L3 Leptin Modulates Airway Remodeling Processes and Responses to Interleukin-13 in Lung Fibroblasts in a Murine Model of Chronic Allergic Airways Disease Jennifer L. Ingram, Robert W. Sigmon, Barbara Theriot, Michael Ghio, Akhil Hegde, Dave Francisco, Julia K. L. Walker, Monica Kraft, MD; Duke University, Durham, NC. RATIONALE: Obese asthma is characterized by late-onset disease and reduced T-helper 2 (TH2)-driven inflammation. Leptin is an adipokine produced in elevated levels in obese individuals. Interleukin-13 (IL-13) is a TH2 cytokine that directs airway remodeling in asthma, including subepithelial fibrosis. We hypothesized that leptin acts to suppress lung fibroblast responses to IL-13 in obese asthma. METHODS: Wildtype (C57BL6), leptin-resistant (db/db), and leptindeficient (ob/ob) mice (n53 per group) were intranasally administered house dust mite (HDM) allergen (2.5 mg/mL) or saline as control 5 days/ week for 6 weeks. Lung mechanics were measured using the forced oscillation technique, and Newtonian resistance was calculated. Lung sections were stained with Masson’s trichrome. Lung fibroblasts were cultured from digested lung tissue and exposed to serum-free media or 50 ng/mL IL-13 for 24 hours. Lung fibroblast invasion and migration were determined using Matrigel assays, and mRNA expression was analyzed using quantitative RT-PCR. RESULTS: Following exposure to HDM, peribronchiolar trichrome staining and IL-13-induced lung fibroblast invasion and migration were significantly reduced in ob/ob and db/db mice as compared to wildtype (p<0.05). IL-13-stimulated elastin gene expression in lung fibroblasts was significantly increased in ob/ob mice as compared to wildtype (p<0.05). Compared to saline treatment, exposure to HDM resulted in significantly increased Newtonian airway resistance (p<0.05) in wildtype and db/db mice, but not ob/ob mice. Saline-treated ob/ob mice were hyperresponsive and displayed a paradoxical response to methacholine challenge. CONCLUSIONS: Lung fibroblasts from leptin-deficient and –resistant mice demonstrate impaired responses to IL-13, which may contribute to altered airway remodeling and lung mechanics in obese asthma.