. [Full Text] [PDF]
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P. F. Piguet and J. Gauldie Inflammation in idiopathic pulmonary fibrosis Am. J. Respir. Crit. Care Med., April 1, 2003; 167(7): 1037 - 1037. [Full Text]
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G. S. Warshamana, D. A. Pociask, P. Sime, D. A. Schwartz, and A. R. Brody Susceptibility to Asbestos-Induced and Transforming Growth Factor-{beta}1-Induced Fibroproliferative Lung Disease in Two Strains of Mice Am. J. Respir. Cell Mol. Biol., December 1, 2002; 27(6): 705 - 713. [Abstract] [Full Text] [PDF]
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 D. L. Mann Inflammatory Mediators and the Failing Heart: Past, Present, and the Foreseeable Future Circ. Res., November 29, 2002; 91(11): 988 - 998. [Abstract] [Full Text] [PDF]
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D. N. Cook, D. M. Brass, and D. A. Schwartz A Matrix for New Ideas in Pulmonary Fibrosis Am. J. Respir. Cell Mol. Biol., August 1, 2002; 27(2): 122 - 124. [Full Text] [PDF]
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J. C. Bonner, A. B. Rice, J. L. Ingram, C. R. Moomaw, A. Nyska, A. Bradbury, A. R. Sessoms, P. C. Chulada, D. L. Morgan, D. C. Zeldin, et al. Susceptibility of Cyclooxygenase-2-Deficient Mice to Pulmonary Fibrogenesis Am. J. Pathol., August 1, 2002; 161(2): 459 - 470. [Abstract] [Full Text] [PDF]
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 Y. Yang, C. McKerlie, S. H. Borenstein, Z. Lu, M. Schito, J. W. Chamberlain, and M. Buchwald Transgenic Expression in Mouse Lung Reveals Distinct Biological Roles for the Adenovirus Type 5 E1A 243- and 289-Amino-Acid Proteins J. Virol., July 29, 2002; 76(17): 8910 - 8919. [Abstract] [Full Text] [PDF]
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H. Matsuoka, T. Arai, M. Mori, S. Goya, H. Kida, H. Morishita, H. Fujiwara, I. Tachibana, T. Osaki, and S. Hayashi A p38 MAPK inhibitor, FR-167653, ameliorates murine bleomycin-induced pulmonary fibrosis Am J Physiol Lung Cell Mol Physiol, July 1, 2002; 283(1): L103 - L112. [Abstract] [Full Text] [PDF]
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T. R. Meusel, K. E. Kehoe, and F. Imani Protein Kinase R Regulates Double-Stranded RNA Induction of TNF-{alpha} But Not IL-1{beta} mRNA in Human Epithelial Cells J. Immunol., June 15, 2002; 168(12): 6429 - 6435. [Abstract] [Full Text] [PDF]
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P. J. Margetts, M. Kolb, L. Yu, C. M. Hoff, C. J. Holmes, D. C. Anthony, and J. Gauldie Inflammatory Cytokines, Angiogenesis, and Fibrosis in the Rat Peritoneum Am. J. Pathol., June 1, 2002; 160(6): 2285 - 2294. [Abstract] [Full Text] [PDF]
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R. M. Strieter Inflammatory Mechanisms Are Not a Minor Component of the Pathogenesis of Idiopathic Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., May 1, 2002; 165(9): 1206 - 1207. [Full Text] [PDF]
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 D.L. MANN The Yin/Yang of Innate Stress Responses in the Heart Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 363 - 370. [Abstract] [PDF]
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W. H. Chung, B. M. Bennett, W. J. Racz, J. F. Brien, and T. E. Massey Induction of c-jun and TGF-beta 1 in Fischer 344 rats during amiodarone-induced pulmonary fibrosis Am J Physiol Lung Cell Mol Physiol, November 1, 2001; 281(5): L1180 - L1188. [Abstract] [Full Text] [PDF]
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J.-Y. Liu, P. J. Sime, T. Wu, G. S. Warshamana, D. Pociask, S.-Y. Tsai, and A. R. Brody Transforming Growth Factor-beta 1 Overexpression in Tumor Necrosis Factor-alpha Receptor Knockout Mice Induces Fibroproliferative Lung Disease Am. J. Respir. Cell Mol. Biol., July 1, 2001; 25(1): 3 - 7. [Abstract] [Full Text] [PDF]
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 G.M. Verleden, R.M. du Bois, D. Bouros, M. Drent, A. Millar, J. Muller-Quernheim, G. Semenzato, S. Johnson, G. Sourvinos, D. Olivieri, et al. Genetic predisposition and pathogenetic mechanisms of interstitial lung diseases of unknown origin Eur. Respir. J., July 1, 2001; 18(32_suppl): 17S - 29s. [Abstract] [Full Text] [PDF]
