| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
Receptor Knockout Mice Are Protected from the Fibroproliferative Effects of Inhaled Asbestos Fibers
From the Lung Biology Program*
of the Department
of Pathology and the Department of Medicine,
Tulane University Medical Center, New Orleans, Louisiana
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
knocked out
(TNF-RKO) fail to develop fibroproliferative lesions after asbestos
exposure. There is good evidence that TNF- plays a major role in
mediating interstitial pulmonary fibrosis. Our findings support this
view and we present here new data obtained by in situ
hybridization showing that expression of the genes coding for
transforming growth factor (TGF-) and platelet-derived growth
factor A-chain (PDGF-A) is reduced in the TNF-RKO mice compared with
control animals. In accordance with this observation, data on
bromodeoxyuridine (BrdU) incorporation in the lungs of the TNF-RKO
mice show no increases over unexposed control animals. In
contrast, wild-type control mice exposed to asbestos exhibit
15- to 20-fold increases in BrdU uptake and consequently develop
fibrogenic lesions. Even though the levels of TNF- gene expression
and protein production were increased in the asbestos-exposed
TNF-RKO mice, the lack of receptor signaling protected the
mice from developing fibroproliferative lesions. We agree with the view
that TNF- is essential for the development of interstitial pulmonary
fibrosis and postulate that TNF- mediates its effects through
activation of other growth factors such as PDGF and TGF- that
control cell growth and matrix production.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Among the many cytokines and peptide growth factors found in human and
animal lungs with fibrogenic disease are platelet-derived growth factor
(PDGF),6
transforming growth factors
7
and ß8
(TGF- and
TGF-ß), and tumor necrosis factor
(TNF-).9
PDGF is the most potent mesenchymal
cell mitogen yet described6
and TGF- is a
powerful inducer of epithelial and mesenchymal cell
proliferation.7
On the other hand, TGF-ß
generally blocks cell growth but is a potent stimulus for extracellular
matrix production.8
TNF- has been postulated
as a central mediator of fibrogenic lung disease caused by such diverse
agents as bleomycin and silica.10
TNF- clearly
is a multipotent cytokine, acting on the one hand as a growth factor
and on the other as an activator of gene
expression.11,12
To determine the role TNF-
might play in the initial fibroproliferative response to lung injury,
we have exposed mice to fibrogenic asbestos fibers for a single 5-hour
time period. This brief exposure induces a fibroproliferative disease
process localized initially at bronchiolar-alveolar duct regions of the
lung.4,5,13
Here we show that mice deficient in
both the 55kd and 75kd receptors for TNF- are protected from the
initial fibroproliferative effects of inhaled asbestos fibers. We also
demonstrate that although levels of TNF- expression increased in
these animals, expression of PDGF and TGF- are significantly reduced
in the receptor knockout mice, supporting the view that TNF- may
exert its effects on disease development by controlling growth factor
synthesis.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Mice with mutations in both the p55 and p75 TNF receptor genes have been described previously.14 These mice (kindly supplied by Dr. Jacques Peschon, Immunex Corporation, Seattle) were generated by disrupting the individual receptor genes and then interbreeding the single-receptor knockout lines. TNFR double-knockout mice were maintained on a mixed genetic background of the C57BL/6 and 129 inbred strains (B6129). B6129 F2 hybrid mice and C57BL/6 mice purchased from the Jackson Laboratories (Bar Harbor, ME) were used as wild-type controls. All mice were housed according to NIH guidelines under specific pathogen-free conditions.
