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2 modulates basal and wound healing subepithelial matrix homeostasis
1 Biomedical Engineering, University of California, Irvine, Irvine, California, United States
2 Beckman Laser Institute, University of California, Irvine, Irvine, California, United States
3 Biomedical Engineering, University of California, Irvine, Irvine, California, United States; Beckman Laser Institute, University of California, Irvine, Irvine, California, United States; Surgery, University of California, Irvine, Irvine, California, United States
4 Biomedical Engineering, University of California, Irvine, Irvine, California, United States; Chemical Engineering and Materials Science, University of California, Irvine, Irvine, California, United States
* To whom correspondence should be addressed. E-mail: scgeorge{at}uci.edu.
The epithelium influences the mesenchyme during dynamic processes such as embryogenesis, wound healing, fibrosis, and carcinogenesis. Since TGF-
modulates these processes, we hypothesized that epithelial-derived TGF- also plays a critical role in maintaining the extracellular matrix at basal conditions. We utilized an in vitro model of the epithelial-mesenchymal trophic unit in the human airways to determine the role of epithelial-derived TGF- in modulating the extracellular matrix under basal and wound healing conditions. When differentiated at an air-liquid interface, the human bronchial epithelium produces active TGF-2 at a concentration of 50-70 pg/ml, whereas TGF-1 is undetectable. TGF-2 increases 2-3 fold following scrape injury in a dose-dependent fashion, and significantly enhances both 
-smooth muscle actin expression in the underlying collagen-embedded fibroblasts, and secretion of tenascin C into the matrix. Multiphoton microscopy demonstrates substantially enhanced second harmonic generation from fibrillar collagen in the matrix. Pre-treatment of the matrix with either sirolimus (2.5 nM) or paclitaxel (10 nM) abolishes the increases in both TGF-2 and second harmonic generation in response to epithelial injury. In the absence of the epithelium, exogenous active TGF-2 (0-400 pg/ml) produces a biphasic response in the second harmonic signal with a minimum occurring at the epithelial-derived basal level. We conclude that epithelial-derived TGF-2 is secreted in response to injury, significantly alters the bulk optical properties of the extracellular matrix, and its tight regulation may be required for normal collagen homeostasis.
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