Role of specialized pro-resolving mediators of inflammation resolution in emphysema: analyses of SPIROMICS and LEEP

Project Summary/Abstract Inflammation is a central pathologic mechanism across a variety of chronic diseases, including cardiovascular, metabolic, and pulmonary disorders. Current approaches to disease management center on non-specific strategies to attenuate local and systemic inflammation to improve health outcomes. However, emerging data supports the presence of endogenous mechanisms increasing an individual’s capacity to resolve inflammation, highlighting a yet untapped novel therapeutic target. New insights into the resolution of inflammation reveal this process can be mediated by lipid-derived specialized pro-resolving mediators (SPMs), which trigger a cascade of events that attenuate the inflammatory response. SPMs have been implicated in the resolution of inflammation in a variety of diseases such as cardiovascular disease, COVID-19, and asthma; however, their role in resolving inflammation and counteracting lung injury in COPD patients is unknown. The objective of this proposal is to determine if greater plasma circulating SPM concentrations (reflecting individual capacity to resolve inflammation) are associated with improved respiratory outcomes in individuals with emphysema. To accomplish this, we will leverage data from the robustly-phenotyped and diverse Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort with available biospecimens in BIOLINCC. We will then validate our findings in The Losartan Effects on Emphysema Progression (LEEP) cohort. This proposal will accomplish the following specific aims: in SA 1: we will characterize circulating SPM concentrations as a biomarker for decreased potential to resolve chronic inflammation across two diverse populations of emphysema patients and identify risk factors (e.g.race/ethnicity, economic deprivation, etc.) for low SPM status. We hypothesize that there will be clear disparities in SPM across subpopulations reflecting differences in resilience to inflammatory insults. In SA 2: we will determine the association between circulating SPM concentrations and COPD health outcomes (i.e., lung function, respiratory symptoms) across two populations of emphysema patients. We hypothesize that greater SPM status will be associated with greater lung function and decreased respiratory morbidity. This work is directly related to the mission of NHLBI as it will provide foundational evidence for SPMs as an emerging therapeutic target for the prevention and treatment of COPD, stimulating basic discoveries about the causes of, and resilience factors for, lung disease and enabling the translation of these findings into clinical practice.