Pelletier J P, Jovanovic D, Fernandes J C, Manning P, Connor J R, Currie M G, Di Battista J A, Martel-Pelletier J
Université de Montréal, and Centre Hospitalier de l'Université de Montréal, Quebec, Canada.
Arthritis Rheum. 1998 Jul;41(7):1275-86. doi: 10.1002/1529-0131(199807)41:7<1275::AID-ART19>3.0.CO;2-T.
OBJECTIVE: To evaluate the in vivo therapeutic efficacy of N-iminoethyl-L-lysine (L-NIL), a selective inhibitor of inducible nitric oxide synthase (iNOS), on the progression of lesions in an experimental osteoarthritis (OA) dog model. The effect of L-NIL on metalloprotease activity, levels of interleukin-1beta (IL-1beta), prostaglandin E2 (PGE2), and nitrite/nitrate in synovial fluid was determined. METHODS: The OA model was created by sectioning the anterior cruciate ligament of the right stifle joint of mongrel dogs by a stab wound. Dogs were separated into experimental groups: Group 1 was made up of unoperated dogs that received no treatment, group 2 were operated dogs with no treatment, and group 3 were operated dogs that received oral L-NIL (10 mg/kg/twice daily) starting immediately after surgery. The OA dogs were killed at 10 weeks after surgery. RESULTS: Experiments showed that dog OA cartilage explants in culture produced an increased amount of NO (nitrite). Immunohistochemical study demonstrated that this was due to an increased level of iNOS in chondrocytes. OA dogs treated with L-NIL showed a reduction in the incidence of osteophytes compared with the untreated OA dogs (58% versus 92%) as well as in their size (mean +/- SEM 1.92 +/- 0.58 mm versus 5.08 +/- 0.66 mm). Macroscopically, L-NIL decreased the size of the cartilage lesions by approximately 50% both on condyles and plateaus. The histologic severity of both the cartilage lesions and synovial inflammation was significantly decreased in the L-NIL-treated dogs. Treatment with L-NIL also significantly decreased both collagenase and general metalloprotease activity in the cartilage and the levels of IL-1beta, PGE2, and nitrite/nitrate in synovial fluid. CONCLUSION: This study demonstrated the effectiveness of a selective inhibitor of iNOS, L-NIL, in attenuating the progression of experimental OA. The data suggest that L-NIL may act by reducing the activity of metalloproteases in cartilage and the production of IL-1beta by synovium, both of which are known to play a major role in the pathophysiology of OA structural changes.
目的：评估诱导型一氧化氮合酶（iNOS）选择性抑制剂N-亚氨基乙基-L-赖氨酸（L-NIL）对实验性骨关节炎（OA）犬模型中病变进展的体内治疗效果。测定L-NIL对滑膜液中金属蛋白酶活性、白细胞介素-1β（IL-1β）、前列腺素E2（PGE2）和亚硝酸盐/硝酸盐水平的影响。 方法：通过刺伤切断杂种犬右膝关节前交叉韧带建立OA模型。将犬分为实验组：第1组由未手术且未接受治疗的犬组成，第2组为手术但未治疗的犬，第3组为术后立即开始口服L-NIL（10mg/kg/每日两次）的手术犬。OA犬在术后10周处死。 结果：实验表明，培养的犬OA软骨外植体产生的一氧化氮（亚硝酸盐）量增加。免疫组织化学研究表明，这是由于软骨细胞中iNOS水平升高所致。与未治疗的OA犬相比，用L-NIL治疗的OA犬骨赘的发生率降低（58%对92%），其大小也减小（平均±标准误1.92±0.58mm对5.08±0.66mm）。宏观上，L-NIL使髁和平台上的软骨损伤大小均减少约50%。在接受L-NIL治疗的犬中，软骨损伤和滑膜炎症的组织学严重程度均显著降低。L-NIL治疗还显著降低了软骨中的胶原酶和总金属蛋白酶活性以及滑膜液中IL-1β、PGE2和亚硝酸盐/硝酸盐的水平。 结论：本研究证明了iNOS选择性抑制剂L-NIL在减轻实验性OA进展方面的有效性。数据表明，L-NIL可能通过降低软骨中金属蛋白酶的活性和滑膜中IL-1β的产生而起作用，这两者在OA结构变化的病理生理学中均起主要作用。
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