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(Chest. 2003;123:384S-385S.)
© 2003 American College of Chest Physicians

Proliferation of the Airway Epithelium in Asthma*

Are Inflammatory Cells Required?

Brian W. Booth, BS; Dawn C. Newcomb, BS; Shaun A. McKane, BVSc, BSc(vet), PhD; Anne L. Crews, MS; Kenneth B. Adler, PhD; James C. Bonner, PhD and Linda D. Martin, PhD

From North Carolina State University (Mr. Booth, Mss. Newcomb and Crews, and Drs. McKane, Adler, and Martin), Raleigh, NC; and NIEHS (Dr. Bonner), Research Triangle Park, NC.

Correspondence to: Linda D. Martin, PhD, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough St, Raleigh, NC 27606; e-mail: linda_martin{at}ncsu.edu

Asthma is associated with a T helper type 2 phenotype in which interleukin (IL)-4, IL-5, and IL-13 predominate. In addition, the long-term presence of these inflammatory mediators is thought to lead to airway structural changes that are collectively referred to as airway remodeling. Data from our laboratory, and those of others, have suggested a role for IL-13 in the development of mucous cell hyperplasia that is associated with such remodeling. Others also have suggested a role for inflammatory cells such as neutrophils in mediating this process. Using normal human bronchial epithelial (NHBE) cells differentiated in vitro, we have shown recently that IL-13 (10 ng/mL for 24 h) induces the proliferation of NHBE cells via a mechanism that is dependent on the IL-13-induced release of transforming growth factor (TGF)-{alpha} by the epithelial cells. This epithelium-derived TGF-{alpha} then acts in an autocrine/paracrine manner to bind the epidermal growth factor receptor (EGFR) on these NHBE cells, enhancing proliferation. Specifically, soluble TGF-{alpha} is released by NHBE cells in response to IL-13 exposure (1 h), and the immunohistochemical analysis of cells exposed to IL-13 (after 1 and 4 h) has revealed a lack of membrane-bound TGF-{alpha} when compared to control cells. The IL-13-induced proliferative response can be blocked in a concentration-dependent manner by AG1478 (0.1, 1, and 5 µg/mL), which is a specific inhibitor of EGFR tyrosine kinase activity, and is eliminated by neutralizing TGF-{alpha} antibodies, while control antibodies (ie, anti-platelet-derived growth factor, epidermal growth factor [EGF], and heparin-binding EGF) have no effect.

These results suggest that the proliferation associated with epithelial cell hyperplasia during airway remodeling may not require the action of any mediators from inflammatory cells, except IL-13. This concept is further supported by the results of additional studies examining the effects of glucose on NHBE cell proliferation. NHBE cells exposed to hyperglycemic conditions (600 mg/dL) were found to increase their release of soluble TGF-{alpha} coincident with enhanced proliferation. This finding raises the possibility that a TGF-{alpha}/EGFR autocrine/paracrine loop may function to cause proliferation of airway epithelial cells under a variety of conditions, even in the absence of inflammatory cells. This concept has implications for the design of asthma therapeutics affecting airway remodeling.


   Footnotes
 
Abbreviations: EGF = epidermal growth factor; EGFR = epidermal growth factor receptor; IL = interleukin; NHBE = human bronchial epithelial; TGF = transforming growth factor





This Article
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Right arrow Articles by Martin, L. D.

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