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Airway Epithelial NF-B Activation Modulates Asbestos-Induced Inflammation and Mucin Production In Vivo¹

Astrid Haegens^*, Trisha F. Barrett^*, Joanna Gell^*, Arti Shukla^*, Maximilian MacPherson^*, Pamela Vacek, Matthew E. Poynter, Kelly J. Butnor^*, Yvonne M. Janssen-Heininger^*, Chad Steele and Brooke T. Mossman^2,*

^* Department of Pathology, Department of Medical Biostatistics, and Department of Medicine, University of Vermont, Burlington, VT 05405; and Pediatric Pulmonary Division, Children’s Hospital of Pittsburgh, PA 15213

To investigate the role of bronchiolar epithelial NF-B activity in the development of inflammation and fibrogenesis in a murine model of asbestos inhalation, we used transgenic (Tg) mice expressing an IB mutant (IBsr) resistant to phosphorylation-induced degradation and targeted to bronchial epithelium using the CC10 promoter. Sham and chrysotile asbestos-exposed CC10-IBsr Tg⁺ and Tg^– mice were examined for altered epithelial cell proliferation and differentiation, cytokine profiles, lung inflammation, and fibrogenesis at 3, 9, and 40 days. KC, IL-6 and IL-1 were increased (p 0.05) in bronchoalveolar lavage fluid (BALF) from asbestos-exposed mice, but to a lesser extent (p 0.05) in Tg⁺ vs Tg^– mice. Asbestos also caused increases in IL-4, MIP-1, and MCP-1 in BALF that were more elevated (p 0.05) in Tg⁺ mice at 9 days. Differential cell counts revealed eosinophils in BALF that increased (p 0.05) in Tg⁺ mice at 9 days, a time point corresponding with significantly increased numbers of bronchiolar epithelial cells staining positively for mucus production. At all time points, asbestos caused increased numbers of distal bronchiolar epithelial cells and peribronchiolar cells incorporating the proliferation marker, Ki-67. However, bronchiolar epithelial cell and interstitial cell labeling was diminished at 40 days (p 0.05) in Tg⁺ vs Tg^– mice. Our findings demonstrate that airway epithelial NF-B activity plays a role in orchestrating the inflammatory response as well as cell proliferation in response to asbestos.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by Grant P01HL67004 from the National Heart, Lung and Blood Institute.

² Address correspondence and reprint requests to Professor Brooke T. Mossman, Department of Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405. E-mail address: Brooke.Mossman{at}uvm.edu

³ Abbreviations used in this paper: ATII, alveolar type II; BAL, bronchoalveolar lavage; BALF, BAL fluid; RPA, RNase protection assay; Tg, transgenic.

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