Background/Purpose: Treatment of acute gout involves the use of NSAIDs, colchicine or corticosteroids. Unfortunately, co-morbid conditions such as chronic kidney disease, peptic ulcer disease and congestive heart failure make the use of these agents dangerous or contraindicated. Therefore, there is an unmet need for new therapies in acute gout. Eicosanoids have been implicated in a vast number of inflammatory conditions, such as gout. Currently, over a hundred different eicosanoids have been identified, with many having potent bioactive signaling capacity. Monosodium uric (MSU) crystals are known to induce eicosanoid inflammatory mediators. We hypothesized that a complete study of these eicosanoid mediators might identify new therapeutic targets in acute gout.

Methods: Complete eicosanoid profiling was determined by ultra-performance liquid chromatography-electrospray ionization triple quadrupole mass spectrometric (UPLC-QTRAP/MS/MS) method, and was conducted in peritoneal lavage 7 hours after MSU (3mg) intraperitoneal injection, and in bone marrow derived macrophages (BMDM) supernatants after either MSU (0.25mg/ml) stimulation for 4 hours, or LPS (100ng/ml) for one hour plus MSU (0.25mg/ml) stimulation for 4 hrs. To test the hypothesis that selective 12/15-lipoxygenase (LOX) inhibition by intraperitoneal ML351 (50mg/kg) protects against MSU inflammation, we used two MSU crystals-induced inflammation murine models: subcutaneous air-pouch model to measure MSU crystal-induced cytokine production by ELISA and inflammatory cell accumulation 7hrs after MSU (3mg) injection; and intraarticular injection of MSU (100μg) crystals. Histopathological studies from the injected joints were carried after 7hrs.

Results: Complete eicosanoid profiling identified COX and 15 LOX eicosanoids as the mediators more abundant in BMDM after LPS/MSU stimulation. Of note, only 15 LOX eicosanoids were released after just MSU stimulation in BMDM. Interestingly, 12/15 LOX eicosanoids were highly represented in the peritoneal lavages after MSU intraperitoneal injection. In the in vivomodels, intra-articularly injected MSU crystals provoked a neutrophilic infiltration that was significantly reduced in joints from mice treated with ML351 inhibitor. MSU crystal-induced inflammatory cell infiltration was also significantly attenuated in mice treated with the 12/15 LOX inhibitor. Of interest, amount of IL-6 and IL-1β in the pouch were not decreased in the 12/15 LOX inhibitor group suggesting an IL-1β independent effect.

Conclusion: 12/15 LOX eicosanoids are abundant after MSU crystal stimulation, and their inhibition by ML351 decreased cellular infiltration in two models of MSU crystal induced inflammation. Therefore, selective 12/15 LOX inhibition might be an attractive potential target in acute gout flares safer than the current treatments.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/1215-lipoxygenase-inhibition-by-ml351-protects-against-uric-acid-crystal-induced-acute-arthritis-in-mice/