Asbestos Exposure and Tissue Preparation
Mice were exposed to asbestos in a 39-L inner aluminum chamber containing the exposure atmosphere within a 1.5-m3 stainless steel Rochester outer chamber. Asbestos aerosol was generated from California chrysotile15 and passed through a vertical elutriator to allow only particles <10 µm aerodynamic equivalent diameter to enter the chamber. Mice were exposed via the nose only. Dust concentrations in the exposure chamber were measured by sampling onto 37-mm PVC membrane filters placed in unused animal ports followed by gravimetric analysis of the samples. TNFR double knockout mice (p55-/- p75-/-) were exposed to an aerosol of chrysotile asbestos (10 mg/m3 respirable mass) or to room air (sham) for 5 hours. C57BL/6 and B6129 F2 hybrid mice (Jackson Laboratories) were exposed simultaneously as background controls. Five animals per group were euthanized at periods of 0 hours, 48 hours, and 2 weeks after the single 5-hour exposure. Lungs were perfused through the trachea with 10% neutral buffered formalin at a pressure of 25 cm H20 for 30 minutes. After perfusion, the trachea was clamped and the lungs were removed from the chest cavity and placed in fresh fixative for 16 hours at 4°C. After fixation, lungs were embedded in paraffin, and 5-µm-thick sections were cut onto positively charged slides for immunohistochemistry and in situ hybridization. The general histopathological appearance of tissues was assessed after routine hematoxylin and eosin staining. Before starting any exposures, five animals were sacrificed and the fixed lungs were processed for routine histopathology to be sure that the mice were healthy. The exposure and tissue preparation protocols were carried out two separate times several months apart with no apparent differences in any of the parameters studied (see Results).
In Situ Hybridization
Tissue and Probe Preparation
Tissue sections for in situ hybridization were kept at
4°C until used. The nonradioactive in situ hybridization
method used in this experiment has been described
previously.4,5
The cDNAs encoding rat PDGF-A, rat
TGF-, and mouse TNF- (kindly provided by Dr. Dai Katayose,
NHLBI/NIH, Bethesda, MD; Dr. David Lee, University of North Carolina at
Chapel Hill; and Dr. Bruce Beutler, University of Texas Southwestern
Medical Center, respectively) were used as templates to generate RNA
probes. Labeled cRNA probes for PDGF-A, TGF-, and TNF- were
transcribed from plasmids containing restriction fragments of growth
factor cDNAs as follows: PDGF-A, a 0.8 kb SmaI fragment in
pBluescript KS+;5
TGF-, a 2.0 kb
EcoRI/SalI fragment in
pGEM4;4
TNF-a, a 1.1 kb
PstI/EcoRI fragment in
pGEM3.16
Linearized plasmids were used as
templates for in vitro transcription reactions to produce
digoxigenin-11-UTP-labeled antisense and sense riboprobes with T7 and
T3 RNA polymerase (Genius 4 RNA labeling Kit, Boehringer Mannheim,
Indianapolis, IN).
Hybridization
Hybridization of cRNA probes to lung tissue sections was performed as described previously.4,5 Slides were counterstained with Mayer's hematoxylin.
Immunohistochemistry
TNF-
Immunohistochemical staining for TNF- was performed using the
immunoperoxidase technique described
previously.4,5
Briefly, slides were incubated in
methanol containing 0.3% hydrogen peroxide for 30 minutes and then in
5% normal goat serum for 30 minutes. Slides were incubated with a
rabbit anti-mouse TNF- antibody (1:100, a kind gift from Dr. Steven
Kunkel, University of Michigan, Ann Arbor, MI) at room temperature for
1 hour. A parallel set of sections was incubated with the same dilution
of normal rabbit serum as a control for nonspecific binding. The slides
were then incubated with biotinylated goat anti-rabbit (1:4,000,
Jackson Immunoresearch, West Grove, PA) and streptavidin-horseradish
peroxidase (1:2000, Jackson Immunoresearch). Peroxidase activity was
visualized with a 10-minute incubation in 0.05 mol/L Tris-HCl, pH 7.6,
containing 200 µg/ml diaminobenzidine and 0.006% hydrogen peroxide.
The slides were counterstained with Lerner-3 hematoxylin (Lerner,
Pittsburgh, PA).
Bromodeoxyuridine (BrdU) Labeling
The asbestos-exposed and control mice were injected intraperitoneally with BrdU (50 mg/kg) 4 hours before sacrifice as reported previously.17 Sections were pretreated with 0.01% trypsin in 0.05 mol/L Tris-HCl, pH 7.8, containing 0.1% CaCl2 for 6–10 minutes at 37°C. Sections were incubated in methanol containing 0.3% hydrogen peroxide for 30 minutes and then in 5% normal goat serum for 30 minutes. The slides were incubated with a mouse monoclonal antibody against BrdU (clone B44, 1:100, Becton Dickinson, San Jose, CA) at room temperature for 1 hour. A parallel set of sections was incubated with the same dilution of normal rabbit serum as a control for nonspecific binding. Following biotin-conjugated goat anti-mouse (1:4000) and streptavidin-horseradish peroxidase (1:2000) incubation, peroxidase activity was visualized with diaminobenzidine as described above. The slides were counterstained with Lerner-3 hematoxylin (Lerner).
