Resolution of Gouty Inflammation

描述（由申请人提供）：随着新的概念和不断发展的方法，这个实验室在过去的40年里一直致力于急性痛风性关节炎的研究，这既是因为它的内在重要性，也是因为它是急性炎症反应的模型。在本应用中，我们根据最近脂质代谢途径的进展来评估急性痛风（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，为什么尽管尿酸盐晶体持续存在，但未经治疗的发作通常会消退。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、前列腺素）和其他传播和放大炎症反应的介质的产生。我们假设早期的脂质介质为后来具有抗炎特性的脂质介质（脂毒素和可能的新部分）播下了种子，从而导致解决。我们进一步认为脂质介质的重编程可能部分解释了秋水仙碱等治疗剂的作用。在Aim 1中，我们将采用脂质组学分析，通过lc - uv串联质谱法来检测体外由尿酸钠或焦磷酸钙晶体（分别为痛风和伪痛风）与人中性粒细胞（PMN）相互作用产生的脂质介质。在Aim 2中，我们将用光谱法研究秋水仙碱和其他抗炎剂（阿司匹林、糖皮质激素）对促炎性和抗炎性脂质介质生成的影响。本研究的更大意义在于为基于本研究的内源性脂质介质的新型抗炎药的应用奠定了基础。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。痛风炎症的控制成为抗炎治疗新方法的典范。我们正在利用脂质代谢途径的最新进展来解释急性痛风性关节炎这一常见疾病的临床事实。我们假设早期的炎性脂质介质为后来具有抗炎特性的介质播下了种子，从而导致解决。我们进一步认为，脂质介质的这种重编程可能部分解释了秋水仙碱等治疗剂的作用，并可能导致对这种情况的更好治疗。

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.