Resolution of Gouty Inflammation

描述（由申请人提供）：随着新概念和不断发展的方法，该实验室在40多年来一直致力于急性痛风性关节炎的研究，这既是因为其内在的重要性，也是因为其作为急性炎症反应模型。在本申请中，我们根据脂质代谢途径的最新进展评估急性痛风（和假性痛风）关节炎的发病机制，以解释痛风的临床事实-特别是，为什么未经治疗的攻击通常会消退，尽管持续存在尿酸盐晶体。尿酸盐晶体与白细胞的相互作用导致内源性促炎脂质（白三烯、白藜芦醇）和其他介质的产生，这些介质传播并放大炎症反应。我们推测，早期脂质介质播下种子，为后来的（脂氧素，也许是新的部分）与抗炎特性，导致决议。我们进一步建议，这种脂质介质的重新编程可以部分解释治疗剂，如秋水仙碱的作用。在目的1中，我们将采用脂质组学分析，通过LC-UV-串联质谱法来检查体外产生的脂质介质的相互作用，尿酸盐或焦磷酸钙晶体（痛风和假痛风，分别）与人中性粒细胞（PMN）随着时间的推移。在目标2中，我们将通过光谱法研究秋水仙碱和其他抗炎剂（阿司匹林，糖皮质激素）对促炎和抗炎脂质介质产生的影响。这项工作的更大意义是作为序幕，使用新的抗炎剂的基础上内源性脂质介质在这里研究。这种基于天然介质的药物可能比目前可用的治疗方式毒性更小。痛风炎症的控制，然后成为一种新的抗炎治疗方法的模型。我们采用脂质代谢途径的最新进展，解释常见疾病急性痛风性关节炎的临床事实。我们假设早期炎症脂质介质为后来的抗炎特性播下种子，导致解决。我们进一步建议，这种脂质介质的重新编程可以部分解释治疗药物如秋水仙碱的作用，并可能导致更好的治疗这种情况。

DESCRIPTION (provided by applicant): 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.