Type I pneumocytes, which cover over ninety percent of the alveolar surface of the lung, are particularly susceptible to injury, such as that induced by air-borne toxicants or oxidant stress. Replacement/renewal of these cells following injury requires division and differentiation of a second cell, the type II pneumocyte. Interruption or delay of this process results in faulty repair and irreversibly-impaired function in the alveolar region. The mechanism(s) which govern these critical events are not clear, but preliminary evidence suggests that differences in the composition of the extracellular matrix (basement membrane) microdomains associated with the type I cell compared to the type II cell may influence the known responsiveness of the latter to epidermal, and acidic and basic fibroblast growth factors. The hypothesis to be tested in this proposal is that the specific molecular composition of the alveolar basement membrane and, in particular, its unique sulfated characteristics determines the type II cell's capacity to proliferate, differentiate, and regulate/repair its environment by synthesizing extracellular matrix molecules in response to acidic and basic fibroblast growth factors, and epidermal growth factor. We propose to characterize the proliferative, differentiative, and regulative responses of isolated rat type II cells to acidic and basic fibroblast growth factors, and epidermal growth factor, while maintained in culture on different matrix substrata that vary only in their levels of sulfation. The level of sulfation will be specifically reduced in selected, purified matrix preparations by chemical desulfation, or in biosynthesized substrata by interfering with the normal sulfation of matrix components produced by substrata producer cells. Type II cell proliferative responses to different matrix and sulfate compositions will be measured by 5-bromo- deoxyuridine incorporation; differentiation will be defined by morphologic and histochemical characteristics; and regulation/repair of their environment will be measured by type II cell biosynthesis of extracellular matrix components. These studies will elucidate molecular, structural, and functional relationships between epithelial cells, connective tissue matrices, and soluble growth factors in the pulmonary alveolus. They will provide a foundation for defining the mechanisms of extracellular matrix macromolecular regulation of critical re-epithelialization/repair processes in lung tissue following injury and/or disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL044497-02
Application #
3363299
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1992-04-08
Project End
1995-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
North Carolina State University Raleigh
Department
Type
Schools of Veterinary Medicine
DUNS #
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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