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A. R. Brody, G. S. Warshamana, Jing-Yao, and D. A. Pociask Expression of Transforming Growth Factor-{beta} Induces Fibroproliferative Pulmonary Disease in Fibrosis-Resistant Mice Chest, July 1, 2001; 120(2007): 48S - 49S. [Full Text] [PDF]
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R. M. Strieter Mechanisms of Pulmonary Fibrosis : Conference Summary Chest, July 1, 2001; 120(2007): 77S - 85S. [Full Text] [PDF]
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J. Yamate, M. Maeda, S. J. Benn, J. E. Laithwaite, A. Allan, M. Ide, M. Kuwamura, T. Kotani, S. Sakuma, and J. Lamarre Differential Effects of Transforming Growth Factor-{beta}1, a Fibrogenic Factor, on Macrophage-Like Cells (HS-P) and Myofibroblastic Cells (MT-9) In Vitro Toxicol Pathol, June 1, 2001; 29(4): 483 - 491. [Abstract] [PDF]
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E. Cavarra, P.A. Martorana, B. Bartalesi, S. Fineschi, F. Gambelli, M. Lucattelli, L. Ortiz, and G. Lungarella Genetic deficiency of {alpha}1-PI in mice influences lung responses to bleomycin Eur. Respir. J., March 1, 2001; 17(3): 474 - 480. [Abstract] [Full Text] [PDF]
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M. KOLB, P. J. MARGETTS, T. GALT, P. J. SIME, Z. XING, M. SCHMIDT, and J. GAULDIE Transient Transgene Expression of Decorin in the Lung Reduces the Fibrotic Response to Bleomycin Am. J. Respir. Crit. Care Med., March 1, 2001; 163(3): 770 - 777. [Abstract] [Full Text] [PDF]
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L. A. ORTIZ, J. LASKY, E. GOZAL, V. RUIZ, G. LUNGARELLA, E. CAVARRA, A. R. BRODY, M. FRIEDMAN, A. PARDO, and M. SELMAN Tumor Necrosis Factor Receptor Deficiency Alters Matrix Metalloproteinase 13/Tissue Inhibitor of Metalloproteinase 1 Expression in Murine Silicosis Am. J. Respir. Crit. Care Med., January 1, 2001; 163(1): 244 - 252. [Abstract] [Full Text]
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M. Fujita, J. M. Shannon, C. G. Irvin, K. A. Fagan, C. Cool, A. Augustin, and R. J. Mason Overexpression of tumor necrosis factor-{alpha} produces an increase in lung volumes and pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, January 1, 2001; 280(1): L39 - L49. [Abstract] [Full Text] [PDF]
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T. Arai, K.'Y. Abe, H. Matsuoka, M. Yoshida, M. Mori, S. Goya, H. Kida, K. Nishino, T. Osaki, I. Tachibana, et al. Introduction of the interleukin-10 gene into mice inhibited bleomycin-induced lung injury in vivo Am J Physiol Lung Cell Mol Physiol, May 1, 2000; 278(5): L914 - L922. [Abstract] [Full Text] [PDF]
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 A. Oriente, N. S. Fedarko, S. E. Pacocha, S.-K. Huang, L. M. Lichtenstein, and D. M. Essayan Interleukin-13 Modulates Collagen Homeostasis in Human Skin and Keloid Fibroblasts J. Pharmacol. Exp. Ther., March 1, 2000; 292(3): 988 - 994. [Abstract] [Full Text]
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D. Warburton, J. Zhao, M. A. Berberich, and M. Bernfield Molecular embryology of the lung: then, now, and in the future Am J Physiol Lung Cell Mol Physiol, May 1, 1999; 276(5): L697 - L704. [Abstract] [Full Text] [PDF]
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D. M. Brass, G. W. Hoyle, H. G. Poovey, J.-Y. Liu, and A. R. Brody Reduced Tumor Necrosis Factor-{alpha} and Transforming Growth Factor-ß1 Expression in the Lungs of Inbred Mice that Fail to Develop Fibroproliferative Lesions Consequent to Asbestos Exposure Am. J. Pathol., March 1, 1999; 154(3): 853 - 862. [Abstract] [Full Text] [PDF]
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L. A. Ortiz, H. C. Champion, J. A. Lasky, F. Gambelli, E. Gozal, G. W. Hoyle, M. B. Beasley, A. L. Hyman, M. Friedman, and P. J. Kadowitz Enalapril protects mice from pulmonary hypertension by inhibiting TNF-mediated activation of NF-kappa B and AP-1 Am J Physiol Lung Cell Mol Physiol, June 1, 2002; 282(6): L1209 - L1221. [Abstract] [Full Text] [PDF]
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