Cuzzocrea S, McDonald M C, Mota-Filipe H, Mazzon E, Costantino G, Britti D, Mazzullo G, Caputi A P, Thiemermann C
Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario, Italy.
Arthritis Rheum. 2000 Feb;43(2):320-8. doi: 10.1002/1529-0131(200002)43:2<320::AID-ANR11>3.0.CO;2-9.
To investigate the effects of tempol, a membrane-permeable radical scavenger, in rats with collagen-induced arthritis (CIA).
CIA was induced in Lewis rats by intradermal injection of 100 microl of an emulsion of 100 microg of bovine type II collagen (CII) in complete Freund's adjuvant (FCA) at the base of the tail. On day 21, a second injection of CII in FCA was administered.
Lewis rats developed an erosive arthritis of the hind paws when immunized with CII in FCA. Macroscopic evidence of CIA first appeared as periarticular erythema and edema in the hind paws. The incidence of CIA was 100% by day 27 in the CII-challenged rats, and the severity of CIA progressed over a 35-day period. Radiographs revealed focal resorption of bone, with osteophyte formation in the tibiotarsal joint, and soft tissue swelling. The histopathologic features included erosion of the cartilage at the joint margins. Treatment of rats with tempol (10 mg/kg/day intraperitoneally) starting at the onset of arthritis (day 23) delayed the development of the clinical signs on days 24-35 and improved the histologic status of the knee and paw. Immunohistochemical analysis for nitrotyrosine and poly(ADP-ribose) synthetase (PARS) revealed positive staining in the inflamed joints of CII-treated rats. The degree of nitrotyrosine and PARS staining was markedly reduced in tissue sections obtained from CII-treated rats that had received tempol. Furthermore, radiographs revealed protection against bone resorption and osteophyte formation in the joints of tempol-treated rats.
This study is the first to provide evidence that tempol, a small molecule that permeates biologic membranes and scavenges reactive oxygen species, attenuates the degree of chronic inflammation and tissue damage associated with CIA in the rat.
研究膜通透性自由基清除剂tempol对胶原诱导性关节炎（CIA）大鼠的影响。
在Lewis大鼠尾根部皮内注射100微升含100微克牛II型胶原（CII）的完全弗氏佐剂（FCA）乳剂诱导CIA。在第21天，再次在FCA中注射CII。
用FCA中的CII免疫后，Lewis大鼠出现后爪侵蚀性关节炎。CIA的宏观证据首先表现为后爪关节周围红斑和水肿。在接受CII攻击的大鼠中，到第27天CIA发病率为100%，且CIA严重程度在35天内进展。X线片显示骨局部吸收，胫跗关节有骨赘形成，以及软组织肿胀。组织病理学特征包括关节边缘软骨侵蚀。从关节炎发作（第23天）开始用tempol（10毫克/千克/天，腹腔注射）治疗大鼠，可延缓第24 - 35天临床症状的发展，并改善膝关节和爪子的组织学状况。对硝基酪氨酸和聚（ADP - 核糖）合成酶（PARS）的免疫组织化学分析显示，在接受CII治疗的大鼠炎症关节中有阳性染色。在接受tempol的CII治疗大鼠获得的组织切片中，硝基酪氨酸和PARS染色程度明显降低。此外，X线片显示tempol治疗大鼠关节中可防止骨吸收和骨赘形成。
本研究首次提供证据表明，tempol这种可穿透生物膜并清除活性氧的小分子，可减轻大鼠CIA相关的慢性炎症程度和组织损伤。