Quantitative Analysis of BrdU Labeling
BrdU labeling was quantitated by counting labeled cells at bronchiolar-alveolar duct junctions. Two histological sections per lung were prepared and analyzed from 5 different animals at each of 3 time points (0 hours, 48 hours, and 2 weeks) after a single 5-hour asbestos or sham exposure. Bronchiolar/alveolar anatomical units were selected at random from each animal for analysis. Each anatomical unit consisted of the following features: a terminal bronchiole, alveolar duct walls between the terminal bronchiole and first alveolar duct bifurcation, and a first alveolar duct bifurcation. A total of 1500 cells, typically comprising 4–6 anatomical units, were counted per animal. A BrdU labeling index was calculated by dividing the number of BrdU-positive nuclei by the total number of cells counted in the given units. Differences between groups were analyzed by one-way analysis of variance.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The TNF- receptor knockout (TNF-RKO) mice and wild-type mice
of the same genetic background, ie, C57BL/6–129
F2 hybrids (B6129), were exposed simultaneously
to an aerosol of chrysotile asbestos fibers. Additional groups of these
mice were exposed to room air as negative controls. We have shown
previously that 5 hours of exposure to chrysotile asbestos fibers
induces the development of fibroproliferative lesions at
bronchiolar-alveolar duct (BAD) junctions in rats and
mice.3-5,13
C57BL/6 (C57) mice exposed to
asbestos at the same time served as positive controls to contrast the
response of the B6129 hybrids and the TNF-RKO mice exposed
identically. Figure 1
shows typical
histopathological sections from these animals. The air-exposed B6129
mice exhibited normal architecture with no inflammatory lesions in any
animals (Figure 1A)
. The asbestos-exposed C57 and B6129 mice developed
typical lesions at the BAD junctions 48 hours after exposure (Figure 1, B and C)
. These lesions have been described in detail
previously4,5,13
and are hypercellular and
hypertrophic, with numerous alveolar and interstitial macrophages as
well as asbestos fibers and increased numbers of mesenchymal
cells.18
In contrast, the TNF-RKO mice failed
to develop significant lesions (Figure 1D)
. An experienced
histopathologist, blinded as to the identity of the tissue sections
from the groups of animals, placed the great majority of the
asbestos-exposed TNF-RKO mice in the normal category. A few of the
animals had increased alveolar macrophages at the BAD junctions and
could be identified as asbestos-exposed, but there were no
fibroproliferative lesions in these animals.
|
BrdU incorporation is a valuable measure of cell
proliferation.17
As expected, the air-exposed
mice had few stained cells at any time after exposure (Figure 2B)
. Also as expected, the C57 and B6129
mice exhibited numerous densely labeled cells in the developing
lesions. There was no staining immediately after exposure, but at 48
hours after exposure, numerous interstitial, epithelial, and
bronchiolar Clara cells had incorporated BrdU (Figure 2C)
. Analysis of
the percentages of labeled cells demonstrated that the increased
staining persisted for at least 2 weeks after exposure (Figure 3)
.
