With new concepts and evolving methodologies, this laboratory has kept returning over 4 decades to the study of acute gouty arthritis, both for its intrinsic importance and as a model of the acute inflammatory response. In this application, we evaluate the pathogenesis of acute gouty (and pseudogouty) arthritis in the light of recent advances in pathways of lipid metabolism, to explain clinical facts of gout - specifically, why untreated attacks typically subside despite the continued presence of urate crystals. The interaction of urate crystals with leukocytes leads to the generation of endogenous pro-inflammatory lipid (leukotrienes, prostaglandins) and other mediators that propagate and amplify the inflammatory response. We hypothesize that early lipid mediators sow the seeds for later ones (lipoxins and perhaps novel moieties) with anti-inflammatory properties, leading to resolution. We suggest further that this reprogramming of lipid mediators may explain in part the action of therapeutic agents such as colchicine.
In Aim 1 we will employ lipidomic analysis via LC-UV-tandem mass spectrometry to examine the lipid mediators generated in vitro by the interaction of monosodium urate or calcium pyrophosphate crystals (gout and pseudogout, respectively) with human neutrophils (PMN) over time.
In Aim 2 we will examine spectrometrically the effects of colchicine and other anti-inflammatory agents (aspirin, glucocorticoids) on the generation of pro- and anti-inflammatory lipid mediators. The larger significance of this work is as prologue to the use of novel anti-inflammatory agents based on the endogenous lipid mediators studied here. Such agents, based on natural mediators, are likely to be less toxic than the therapeutic modalities currently available. The control of gouty inflammation then becomes a model for a new approach to anti-inflammatory therapy. We are employing recent advances in pathways of lipid metabolism, to explain clinical facts of the common disease, acute gouty arthritis. We hypothesize that early inflammatory lipid mediators sow the seeds for later ones with anti-inflammatory properties, leading to resolution. We suggest further that this reprogramming of lipid mediators may explain in part the action of therapeutic agents such as colchicine, and could lead to better treatment for this condition. ? ? ?
