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(American Journal of Pathology. 2005;167:1243-1256.)
© 2005 American Society for Investigative Pathology

Gene Expression Profiles Reveal Increased mClca3 (Gob5) Expression and Mucin Production in a Murine Model of Asbestos-Induced Fibrogenesis

Tara Sabo-Attwood^*, Maria Ramos-Nino^*, Jeffrey Bond, Kelly J. Butnor^*, Nicholas Heintz^*, Achim D. Gruber, Chad Steele, Douglas J. Taatjes^*, Pamela Vacek^¶ and Brooke T. Mossman^*

From the Departments of Pathology,^* Microbiology and Molecular Genetics, and Medical Biostatistics,^¶ University of Vermont, Burlington, Vermont; the Pediatric Pulmonary Division, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania; and the Department of Veterinary Pathology, Free University Berlin, Berlin, Germany

To elucidate genes important in development or repair of asbestos-induced lung diseases, gene expression was examined in mice after inhalation of chrysotile asbestos for 3, 9, and 40 days. We identified changes in the expression of genes linked to proliferation (cyclin B2, CDC20, and CDC28 protein kinase regulatory subunit 2), inflammation (CCL9, CCL6, complement component 1, chitinase3-like 3, TNF superfamily member 10, and IL-1B), and matrix remodeling (MMP12, MMP3, integrin X, and cathepsins K, Z, B, and S). The most highly induced gene at all time points was mclca3 (gob5), a putative calcium-activated chloride channel involved in the regulation of mucus production and/or secretion. Using histochemistry, we demonstrated accumulation of mucus and increased mClca3 protein in the bronchiolar epithelium of asbestos-exposed mice at all time points but peaking at 9 days. Cytokine levels (interleukin-1ß, interleukin-4, interleukin-6) in bronchoalveolar lavage fluid also increased at 9 days, suggesting Th2-mediated immunity may play a role in asbestos-induced mucus production. In contrast, levels of cathepsin K, a potent elastase, increased between 3 and 40 days at both the mRNA and protein levels, localizing primarily in CD45-positive leukocytes and interstitial cells. Identification of genes involved in lung injury and remodeling after asbestos exposure could aid in defining mechanisms of airborne particulate-induced disease and in developing therapeutic strategies.

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