Inhaled Carbon Monoxide Accelerates Resolution of Inflammation via Novel Pro‐resolving Mediators and Heme Oxygenase‐1

Abstract

Resolution of acute inflammation is an active event accompanied by biosynthesis of specialized pro‐resolving mediators (SPM). We employed a systems approach to determine the impact of carbon monoxide (CO) in resolution active programs. In zymosan induced murine peritonitis model, inhaled CO gas (250 ppm) significantly limited PMN infiltration (~44% reduction at 6h) into peritoneum and shortened resolution interval. We profiled exudate lipid mediators (LM), CO reduced leukotriene (LT) B4 (21±11 vs. 59±24 pg/mouse at 6h) and elevated SPM including resolvin (Rv) E2 (1,201±197 vs. 864±125 pg/mouse), RvD1 (27±4 vs. 16±5 pg/mouse) and maresin 1 (MaR1; 26±9 vs. 15±3 pg/mouse). With human macrophages, SPM (10 pM–10 nM) elevated heme oxygenase (HO)‐1 (~50% at 8h). CO also enhanced HO‐1 expression (~25%), an action reversed by blockage of a key SPM biosynthesis enzyme 15‐lipoxygenase (LOX) type 1. CO increased phagocytosis with human macrophage, that was further enhanced by SPM. This CO increased phagocytosis was blocked by 15‐LOX inhibition and SPM stimulated phagocytosis was diminished by HO‐1 inhibition. In murine peritonitis, CO inhalation significantly increased numbers of macrophages carrying ingested apoptotic PMN at 12h in both exudates (1.9 vs. 3.4%) and inguinal lymph nodes (2.0 vs. 4.7%).These results indicate that CO accelerates resolution of acute inflammation, shortens resolution intervals, enhances macrophage efferocytosis and temporally regulates local levels of LM/SPM. Moreover, they provide pro‐resolving mechanisms for HO‐1/CO that is part of the SPM‐initiated resolution circuit.