Blood-borne bacteria can lead to inflammation, coagulation, sepsis and mortality. New non- immunosuppressive treatments are needed. Phagocytes are the major white blood cells [neutrophils (PMN), monocytes and macrophages (MF)] key to successful defense as well as clearance of debris and bacteria. Ideally acute inflammation is protective and normally self-limited to resolve on its own, namely timely resolution. It is now appreciated that, when uncontrolled, inflammation is a component of many widely occurring chronic diseases. This proposal?s overall goal is to elucidate the lipid mediators that link coagulation to resolution of inflammation. With support from GM38765, we obtained the first evidence (and now other investigators) that resolution is an active process with identification of novel resolution phase mediators and their receptors. This new super-family of specialized pro-resolving mediators (SPM) includes resolvins (Rv), protectins (PD) and maresins (MaR). Each of the main SPM have proven to be anti-inflammatory, pro-resolving and stimulate killing of bacteria. It?s now evident that resolution of inflammation and its link(s) to blood coagulation are uncharted and critically needed. This proposal is based on innovative findings giving new concepts where we uncovered an entirely new link between coagulation-resolution of inflammation involving specific SPM. We identified a specific cluster of SPM produced during coagulation using a new lipid mediator-metabolipidomics profiling approach devised in this lab. We found hemorrhagic exudates increase SPM in mice, and in human whole blood this specific SPM cluster (RvE1, RvD1, RvD5, LXB4 and MaR1) is temporally produced. The cluster includes maresin 1 (MaR1), a potent regulator of PMN and MF responses in resolution. Unique and innovative features of this proposal include systematic identification of resolution pathway mediators together with resolution indices to assess in hemorrhagic exudates, cells and chemical mediators. Our mission is to test the following new hypothesis: Coagulation of blood temporally activates a specific cluster of SPM (RvE1, RvD1, RvD5, LXB4 and MaR1) linking coagulation to resolution and innate host defense. Together with resolvins and their receptors, MaR1 is a potent agonist governing local phagocyte resolution responses via new receptors required for effective microbial killing. To address this, a research design of 3 specific aims and multi-pronged approach will be carried out: 1) Profiling of hemorrhagic exudates and coagulation activating SPM-resolution; 2) Evidence for novel MaR1 pro-resolving receptors; and 3) Validation of specific MaR1 receptor pro-resolving function(s). Since new anti-inflammatories are needed that are not immunosuppressive, our results from these innovative studies will impact this scientific area and patient care by providing rigorous evidence for novel resolution pathways and agonist-driven mechanisms controlling resolution of bacterial inflammation. Long-term objectives include providing novel approaches for clinicians to activate resolution and improve treatment of excessive inflammation.
Inflammation is normally protective and should self resolve. When uncontrolled, inflammation underlies many widely occurring diseases. This proposal focuses on elucidating the body?s own new resolution mediators that link blood coagulation to resolution of acute inflammation, its termination and bacterial clearance needed to obtain innovative non-immunosuppressive treatment approaches.
Showing the most recent 10 out of 102 publications
