Phagocyte-derived lipid mediators (LM) play important roles in the inflammation. However, the roles of LM in resolution are unknown. In project 3, we identified novel LM (Aspirin-triggered 15-epi lipoxins; ATL) that act together with native lipoxins (LX) and appear to serve as potent endogenous """"""""anti-inflammatory LM"""""""". By preventing their rapid conversion, we enhanced their capacity to inhibit key events in neutrophil-mediated inflammation. Since phagocyte recruitment and their liberation of noxious agents are important in many diseases, we proposed the following novel hypotheses: Local enzymatic conversion of both """"""""pro- and anti-inflammatory"""""""". LM is required to orchestrate resolution by governing the phagocyte traffic required for resolution. Appearance of a newly identified oxo-eicosanoid reductase dictates the role of LM in resolution by regulate the duration and actions of both pro- and anti-inflammatory LM. To address this: Experiments in Aim I focus on establishing the role of """"""""oxo-eicosanoid reductase"""""""" (OER)"""""""" in oxo-LX further metabolism and on determining the temporal relationships between conversion of individual classes of eicosanoids during resolution and the impact of anti- inflammatory therapies.
Aim 2 will investigate the actions of dihydro- oxo-LX and dihydro-LX with human phagocytes and murine models of local inflammation. There are designed to determine whether LX-derived dihydro-oxo-metabolites carry signals for initiating resolution. Experiments proposed in Aim 3 will establish the properties of recombinant murine """"""""oxo-eicosanoid reductase"""""""" that will be clones, expressed, and directly compared with the human renal leukotriene B4 dehydrogenase and prostaglandin reductase. A second set of experiments will focus on their co-substrates.
In Aim 4 an integrated approach is taken to examine the role of LM in inflammation-resolution by establish temporal relationships for classes of LM in exudates from LTB4 receptor- transgenic and OER transgenic mice. Results from these studies will impact this area by providing direct evidence for the role of LM in resolution of local inflammation. The long-term goals are two fold: 1) to elucidate the role of host-derived small molecules and their inactivating pathways in the resolution of inflammation; and 2) use these endogenous molecules as biotemplates to provide the groundwork for novel therapeutic approaches
Showing the most recent 10 out of 98 publications