|
|
RKO mice exhibited very few BrdU-stained cells at any time
after exposure (Figure 2D
and Figure 3
), and these animals had
significantly fewer cells incorporating BrdU than the B6129 hybrid
controls. There were no significant differences between the percentages
of labeled cells in air-exposed B6129 mice and the asbestos-exposed
TNF-RKO animals. Growth Factor Expression
In situ hybridization was carried out to determine the
distribution of TNF-, PDGF-A, and TGF- mRNA expression. Figure 4
shows that asbestos-exposed B6129 mice
exhibited strong hybridization of the mRNAs for each of the three
growth factors studied at 48 hours after exposure. Air-exposed animals
were essentially negative. The sense strand of the mRNAs served as
negative controls for the in situ hybridization technique
(see Figure 5A
). Most interesting was our
finding that expression of the mRNAs for PDGF-A and TGF- were
markedly reduced in asbestos-exposed TNF-RKO mice compared to the
asbestos-exposed wild-type mice. In contrast, dense hybridization of
the TNF- mRNA was observed in both these animal groups after
asbestos exposure (Figure 4, G and H)
. Immunohistochemical staining of
TNF- protein in sections from the TNF-RKO (Figure 5D)
and B6129
mice (Figure 5C)
confirmed that asbestos exposure induces TNF-
expression regardless of whether fibroproliferative lesions are
developing. TNF- gene and protein expression were observed primarily
in bronchiolar-alveolar epithelial cells and alveolar macrophages
(Figures 4 and 5)
.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
fail to develop
fibroproliferative lung lesions following brief exposure to chrysotile
asbestos fibers. The lesions developed as expected at the
bronchiolar-alveolar duct (BAD) junctions of asbestos-exposed C57 and
wild-type mice of the same genetic background as the TNF-RKO
knockout animals. These wild-type control animals exhibited dense
staining of BrdU in multiple cell types of the developing lesions, and
there was strong expression of the mRNAs coding for TNF-, TGF-,
and PDGF-A. These findings are consistent with the current postulate
that fibrogenic lung disease develops as a result of growth
factor-induced cell proliferation. These data also support the view
that TNF- plays a major role in mediating the fibroproliferative
process. Thus, in mice with normal TNF- receptors there is
expression of growth factors, such as PDGF-A and TGF-, that can
induce mesenchymal and epithelial cell proliferation respectively. When
the TNF- receptors are lacking, TNF- gene and protein expression
remain up-regulated after asbestos exposure, but PDGF-A and TGF- are
clearly reduced. This could explain the lack of fibroproliferative
lesions in the knockout mice.
What is the role of TNF- as an essential factor in the development
of fibroproliferative lung disease? Unfortunately, it is not possible
to answer this central question definitively at this time, but the data
are consistent with a number of other model systems in which TNF-
appears to play a significant role in several disease processes.
TNF- was discovered in 1975 as a soluble polypeptide of about 17kd
in monomeric form.19
As a trimeric complex,
TNF- binds to the two demonstrated membrane receptors of 55kd and
75kd. The biology of these receptors is not completely understood, but
it appears that both are necessary for TNF- to produce its maximum
effect.20
TNF- is known to have multiple
biological actions on a number of cell
types.21-23
For example, there is a broad
literature on its role in cytolysis and
infection.20,23
We will confine our discussion to
the effects of TNF- that are most relevant to the fibroproliferative
response. Indeed, TNF- has been implicated as a central mediator in
pulmonary fibrogenesis caused by bleomycin,10
silica,24
and asbestos.25
In addition, TNF- has been demonstrated in the formation of the
collagen associated with chronic arthritis in a mouse
model.26
These claims have been made because the
processes have been blocked or ameliorated by treatment with
anti-TNF- antibodies (Ab) and/or with recombinant soluble TNF-
receptor (TNF--R). In each case cited above, the Abs or the soluble
receptor were administered intraperitoneally or intravenously, and they
significantly reduced lung collagen accumulation and severity of
disease in general.10,24,26,27
In one very
