Abstract 14038: Deficiency of Arachidonate 5-Lipoxygenase Intensifies Sepsis-Induced Cardiac Dysfunction in Aging

Abstract

Introduction: Age-related cardiac dysfunction is a prime component of sepsis-induced multi-organ failure in the clinical setting. Arachidonate 5-lipoxygenase (5LOX) pathway and 5LOX-derived lipid mediators are critical in early inflammation and immune response signaling. In addition, 5LOX derived mediators activate macrophages and other cells to counter infection via surface receptors. However, the role of 5LOX in sepsis-induced cardiac dysfunction superimposed on aging is still under-investigated. Hypothesis: Given that the inflammatory role of 5LOX, we tested the hypothesis that deletion of 5LOX in aging would be deleterious to cardiac function in sepsis. Methods: To induce sepsis, lipopolysaccharide (LPS; E. coli O55:B5) was injected into aging male C57BL/6J (WT) and 5LOX -/- mice (18-20 months). To study heart function, molecular, and cellular mechanisms, mice were challenged with a single subcutaneous dose of LPS (20mg/kg) for 4 hours. Survival was monitored for 7 days post-LPS challenge to testify therapeutic application of outcome. Results: Lack of 5LOX increased mortality (~70%) in aging mice with severe depression in cardiac function post-LPS compared with age-matched WT controls. LPS challenge in 5LOX -/- aging mice decreased resolution mediators (RvD1) and inflammation mediators (LTB 4 ) in the spleen with robust recruitment of leukocytes in a spleno-cardiac manner indicative of non-resolving inflammation. The spleen monocytes (CD11b + ), macrophages (F4/80 + ), and neutrophils (Ly6G + ) were significantly decreased in 5LOX -/- mice post-LPS with the consistent increase in the heart. The absence of 5LOX blunted physiological inflammatory response in aging by attenuating TLR4 and CD169 in both the heart and spleen as a sign of immunosuppression. Conclusion: Our results suggest that 5LOX -/- aging mice fail to initiate physiological inflammation-resolution signaling in response to LPS-induced septic shock, leading to cardiac dysfunction and immunosuppression. Our study highlights the role of 5LOX and 5LOX-derived mediators as targets for the inflammation-resolution response and therapeutics potential in aging-related sepsis.