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Interleukin-13, a Mediator of Subepithelial Fibrosis, Enhances Growth Factor Production and Proliferation in Human Airway Epithelial Cells*

Brian Booth, BS; James Bonner, PhD; Nancy Akley, MS; Mariangela Macchione, PhD; Kenneth Adler, PhD; Linda D. Martin, PhD
Author and Funding Information

*From the North Carolina State University (Mr. Booth, Ms. Akley, and Drs. Macchione, Adler, and Martin), Raleigh, NC; and National Institute of Environmental Health Sciences (Dr. Bonner), Research Triangle Park, NC.

Correspondence to: Linda D. Martin, PhD, Research Assistant Professor of Cell Biology, North Carolina State University, College of Veterinary Medicine, 4700 Hillsborough St, Raleigh, NC 27606



Chest. 2001;120(1_suppl):S15. doi:10.1378/chest.120.1_suppl.S15
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Extract

Subepithelial fibrosis is a prominent feature of the remodeled asthmatic airway. The cytokine interleukin (IL)-13, implicated as a mediator in the development of asthma, induces a significant degree of subepithelial fibrosis in the lungs of transgenic mice. Since IL-13 has been shown to exert effects on the airway epithelium, including the development of a mucous phenotype, we have begun to determine whether IL-13 provokes production of factors from the epithelium that could elicit the observed subepithelial fibrotic response. In the studies reported herein, injured airways with regions of regenerating/differentiating cells and regions of normal fully differentiated cells have been mimicked by examining the effects of IL-13 on normal human bronchial epithelial cells during mucociliary differentiation in air/liquid interface culture. Exposure of normal human bronchial epithelial cells to IL-13 resulted in increased production of soluble transforming growth factor (TGF)-α, with the growth factor interacting in an autocrine manner with the epidermal growth factor receptor. Production of soluble TGF-α was very rapid, with a threefold increase observed in response to IL-13 (10 ng/mL) by 1 h of exposure. Continuous exposure to IL-13 throughout the course of mucociliary differentiation (a total of 10 days) resulted in a twofold increase in cell number by day 7 when cells are differentiated. Exposure to IL-13 (10 ng/mL; 24 h) provoked a threefold increase in proliferation once the cells were differentiated, an effect that could be duplicated in differ- entiated, but not undifferentiated cells, by the direct addition of TGF-α (5 ng/mL or 25 ng/mL; 24 h). Proliferation of differentiated cells in response to continuous IL-13 treatment was followed 2 days later by a decrease in proliferation compared to control mice. Soluble TGF-α, however, continued to be produced from these nonproliferating cultures. Thus, an increase in soluble TGF-α in response to IL-13 may serve to promote proliferation of injured epithelial cells in an autocrine manner. Once this proliferative effect is no longer necessary, the soluble TGF-α may promote proliferation of other cells. These data suggest that any injury to the airway epithelium resulting in the production of IL-13 from infiltrating inflammatory cells may provoke the release of soluble TGF-α from the airway epithelium. The availability of this growth factor may contribute to the subepithelial fibrosis observed in chronic asthma.

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