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* From the Department of Pathology, Tulane University Health Sciences Center, New Orleans, LA.
Correspondence to: Arnold R. Brody, PhD, Professor and Vice Chair, Director, Lung Biology Program, Tulane University Health Sciences Center, 1430 Tulane Ave, New Orleans, LA 70112-2699
While
it appears that a number of growth factors must play an essential role
in the development of fibroproliferative pulmonary disease, it is not
known how each factor contributes to the various components that
define the consequent interstitial fibrosis. We have been
using transgenic and knockout mice to determine the roles of several of
the growth factors. For example, mice with both receptors for tumor
necrosis factor (TNF)-
knocked out are protected from the fibrogenic
effects of asbestos1
and silica.2
Expression
of transforming growth factor (TGF)-ß1, platelet-derived growth
factor, and TGF- was clearly reduced in these knockout mice.
Inasmuch as these mice failed to develop interstitial fibrosis after
exposure to potent fibrogenic agents, we have now asked whether or not
reconstitution of TGF-ß1 expression through an adenovirus vector will
induce fibroproliferative lung disease. Herein we report that
transduction of the gene that codes for active TGF-ß1 induces
inflammation and a fibroproliferative process in the
bronchiolar-alveolar regions of the lung in normal control mice as well
as in the TNF- receptor knockout mice (C57BL/6 X 129J, F2
generation). One-hundred million plaque-forming units (pfu) of
replication-deficient adenovirus particles that expressed a porcine
TGF-ß1 gene were instilled into the lungs as described originally in
a rat model.3
Vector alone caused slight perivascular
lymphocyte accumulation. Under control of a cytomegalovirus promoter,
the TGF-ß1 gene was expressed rapidly, and active TGF-ß1 protein
was released causing interstitial inflammation and fibrogenesis during
the first 7 days after instillation in the TNF- receptor knockout
mice. In addition, in C57BL/6 mice, large amounts of latent TGF-ß1
were produced by the mice, as determined by enzyme-linked immunosorbent
assay. The inflammation and fibrogenesis were documented by
histopathology first at 4 days posttreatment and persisted through a
2-week period. Disease subsided, but the lungs had not returned to
normal by the 4-week period studied in these experiments. A
dose-response study was carried out in C57BL/6 mice, and a virus
concentration of 106 pfu caused no apparent disease,
whereas 109 pfu virus caused an overwhelming inflammatory
response. At 108 pfu, BrdU incorporation showed 10-fold to
20-fold increases in cell proliferation. In conclusion, these findings
demonstrate that expression of active TGF-ß1 in the lungs of
fibrosis-resistant TNF- receptor knockout mice is sufficient to
cause fibroproliferative pulmonary disease. The mechanisms through
which TGF-ß1 mediates collagen production and influences the
expression of other cytokines are being investigated.
Footnotes
Abbreviations: pfu = plaque-forming units; TGF = transforming growth factor; TNF = tumor necrosis factor
Supported by National Institutes of Health grants RO1-ES06766 and RO1-HL60532.
References
receptor knockout mice are protected from the fibroproliferative effects of inhaled asbestos fibers. Am J Pathol 153,1839-1847 receptor mRNA after silica and bleomycin exposure and protection from lung injury in double receptor knockout mice. Am J Respir Cell Mol Biol 20,825-833 to rat lung induces severe pulmonary inflammation and patchy interstitial fibrogenesis with induction of transforming growth factor-ß1 and myofibroblasts. Am J Pathol 153,825-832
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