Marcouiller Patrick, Pelletier Jean-Pierre, Guévremont Mélanie, Martel-Pelletier Johanne, Ranger Pierre, Laufer Stefan, Reboul Pascal
Osteoarthritis Research Unit, Hôpital Notre-Dame, Centre hospitalier de l'Université de Montréal, Montréal, Québec.
J Rheumatol. 2005 Apr;32(4):704-12.
To study the mechanisms responsible for the cross-talk between lipoxygenase (LOX) and cyclooxygenase (COX) pathways in human osteoarthritic (OA) synovial explants, and to confirm the arachidonic acid (AA) shunting phenomenon and its influence on interleukin 1beta (IL-1beta) synthesis.
Synovial membrane explants were cultured in the absence or presence of different drugs that inhibit COX and/or LOX activities. Concentrations of prostaglandin E2 (PGE2), leukotriene B4 (LTB4), lipoxin A4 (LXA4), and IL-1beta were measured.
When membrane explants were incubated with naproxen (COX inhibitor) under unstimulated conditions, the production of LTB4 was dose-dependently enhanced, reaching a 5-fold increase over the control. This shunt could be partially reversed by the addition of exogenous PGE2. Under lipopolysaccharide (LPS) stimulation, both licofelone (COX/LOX inhibitor) at therapeutic concentrations and NDGA (LOX inhibitor) inhibited LTB4 production, whereas naproxen did not amplify the LPS-induced LTB4 production. Conversely, using NDGA, it was found that a shunt of AA from the LOX to the COX pathway did not occur. Under LPS conditions, both naproxen and licofelone inhibited LXA4, inducing an increase in the LTB4/LXA4 ratio with naproxen treatment but not with licofelone. Under these conditions, naproxen treatment induced a higher level of IL-1beta production.
We demonstrated in OA synovium that a shunt from AA to the LOX pathway occurred and that treatment with a nonselective COX inhibitor could increase the production of LTB4 and secondarily the synthesis of IL-1beta. Therefore treatment with licofelone, which can act on both COX and LOX pathways, may have some interesting properties in the treatment of OA.
研究人类骨关节炎（OA）滑膜外植体中脂氧合酶（LOX）与环氧化酶（COX）途径之间相互作用的机制，并证实花生四烯酸（AA）分流现象及其对白细胞介素1β（IL-1β）合成的影响。
滑膜外植体在不存在或存在抑制COX和/或LOX活性的不同药物的情况下进行培养。测量前列腺素E2（PGE2）、白三烯B4（LTB4）、脂oxin A4（LXA4）和IL-1β的浓度。
当膜外植体在未刺激条件下与萘普生（COX抑制剂）一起孵育时，LTB4的产生呈剂量依赖性增强，比对照增加了5倍。加入外源性PGE2可部分逆转这种分流。在脂多糖（LPS）刺激下，治疗浓度的利考昔芬（COX/LOX抑制剂）和NDGA（LOX抑制剂）均抑制LTB4的产生，而萘普生并未放大LPS诱导的LTB4产生。相反，使用NDGA发现，AA从LOX途径向COX途径的分流并未发生。在LPS条件下，萘普生和利考昔芬均抑制LXA4，萘普生治疗导致LTB4/LXA4比值升高，而利考昔芬治疗则未导致该比值升高。在这些条件下，萘普生治疗诱导了更高水平的IL-1β产生。
我们在OA滑膜中证明了从AA到LOX途径的分流发生，并且用非选择性COX抑制剂治疗可增加LTB4的产生，进而增加IL-1β的合成。因此，可同时作用于COX和LOX途径的利考昔芬治疗可能在OA治疗中具有一些有趣的特性。
