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Asbestos-Induced Lung Inflammation and Epithelial Cell Proliferation Are Altered in Myeloperoxidase-Null Mice

¹ Department of Pathology, College of Medicine, ² Department of Civil and Environmental Engineering, and ³ Department of Biostatistics, University of Vermont, Burlington, Vermont; ⁴ Department of Anesthesiology and Center for Free Radical Biology, University of Alabama at Birmingham, Alabama; and ⁵ Center for Cardiovascular Diagnostics, Cleveland Clinic Foundation, Cleveland, Ohio

Requests for reprints: Brooke T. Mossman, Department of Pathology, College of Medicine, University of Vermont, 215 HSRF, 89 Beaumont Avenue, Burlington, VT 05404. Phone: 802-656-0382; Fax: 802-656-8892; E-mail: Brooke.Mossman{at}uvm.edu.

Asbestos fibers are carcinogens causing oxidative stress and inflammation, but the sources and ramifications of oxidant production by asbestos are poorly understood. Here, we show that inhaled chrysotile asbestos fibers cause increased myeloperoxidase activity in bronchoalveolar lavage fluids (BALF) and myeloperoxidase immunoreactivity in epithelial cells lining distal bronchioles and alveolar ducts, sites of initial lung deposition of asbestos fibers. In comparison with sham mice, asbestos-exposed myeloperoxidase-null (MPO–/–) and normal (MPO+/+) mice exhibited comparable increases in polymorphonuclear leukocytes, predominately neutrophils, in BALF after 9 days of asbestos inhalation. Differential cell counts on BALF revealed decreased proportions of macrophages and increased lymphocytes in all mice exposed to asbestos, but numbers were decreased overall in asbestos-exposed myeloperoxidase-null versus normal mice. Asbestos-associated lung inflammation in myeloperoxidase-null mice was reduced (P 0.05) in comparison with normal asbestos-exposed mice at 9 days. Decreased lung inflammation in asbestos-exposed myeloperoxidase-null mice at 9 days was accompanied by increases (P 0.05) in Ki-67- and cyclin D1-positive immunoreactive cells, markers of cell cycle reentry, in the distal bronchiolar epithelium. Asbestos-induced epithelial cell proliferation in myeloperoxidase-null mice at 30 days was comparable to that found at 9 days. In contrast, inflammation and epithelial cell proliferation in asbestos-exposed normal mice increased over time. These results support the hypothesis that myeloperoxidase status modulates early asbestos-induced oxidative stress, epithelial cell proliferation, and inflammation.

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