interesting model, the "moth-eaten" mutant mouse spontaneously
develops progressive pulmonary inflammation and
fibrosis.28
These animals were found to have high
circulating levels of TNF- and treating them with an anti-TNF- Ab
prevented much of the inflammation and consequent pulmonary
fibrosis.28
In addition, Sendai Virus-induced
bronchiolar fibrogenesis was inhibited by an antibody to the 55kd
TNF- receptor.29
Thus, there is good evidence that TNF- holds a strong position on
the growing list of cytokines that appear to be essential in mediating
fibroproliferative processes. Inasmuch as we have shown that brief
inhalation of chrysotile asbestos fibers in rats and mice causes
macrophage accumulation, cell injury and proliferation, and fibrogenic
lesions,4,5,13,18
this model can be used to
attempt to understand how TNF- exerts its multiple effects on these
processes. Knockout mice deficient in both the p55 and p75 TNF-
receptors offer several clues because we have been able to make three
relevant observations about the exposed mice: (1) none of the knockout
animals exhibited enhanced cell proliferation or developed fibrogenic
lesions; (2) the levels of TNF- gene expression and protein
production were increased; and (3) the levels of PDGF-A and TGF-
gene expression were reduced. Considered together, these findings
demonstrate that TNF- signaling is an essential event in the
development of asbestos-induced fibroproliferative disease. This is in
agreement with the findings of a number of other investigations
referenced above, implicating TNF- as a central mediator of lung
fibrogenesis in general. In addition, we suggest that TNF- exerts
its effects on the fibroproliferative process by influencing the
expression of other, perhaps more downstream factors, like PDGF and
TGF-, that bind to their own cell surface receptors. PDGF-A and -B
are the most potent mesenchymal cell mitogens yet
described,6
while TGF- is a powerful
epithelial cell mitogen.7
Although our data
suggest that TNF- receptor signaling is essential for the
development of fibroproliferative lesions, further experiments will be
necessary to establish whether or not TNF- expression is necessary
for the elaboration of other key growth factors. It is clear that
TNF- has a direct influence on the expression of factors such as
TGF-ß,30,31
and we have new, as yet unpublished
data showing that TGF-ß1 expression is also reduced in the
TNF-RKO mice. In addition, TNF- mediates many of its effects
through the transcription factor NF-
B,32
suggesting the possibility of activating other cytokines that are
regulated by this factor.32
We have focused here on the relationship between TNF- and growth
factors, but there are other scenarios in which TNF- could influence
fibrogenic disease. Briefly, it has become apparent that increased
TNF- induces expression of collagenase33
but
disrupts the normal attachment of fibroblasts to their extracellular
matrix.34,35
This reportedly is due to
down-regulation of collagen-specific receptors, resulting in decreased
turnover of extracellular matrix. Finally, TNF- has been shown to
enhance the release of superoxide ions36
and it
is clear that cellular injury from such anions can lead to fibrogenic
disease.37
Clearly, TNF- has multiple
influences on a wide variety of inflammatory
events38
that are beyond the scope of the
experiments presented here.
In summary, we have shown that mice lacking receptors for both the 55kd
and 75kd receptors for TNF- are protected from the fibrogenic
effects of inhaled asbestos fibers. We have presented data supporting
the postulate that TNF- is essential for the development of the
fibroproliferative process through its effects on the expression of
growth factors such as PDGF, TGF-, and TGF-ß that control cell
growth and matrix production. Even though the TNF- mRNA is
up-regulated and there is increased protein, the lack of TNF-
receptor signaling protected the mice. Further experiments will be
necessary to discover the mechanisms through which TNF-
influences the expression and biological activities of the factors that
could more proximally mediate fibroproliferative lung disease.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
Supported by National Institutes of Health Grants RO1ES60766 and RO1HL60532, the Tulane/Xavier Center for Bioenvironmental Research, and the Tulane Cancer Center.
