PR000600 (Project)

Description:Innovative and novel therapies are urgently needed for the treatment of patients with severe asthma, especially those who are refractory to standard-of-care bronchodilators and inhaled corticosteroids. The Zeki lab is investigating the role of the mevalonate (MA) pathway, in the pathogenesis of airway inflammation and remodeling. Although statins all inhibit HMGCR in the same manner in terms of enzyme binding site, the statins’ varied physiochemical properties with respect to their polarity (i.e. lipophilicity) result in very different immune and lipid effects. The major significance of this work is to advance a new class of inhaler therapies for asthma; the statins which work by an entirely different mechanism than current ICS/LABA mainstays. Evidence suggests that statins may have an additive benefit to corticosteroids in asthma, thereby confirming a unique mechanism, namely via MVA pathway inhibition. This becomes particularly important in the severe asthma population which is highly corticosteroid-resistant, is poorly controlled with high exacerbation rates and hospitalizations, and has the highest healthcare costs of all asthma phenotypes. In essence, the potential public health impact of even an incremental improvement in asthma symptom control cannot be underestimated. Even the prevention of 1 asthma attack preserves lung function and reduces the adverse personal and financial impact. This study aimed to determine if statin polarity affects airway drug concentration and systemic drug absorption and to determine the effect of inhaled statins on naïve airway immune cell populations and alveolar-capillary membrane and epithelial barrier integrity in healthy rhesus monkeys. In this particular component of the study, we investigated the metabolic effects resulting from the use of statins in these healthy rhesus monkeys. Specifically, the Newman lab analyzed for lipid mediator (oxylipin, endocannabinoid, fatty acid, and nitro lipid) in lung and trachea tissue, plasma, and BAL and bile acid changes in the lung and trachea tissue and plasma.