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Pneumonia is inflammation in the lungs, which is usually caused by an infection. The symptoms of pneumonia can vary from mild to life-threatening, where severe illness is often observed in vulnerable populations like children, older adults, and those with preexisting health conditions. Vaccines have greatly reduced the burden of some of the most common causes of pneumonia, and the use of antimicrobials has greatly improved the survival to this infection. However, pneumonia survivors do not return to their preinfection health trajectories but instead experience an accelerated health decline with an increased risk of cardiovascular disease. The mechanisms of this association are not well understood, but a persistent dysregulated inflammatory response post-pneumonia appears to play a central role. It is proposed that the inflammatory response during pneumonia is left unregulated and exacerbates atherosclerotic vascular disease, which ultimately leads to adverse cardiac events such as myocardial infarction. For this reason, there is a need to better understand the inflammatory cross talk between the lungs and the heart during and after pneumonia to develop therapeutics that focus on preventing pneumonia-associated cardiovascular events. This review will provide an overview of the known mechanisms of inflammation triggered during pneumonia and their relevance to the increased cardiovascular risk that follows this infection. We will also discuss opportunities for new clinical approaches leveraging strategies to promote inflammatory resolution pathways as a novel therapeutic target to reduce the risk of cardiac events post-pneumonia.

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Background: Pneumonia is inflammation of the lungs caused by a bacterial or viral infection. Recent studies show an association between pneumonia and an increased risk of a heart attack. It is proposed that inflammatory pathways are left uncontrolled, which exacerbates atherosclerotic vascular disease. As a result, there is a need to develop therapeutics for attenuating pneumonia-associated inflammation to reduce atherosclerotic plaque build-up and improve concomitant cardiac complications. 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 function 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). EPA is used locally by cells and readily degraded in the body. To overcome this barrier, EPA can be encapsulated in nanoparticle carriers to increase bioavailability and therapeutic delivery. We hypothesize that delivery of EPA nanoparticles into the lungs may control the persistent inflammatory response following pneumonia and reduce atherosclerotic burden. Results: In vitro in mouse bone-marrow derived macrophages stimulated with gram-negative or gram-positive toxins, EPA nanoparticles reduced the production of pro-inflammatory markers including IL-6 and TNFa measured using western blot, qPCR and ELISA. To test the efficacy of EPA-nanoparticles in vivo , we have developed a mouse model of atherosclerosis combined with S. pneumoniae lung infection. We are currently evaluating the impact of infection with S.pneumoniae on atherosclerosis progression and will determine whether EPA-nanoparticles can be used to prevent atherosclerotic inflammation and plaque progression. Clinical Impact: The nanoparticles used are already FDA approved, and regular consumption of EPA has well supported benefits. As such, it is possible that this project may translate into a clinical setting more readily.

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