Abstract 706: The Development Of New Therapies Targeting Pneumonia-accelerated Atherosclerosis

Abstract

Background/Objectives: Pneumonia is inflammation of the lungs caused by an infection. Recent studies show an association between pneumonia and an increased risk of a heart attack. This is likely caused by the persistent inflammatory burden in the lungs and arterial vasculature even 30-45 days after clearance of the infection. Therefore, as inflammation is a strong contributor to the progression of atherosclerosis, there is a need to address the persistent inflammatory burden in this patient population. A normal course of inflammation begins with an initial pro-inflammatory phase and ends with a resolution phase, which is marked by tissue return to homeostasis. During pneumonia, resolution pathways are impaired. Returning resolution processes to normal functioning may prove to be an effective strategy to attenuate prolonged pneumonia-associated inflammation. Resolution pathways are mediated by fatty acid derivatives termed specialized pro-resolving lipid mediators (SPMs), the metabolites of poly-unsaturated fatty acids such as eicosapentaenoic acid (EPA). To improve the therapeutic impact, EPA can be encapsulated in nanoparticle carriers to increase bioavailability and therapeutic delivery. We hypothesize that delivery of EPA nanoparticles into the lungs will control the persistent inflammatory response following pneumonia and reduce atherosclerotic burden. Results: Bone-marrow derived macrophages (mouse) stimulated with gram-positive toxins and EPA-nanoparticles demonstrated reduced expression of pro-inflammatory markers measured using ELISA. We have also developed a mouse model of atherosclerosis combined with S. pneumoniae lung infection. Without EPA administration, S.pneumoniae infection followed by 8 weeks on a high fat diet resulted in a trend towards increased plaque size and lesion lipid content. We are currently evaluating if our EPA-nanoparticles promote resolution processes in the S.pneumoniae mouse model. Clinical Impact: We believe that promotion of resolution pathways via increasing SPM production will prove to be an effective strategy to address inflammation during pneumonia while reducing the risk of suppressive effects on the immune system often caused by currently prescribed anti-inflammatories.