Osteopontin modulates inflammation, mucin production, and gene expression signatures after inhalation of asbestos in a murine model of fibrosis

Academic Article

Abstract

  • Inflammation and lung remodeling are hallmarks of asbestos-induced fibrosis, but the molecular mechanisms that control these events are unclear. Using laser capture microdissection (LCM) of distal bronchioles in a murine asbestos inhalation model, we show that osteopontin (OPN) is up-regulated by bronchiolar epithelial cells after chrysotile asbestos exposures. In contrast to OPN wild-type mice (OPN+/+) inhaling asbestos, OPN null mice (OPN-/-) exposed to asbestos showed less eosinophilia in bronchoalveolar lavage fluids, diminished lung inflammation, and decreased mucin production. Bronchoalveolar lavage fluid concentrations of inflammatory cytokines (IL-1β, IL-4, IL-6, IL-12 subunit p40, MIP1α, MIP1β, and eotaxin) also were significantly less in asbestos-exposed OPN-/- mice. Microarrays performed on lung tissues from asbestos-exposed OPN +/+ and OPN-/- mice showed that OPN modulated the expression of a number of genes (Col1a2, Timp1, Tnc, Eln, and Col3a1) linked to fibrosis via initiation and cross talk between IL-1βand epidermal growth factor receptor-related signaling pathways. Novel targets of OPN identified include genes involved in cell signaling, immune system/defense, extracellular matrix remodeling, and cell cycle regulation. Although it is unclear whether the present findings are specific to chrysotile asbestos or would be observed after inhalation of other fibers in general, these results highlight new potential mechanisms and therapeutic targets for asbestosis and other diseases (asthma, smoking-related interstitial lung diseases) linked to OPN overexpression. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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    Digital Object Identifier (doi)

    Author List

  • Sabo-Attwood T; Ramos-Nino ME; Eugenia-Ariza M; MacPherson MB; Butnor KJ; Vacek PC; McGee SP; Clark JC; Steele C; Mossman BT
  • Start Page

  • 1975
  • End Page

  • 1985
  • Volume

  • 178
  • Issue

  • 5