Accepted for publication September 12, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
in the bronchiolar-alveolar duct regions of asbestos-exposed rats. Am J Pathol 1996, 149:205-217[Abstract]
. Adv Cancer Res 1992, 58:27-52[Medline]
-mediated lung cytokine networking, and eosinophil recruitment in pulmonary fibrosis. J Immunol 1997, 158:954-959[Abstract]
B in cytokine gene regulation. Am J Respir Cell Mol Biol 1997, 17:3-9 transgene in murine lung causes lymphocytic and fibrosing alveolitis: a mouse model of progressive pulmonary fibrosis. J Clin Invest 1995, 96:250-259
mediates recruitment of neutrophils and eosinophils during airway inflammation. J Immunol 1995, 154:5411-5418[Abstract]
in the spontaneous development of pulmonary fibrosis in viable motheaten mutant mice. Am J Pathol 1997, 151:1303-1310[Abstract]
(TNF-) gene expression in parainfluenza type I (Sendai) virus-induced bronchiolar fibrosis. Am J Pathol 1998, 152:513-522[Abstract]
. J Immunol 1992, 149:103-106[Abstract]
mediates the release of bioactive transforming growth factor-ß in murine microglial cell cultures. Clin Immunol Immunopathol 1995, 77:358-365[Medline]
B kinase that activates the transcription factor NF-B. Nature 1997, 388:548-554[Medline]
in U937 cells. J Leukoc Biol 1996, 59:125-132[Abstract]
inactivation of collagen receptors: implications for fibroblast function and fibrosis. J Immunol 1996, 156:4354-4362[Abstract]
. Am J Pathol 1997, 151:1425-1435[Abstract]
This article has been cited by other articles:
 |
|
 |
|
  S. Murthy, A. Adamcakova-Dodd, S. S. Perry, L. A. Tephly, R. M. Keller, N. Metwali, D. K. Meyerholz, Y. Wang, M. Glogauer, P. S. Thorne, et al. Modulation of reactive oxygen species by Rac1 or catalase prevents asbestos-induced pulmonary fibrosis Am J Physiol Lung Cell Mol Physiol, November 1, 2009; 297(5): L846 - L855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. D. Salazar, S. M. Lankford, and A. R. Brody Mesenchymal stem cells produce Wnt isoforms and TGF-{beta}1 that mediate proliferation and procollagen expression by lung fibroblasts Am J Physiol Lung Cell Mol Physiol, November 1, 2009; 297(5): L1002 - L1011. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Levis, R. Loi, K. J. Butnor, P. Vacek, C. Steele, B. T. Mossman, and D. J. Weiss Decreased Asbestos-Induced Lung Inflammation and Fibrosis after Radiation and Bone Marrow Transplant Am. J. Respir. Cell Mol. Biol., January 1, 2008; 38(1): 16 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Spees, D. A. Pociask, D. E. Sullivan, M. J. Whitney, J. A. Lasky, D. J. Prockop, and A. R. Brody Engraftment of Bone Marrow Progenitor Cells in a Rat Model of Asbestos-Induced Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., August 15, 2007; 176(4): 385 - 394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Fujita, S. Saika, W. W.-Y. Kao, K. Fujita, T. Miyamoto, K. Ikeda, Y. Nakajima, and Y. Ohnishi Endogenous TNF{alpha} Suppression of Neovascularization in Corneal Stroma in Mice Invest. Ophthalmol. Vis. Sci., July 1, 2007; 48(7): 3051 - 3055. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Yang, M. Bocchetta, B. Kroczynska, A. G. Elmishad, Y. Chen, Z. Liu, C. Bubici, B. T. Mossman, H. I. Pass, J. R. Testa, et al. TNF-{alpha} inhibits asbestos-induced cytotoxicity via a NF-{kappa}B-dependent pathway, a possible mechanism for asbestos-induced oncogenesis PNAS, July 5, 2006; 103(27): 10397 - 10402. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Saika, K. Ikeda, O. Yamanaka, K. C. Flanders, Y. Okada, T. Miyamoto, A. Kitano, A. Ooshima, Y. Nakajima, Y. Ohnishi, et al. Loss of Tumor Necrosis Factor {alpha} Potentiates Transforming Growth Factor {beta}-mediated Pathogenic Tissue Response during Wound Healing Am. J. Pathol., June 1, 2006; 168(6): 1848 - 1860. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Agostini and C. Gurrieri Chemokine/Cytokine cocktail in idiopathic pulmonary fibrosis. Proceedings of the ATS, January 1, 2006; 3(4): 357 - 363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Sullivan, M. Ferris, D. Pociask, and A. R. Brody Tumor Necrosis Factor-{alpha} Induces Transforming Growth Factor-{beta}1 Expression in Lung Fibroblasts Through the Extracellular Signal-Regulated Kinase Pathway Am. J. Respir. Cell Mol. Biol., April 1, 2005; 32(4): 342 - 349. