The epithelium of the alveolar region of the lung is susceptible to injury, such as that induced by air-borne toxicants or oxidant stress. Interruption/delay of the replacement of these cells following injury results in faulty repair and irreversibly impaired function in the alveolus. In this proposal, we will show that there exists a critical, dynamic relationship between lung epithelial cells and fibroblasts that dictate their responsiveness to and expression of sulfated extracellular matrices (SECMs) and growth factors. This constitutes a dynamic barrier, modified by the cells themselves, that defines their selective division of labor, maximizes their common efficiency, and is reflected in specific counter-regulation of expression of these modulatory factors. The hypothesis to be addressed is: The sulfated extracellular matrix between alveolar epithelium and underlying fibroblasts selectively down-regulates generation and activity of key regulatory factors: FGF-1, -2, and -7, and their adaptor molecules (FGF-receptors, FGF-binding protein, and specific sulfated ECMs). These processes constitute critical paracrine and juxtacrine mechanisms for regulating cell numbers, cell functions, and cellular architectural arrangement under normal, hyperplastic, and disease states in the alveolus. Isolated AT2 cells will be co-cultured with fibroblasts and the intervening sulfated ECM environment modified by either exogenous addition or stimulated overproduction (enhancement) or selective inhibition/modification of gene/protein expression (reduction). To define the mechanisms that control critical epithelial cell-fibroblast interactions, cellular responses to over expression of key regulatory growth factors and inhibited translation of growth factor response adapters will be measured by DNA synthesis, relevant signaling events, and expression of selected gene/protein products. Whole animal studies using adenovector-mediated gene transfer will determine if over expression of FGF-BP or syndecan-1 improves or alters injury/repair outcomes in an in vivo model of pulmonary fibrosis. Results of these studies are expected to provide essential information needed to better understand basic cell-cell, celI-ECM relationships in homeostasis, as well as the mechanisms that steer the pathogenesis of fibrogenic change in the lung because of injury and/or disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL044497-12
Application #
6728168
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Denholm, Elizabeth M
Project Start
1996-09-01
Project End
2007-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
12
Fiscal Year
2004
Total Cost
$328,500
Indirect Cost
Name
North Carolina State University Raleigh
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042092122
City
Raleigh
State
NC
Country
United States
Zip Code
27695
Newman, Donna R; Sills, W Shane; Hanrahan, Katherine et al. (2016) Expression of WNT5A in Idiopathic Pulmonary Fibrosis and Its Control by TGF-? and WNT7B in Human Lung Fibroblasts. J Histochem Cytochem 64:99-111
Yi, Na Young; Newman, Donna R; Zhang, Huiying et al. (2015) Heparin and LPS-induced COX-2 expression in airway cells: a link between its anti-inflammatory effects and GAG sulfation. Exp Lung Res 41:499-513
Morales Johansson, Helena; Newman, Donna R; Sannes, Philip L (2014) Whole-genome analysis of temporal gene expression during early transdifferentiation of human lung alveolar epithelial type 2 cells in vitro. PLoS One 9:e93413
Coffey, Emily; Newman, Donna R; Sannes, Philip L (2013) Expression of fibroblast growth factor 9 in normal human lung and idiopathic pulmonary fibrosis. J Histochem Cytochem 61:671-9
Zhang, Huiying; Newman, Donna R; Bonner, James C et al. (2012) Over-expression of human endosulfatase-1 exacerbates cadmium-induced injury to transformed human lung cells in vitro. Toxicol Appl Pharmacol 265:27-42
Zhang, Huiying; Newman, Donna R; Sannes, Philip L (2012) HSULF-1 inhibits ERK and AKT signaling and decreases cell viability in vitro in human lung epithelial cells. Respir Res 13:69
Meuten, Travis; Hickey, Ariel; Franklin, Katherine et al. (2012) WNT7B in fibroblastic foci of idiopathic pulmonary fibrosis. Respir Res 13:62
Dush, Michael K; McIver, Andrew L; Parr, Meredith A et al. (2011) Heterotaxin: a TGF-ýý signaling inhibitor identified in a multi-phenotype profiling screen in Xenopus embryos. Chem Biol 18:252-63
Apparao, K B C; Newman, Donna R; Zhang, Huiying et al. (2010) Temporal changes in expression of FoxA1 and Wnt7A in isolated adult human alveolar epithelial cells enhanced by heparin. Anat Rec (Hoboken) 293:938-46
Newman, Donna R; Walsh, Eric; Apparao, K B C et al. (2007) Fibroblast growth factor-binding protein and N-deacetylase/N-sulfotransferase-1 expression in type II cells is modulated by heparin and extracellular matrix. Am J Physiol Lung Cell Mol Physiol 293:L1314-20

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