D19-09 The Acute Bronchodilatory Effects of Simvastatin Using Non-Human Primate Precision-Cut Lung Slices: A Therapy for Obstructive Airway Diseases

Rationale The 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitor, Simvastatin, attenuates human airway smooth muscle (ASM) contraction within 4-6 hours via mevalonate (MA)-dependent depletion in the ASM. We also previously described the rapid onset (within 5-10 minutes) bronchodilatory effects and MA-, GGPP-, and Cofilin-dependent inhibition of ASM contraction of Pitavastatin, a related statin drug. The fast-acting bronchodilatory and ASM-relaxing effects of Pitavastatin were unexpected. We now hypothesize that Simvastatin has similar rapid onset bronchodilatory effects as Pitavastatin by virtue of their shared mechanism of action (MOA). Methods We established and validated the use of precision-cut lung slices (PCLS) from non-human primates (NHP) rhesus macaques. Normal healthy adult male and female animals were used to produce lung slices of 250-300 um thickness. After a period of acclimation (2-3 days), we confirmed viability of these NHP by three assays: live-dead imaging, airway epithelial ciliary beating, and histamine (Hist, 5 uM)-induced bronchoconstriction (observed at 5-minute intervals for 50 minutes). We had 4 treatment groups: DMSO (negative control, drug vehicle), Simvastatin (Sim, 200 uM), Dexamethasone (Dex, 1 uM), the beta2-agonist Formoterol (Form, 20 nM). Results PCLS ex vivo lung explants were pre-contracted with Hist for 10 minutes to achieve at least 40-50% bronchoconstriction from baseline. Simvastatin (Sim, 200 uM) caused rapid bronchodilation within 5-10 minutes and had a maximal 40% bronchodilation within 30-40 minutes. By comparison DMSO had no effect in either direction, Dex did not cause bronchodilation, and Form bronchodilated the airways within 5 minutes in a pattern similar to Sim. Conclusions The beneficial bronchodilatory effects of Sim in our NHP ex vivo model was similar to the beta2-agonist Form and suggests a new role for Sim as a novel bronchodilator for the treatment of airway diseases, similar to Pitavastatin as previously reported. The rapid-onset effect of Sim cannot be a biochemical or MA dependent effect given the short duration (minutes). MA-dependent mechanisms take hours to days for full effect. This likely represents a direct chemical effect or a MOA involving rapid signal transduction pathways. Plans to develop innovative new Sim formulations for inhalation are ongoing.