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fujita, J. M. Shannon, O. Morikawa, J. Gauldie, N. Hara, and R. J. Mason Overexpression of Tumor Necrosis Factor-{alpha} Diminishes Pulmonary Fibrosis Induced by Bleomycin or Transforming Growth Factor-{beta} Am. J. Respir. Cell Mol. Biol., December 1, 2003; 29(6): 669 - 676. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 C. Jakubzick, E. S. Choi, B. H. Joshi, M. P. Keane, S. L. Kunkel, R. K. Puri, and C. M. Hogaboam Therapeutic Attenuation of Pulmonary Fibrosis Via Targeting of IL-4- and IL-13-Responsive Cells J. Immunol., September 1, 2003; 171(5): 2684 - 2693. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
A. Churg, J. Dai, H. Tai, C. Xie, and J. L. Wright Tumor Necrosis Factor-{alpha} Is Central to Acute Cigarette Smoke-induced Inflammation and Connective Tissue Breakdown Am. J. Respir. Crit. Care Med., September 15, 2002; 166(6): 849 - 854. [Abstract] [Full Text]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
P.J.A. Borm and R.P.F. Schins Genotype and phenotype in susceptibility to coal workers' pneumoconiosis. The use of cytokines in perspective Eur. Respir. J., July 1, 2001; 18(32_suppl): 127S - 133s. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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 (2009): 48S - 49S. [Full Text] [PDF]
|
|
|
|
|
|
P. PANTELIDIS, G. C. FANNING, A. U. WELLS, K. I. WELSH, and R. M. DU BOIS Analysis of Tumor Necrosis Factor-{alpha}, Lymphotoxin-{alpha}, Tumor Necrosis Factor Receptor II, and Interleukin-6 Polymorphisms in Patients with Idiopathic Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., May 1, 2001; 163(6): 1432 - 1436. [Abstract] [Full Text]
|
|
|
|
 |
|
 S. F. Nagueh, S. J. Stetson, N. M. Lakkis, D. Killip, A. Perez-Verdia, M. L. Entman, W. H. Spencer III, and G. Torre-Amione Decreased Expression of Tumor Necrosis Factor-{{alpha}} and Regression of Hypertrophy After Nonsurgical Septal Reduction Therapy for Patients With Hypertrophic Obstructive Cardiomyopathy Circulation, April 10, 2001; 103(14): 1844 - 1850. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Dai and A. Churg Relationship of Fiber Surface Iron and Active Oxygen Species to Expression of Procollagen, PDGF-A, and TGF-{beta}1 in Tracheal Explants Exposed to Amosite Asbestos Am. J. Respir. Cell Mol. Biol., April 1, 2001; 24(4): 427 - 435. [Abstract] [Full Text]
|
|
|
|
|
|
C. Xie, A. Reusse, J. Dai, K. Zay, J. Harnett, and A. Churg TNF-alpha increases tracheal epithelial asbestos and fiberglass binding via a NF-kappa B-dependent mechanism Am J Physiol Lung Cell Mol Physiol, September 1, 2000; 279(3): L608 - L614. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Abraham, X. Shiwen, C. M. Black, S. Sa, Y. Xu, and A. Leask Tumor Necrosis Factor alpha Suppresses the Induction of Connective Tissue Growth Factor by Transforming Growth Factor-beta in Normal and Scleroderma Fibroblasts J. Biol. Chem., May 12, 2000; 275(20): 15220 - 15225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. F. Robledo, S. A. Buder-Hoffmann, A. B. Cummins, E. S. Walsh, D. J. Taatjes, and B. T. Mossman Increased Phosphorylated Extracellular Signal-Regulated Kinase Immunoreactivity Associated with Proliferative and Morphologic Lung Alterations after Chrysotile Asbestos Inhalation in Mice Am. J. Pathol., April 1, 2000; 156(4): 1307 - 1316. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Ortiz, J. A. Lasky, H. Safah, M. Reyes, A. Miller, G. Lungarella, and M. Friedman Exacerbation of bleomycin-induced lung injury in mice by amifostine Am J Physiol Lung Cell Mol Physiol, December 1, 1999; 277(6): L1239 - L1244. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. F. Morris and A. R. Brody Stressing Fibrogenesis in Cell Culture Am. J. Respir. Cell Mol. Biol., October 1, 1999; 21(4): 447 - 448. [Full Text]
|
|
|
|
|
|
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]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
