#53 Intranasal simvastatin prevents allergen challenge-induced changes in lipid metabolites
Christopher Daniel Pascoe, CHRIM; Aruni Jha, CHRIM; Thomas H Mahood, CHRIM; Sujata Basu, CHRIM; Michel Aliani, St. Boniface Research Hospital; Andrew J Halayko, CHRIM
10% of asthmatics exhibit refractoriness to currently used therapies. Simvastatin, which has pleotropic anti-inflammatory and anti-oxidant effects, has been shown in our lab to effectively resolve airway inflammation and hyperresponsiveness at low intranasal doses in a mouse model of asthma. We employed high throughput technology to understand how simvastatin modulates the lung lipid metabolome to resolve airway inflammation and hyperresponsiveness. Hypothesis: Intranasal simvastatin alters the lipid metabolome to promote pathways supporting lipid degradation.
Female BALB/c mice (6-8 week) received intranasal HDM (25µg) 5 times per week for 2 weeks with or without concurrent SIN (6µg/kg/day). Bronchoalveolar lavage fluid (BALF) was collected 48 hours after the last HDM challenge using 1mL of ice-cold saline + 0.1% EDTA. For methanol:choloroform-extracted lipid metabolites, we used non-targeted LC-QTOF-MS-based metabolomics methodology to detect lipid-derived compounds with significant changes. Analysis of lipid signatures was done using multivariate methodology and online omics tools, MBrole 2.0 and Network Analyst.
We identified 1480 metabolites in BALF which were significantly different between allergen-naïve, HDM, and HDM+SIN (FDR<0.0001).
SIN prevents HDM-induced changes in metabolites associated with proteins responsible for phospholipid breakdown. Our new findings suggest that simvastatin delivered to the lungs may prevent the accumulation of bioactive oxidized lipids, in part by supporting their turnover.