? ? Airway mucus hypersecretion is a prominent feature of numerous lung pathologies. Determining its role in exacerbation of lung disease by airborne particulates is the focus of this application, as well as future proposals. The primary goal is to unveil signaling pathways altered by asbestos that regulate the expression of hClcal/mclcaS and muc5ac, two genes involved in mucin production and/or secretion. This hypothesis will be tested in three specific aims which encompass both in vivo and in vitro approaches to elucidate signaling pathways that control the regulation of these genes, and their involvement in asbestos-induced mucus metaplasia. The first hypothesis is that expression of mclcaS and development of mucus production will be ? depressed in CC10-dominant negative (dn)MEK mice compared to normal mice exposed to chrysotile asbestos via inhalation. Furthermore, Clara cells within the bronchiolar airways will acquire the ability to produce and secrete mucus following asbestos insult. To test this hypothesis, the candidate will observe asbestos-induced gene changes in lung epithelial cells of mice expressing an epithelial cell-specific dnMEK transgene previously characterized in the candidate's current lab. The second hypothesis states that asbestos fibers induce the expression of hClcal and muc5ac by altering epidermal growth factor receptor (EGFR)/mitogen activated protein kinase kinase-1 (MEK)/activator protein-1 (AP-1) signaling pathways through the generation of reactive oxygen species (ROS). The third hypothesis is that the asbestos-induced production of Muc5ac requires the presence and up-regulation of hClcal, and that this induction is dependant upon signaling through EGFR/MEK/AP-1. The experiments for aims two and three will be carried out in human lung epithelial cell lines using inhibitors of MAPK signaling pathways and si (small interference)-RNA constructs. Elucidation of critical genes involved in lung injury following asbestos exposure could aid in the development of therapeutic and prognostic strategies to treat asbestos-associated lung diseases. The long term goal of these studies is elucidating mechanisms of gene regulation by pathogenic environmental contaminants, and how these events lead to diseases such as fibrosis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, and cancer. The hope is that enhancing the basic understanding of these diseases will lead to appropriate risk assessment and future development of therapeutic strategies for airborne related diseases. ? ? ? ?
| Sabo-Attwood, Tara; Ramos-Nino, Maria E; Eugenia-Ariza, Maria et al. (2011) Osteopontin modulates inflammation, mucin production, and gene expression signatures after inhalation of asbestos in a murine model of fibrosis. Am J Pathol 178:1975-85 |
