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We are interested in the study of inflammatory and fibrotic (scarring)
diseases in the lung. These conditions are a major cause of morbidity
and mortality for our patients. In particular, we are interested in
understanding the cellular and molecular processes that control both
inflammation and the progression to fibrosis.
Many different cellular mediators have been shown to be important in
cell to cell signaling during inflammation and fibrogenesis, but the
cytokines and growth factors seem to be key. We have recently developed
models of pulmonary inflammation and fibrosis using adenoviral-mediated
cytokine gene transfer techniques. Adenovirus vectors permit a high
level of expression of genes and are currently being used in a variety
of clinical trials. We have used adenovirus gene transfer techniques to
investigate the role of a variety of cytokines and growth factors in
lung disease. Using this technology, we have been able to demonstrate
that overexpression of the cytokines transforming growth factor beta
(TGF-þ) and tumor necrosis factor alpha (TNF-a) in lung tissue can
induce pulmonary fibrosis. Indeed these new models of lung inflammation
and fibrosis are remarkably reflective of human inflammatory and
fibrotic diseases.
We now wish to focus on developing novel, gene therapy based, strategies
to modulate these disease processes. In particular, we will use the
flexible adenovirus vector system to overexpress regulatory proteins in
pulmonary tissues in order to inhibit inflammation and fibrosis. These
strategies will focus on inhibiting some of the cytokines such as
(TGF-þ) which we have already shown to be critically important. Using
these gene transfer techniques, we hope to be able to modulate
inflammation and fibrosis in the lung as well as other tissues.
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Westergren-Thorsson G, Sime P, Jordana M, Gauldie J, Sarnstrand B, Malmstrom A.
Lung fibroblast clones from normal and fibrotic subjects differ
in hyaluronan and decorin production and rate of proliferation.
Int J Biochem Cell Biol. 36:1573-84, 2004.
Pociask DA, Sime PJ, Brody AR.
Asbestos-derived reactive oxygen species activate TGF-beta(1).
Lab Invest. 2004 May 3 [Epub ahead of print].
Kaufman J, Sime PJ, Phipps RP.
Expression of CD154 (CD40 ligand) by human lung fibroblasts: differential regulation
by IFN-gamma and IL-13, and implications for fibrosis.
J Immunol. 172:1862-71, 2004.
Warshamana GS, Pociask DA, Fisher KJ, Liu JY, Sime PJ, Brody AR.
Titration of non-replicating adenovirus as a vector for transducing active
TGF-beta1 gene expression causing inflammation and fibrogenesis in the lungs of C57BL/6 mice.
Int J Exp Pathol. 83:183-202, 2002.
Kolb M, Bonniaud P, Galt T, Sime PJ, Kelly MM, Margetts PJ, Gauldie J.
Differences in the Fibrogenic Response after Transfer of Active Transforming Growth Factor-beta1 Gene to Lungs of "Fibrosis-prone" and "Fibrosis-resistant" Mouse Strains.
Am J Respir Cell Mol Biol. 27:141-50, 2002.
Liu JY, Sime PJ, Wu T, Warshamana GS, Pociask D, Tsai SY, Brody AR.
Transforming growth factor-beta(1) overexpression in tumor necrosis
factor-alpha receptor knockout mice induces fibroproliferative lung disease. Am
J Respir Cell Mol Biol. 25:3-7, 2001.
Kolb M, Margetts PJ, Sime PJ, Gauldie J. Proteoglycans decorin and biglycan
differentially modulate TGF-beta-mediated fibrotic responses in the lung. Am J
Physiol Lung Cell Mol Physiol. 280:L1327-34, 2001.
Sime PJ, O'Reilly KM. Fibrosis of the lung and other tissues: new concepts in
pathogenesis and treatment. Clin Immunol. 99:308-19, 2001.
Kolb M, Margetts PJ, Galt T, Sime PJ, Xing Z, Schmidt M, Gauldie J.
Transient transgene expression of decorin in the lung reduces the fibrotic response to bleomycin.
Am J Respir Crit Care Med 163:770-7, 2001.
Zhao J, Sime PJ, Bringas P Jr, Tefft JD, Buckley S, Bu D, Gauldie J, Warburton
D. Spatial-specific TGF-beta1 adenoviral expression determines morphogenetic
phenotypes in embryonic mouse lung. Eur J Cell Biol. 78:715-25, 1999.
Zhao J, Sime PJ, Bringas P Jr, Gauldie J, Warburton D.
Adenovirus-mediated decorin gene transfer prevents TGF-beta-induced inhibition of lung morphogenesis.
Am J Physiol 277(2 Pt 1):L412-22, 1999.
Publication list, as provided by PubMed.
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