Abstract

This proposal focuses on the molecular mechanisms for inhaled inorganic particle-induced fibroproliferative lung disease (FLD). The central hypothesis being examined is that interstitial fibrogenic lung disease is mediated by the mesenchymal cell growth factors, PDGF, TGF-alpha, TGF-beta and TNF-alpha, that are synthesized and secreted by the bronchiolar-alveolar epithelium as a result of lung injury.
Four specific aims are given to test this hypothesis.
In aim 1, two strains of mice resistant to the fibrogenic effects of inhaled asbestos are used to determine if the temporal and anatomic expression of the genes and growth factors by the alveolar epithelium correlates with resistance.
In aim 2 alveolar epithelial cells are isolated from these same mice strains to determine if the asbestos-resistance phenotype is maintained in vitro.
In aim 3 the principal investigator proposes to focus on PCNA expression in cells capable of forming fibrogenic lesions versus those from resistant mouse strains.
In aim 4 transgenic mice overexpressing human PDGF-B within the bronchiolar-alveolar epithelium and spontaneously developing fibroproliferative abnormalities in the lung will be crossed with asbestos-resistant strains to determine if the offspring have increased susceptibility to asbestos. This would implicate PDGF-B in fibrogenic lung disease and target this growth factor for antibody or gene therapy.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060532-02
Application #
2771682
Study Section
Special Emphasis Panel (ZES1-LKB-A (R1))
Project Start
1997-09-30
Project End
2002-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Tulane University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70118

  Publications

Lin, Rui; Degan, Simone; Theriot, Barbara S et al. (2012) Chronic treatment in vivo with ýý-adrenoceptor agonists induces dysfunction of airway ýý(2) -adrenoceptors and exacerbates lung inflammation in mice. Br J Pharmacol 165:2365-77
Miller, Jeffrey D; Lankford, Susan M; Adler, Kenneth B et al. (2010) Mesenchymal stem cells require MARCKS protein for directed chemotaxis in vitro. Am J Respir Cell Mol Biol 43:253-8
Sullivan, Deborah E; Ferris, Marybeth; Nguyen, Hong et al. (2009) TNF-alpha induces TGF-beta(1) expression in lung fibroblasts at the transcriptional level via AP-1 activation. J Cell Mol Med :
Salazar, Keith D; Lankford, Susan M; Brody, Arnold R (2009) Mesenchymal stem cells produce Wnt isoforms and TGF-beta1 that mediate proliferation and procollagen expression by lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 297:L1002-11
Sullivan, Deborah E; Ferris, Marybeth; Pociask, Derek et al. (2008) The latent form of TGFbeta(1) is induced by TNFalpha through an ERK specific pathway and is activated by asbestos-derived reactive oxygen species in vitro and in vivo. J Immunotoxicol 5:145-9
Spees, Jeffrey L; Pociask, Derek A; Sullivan, Deborah E et al. (2007) Engraftment of bone marrow progenitor cells in a rat model of asbestos-induced pulmonary fibrosis. Am J Respir Crit Care Med 176:385-94
Sullivan, Deborah E; Ferris, MaryBeth; Pociask, Derek et al. (2005) Tumor necrosis factor-alpha induces transforming growth factor-beta1 expression in lung fibroblasts through the extracellular signal-regulated kinase pathway. Am J Respir Cell Mol Biol 32:342-9
Pociask, Derek A; Sime, Patricia J; Brody, Arnold R (2004) Asbestos-derived reactive oxygen species activate TGF-beta1. Lab Invest 84:1013-23
Warshamana, G Sakuntala; Pociask, Derek A; Fisher, Krishna J et al. (2002) 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 83:183-201
Warshamana, G Sakuntala; Pociask, Derek A; Sime, Patricia et al. (2002) Susceptibility to asbestos-induced and transforming growth factor-beta1-induced fibroproliferative lung disease in two strains of mice. Am J Respir Cell Mol Biol 27:705-13

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