A new arthritis therapy with oxidative burst inducers.
A new arthritis therapy with oxidative burst inducers.
复制标题
DOI：
10.1371/journal.pmed.0030348
复制
发表时间：
2006-09
期刊：
影响因子：
15.8
通讯作者：
Holmdahl R
中科院分区：
文献类型：
--
作者：
Hultqvist M;Olofsson P;Gelderman KA;Holmberg J;Holmdahl R
尽管最近生物制剂治疗自身免疫性炎症疾病如类风湿性关节炎（RA）取得了成功，但许多患者对这些治疗没有充分的反应，因此继续寻找新的治疗方法非常重要。最近，在小鼠和大鼠关节炎模型中，当Ncf1多态性（减少氧化爆发）被证明增加疾病严重程度时，活性氧（ROS）促进炎症的流行假设受到了挑战。基于这些发现，我们开发了一种使用氧化爆裂诱导物质治疗关节炎的新疗法。叶绿醇（3,7,11,15-四甲基-2-十六烯-1-醇）处理大鼠体内增加氧化爆发，从而纠正易患关节炎的Ncf1 DA大鼠遗传多态性的影响。重要的是，叶绿醇治疗也降低了自身免疫反应，改善了关节炎的急性和慢性阶段。与RA的标准治疗方法、抗肿瘤坏死因子-α和甲氨蝶呤相比，叶绿醇显示出同样良好或更好的治疗效果。最后，叶绿醇在给药数小时内介导了其作用，并参与了T细胞活化的调节，因为注射阻止了关节炎性T细胞的过继性疾病转移。利用诸如叶绿醇等促ros物质治疗关节炎的目标是一个新发现的导致自身免疫性炎症疾病的途径，并为治疗RA和其他可能的慢性炎症性疾病引入了一类新的治疗方法。叶绿醇（一种促进活性氧的物质）治疗大鼠关节炎，提示了一种自身免疫性炎症疾病的新途径，可能是一种新的治疗策略。类风湿性关节炎（RA）是一种慢性疾病，影响全世界0.3%至1%的人，引起关节、肌腱和其他组织的疼痛和肿胀，并经常导致永久性畸形和残疾。类风湿性关节炎涉及免疫系统细胞对身体自身结缔组织的异常攻击（所谓的自身免疫）。目前治疗类风湿性关节炎的药物是通过对抗引起疼痛和肿胀（炎症）的分子来起作用的。通过降低自身免疫性炎症的严重程度，这些药物也可能减少疾病对关节的长期损害。炎症并不总是不正常的，但事实上，它在人体防御感染方面起着重要作用。作为对抗致病细菌活动的一部分，被称为粒细胞的白细胞产生活性氧（ROS），有时被称为“自由基”。在吞噬入侵的细菌后，中性粒细胞释放出ros的“氧化爆发”——本质上相当于将过氧化氢倒在伤口上消毒。一种被统称为NADPH氧化酶复合物的分子复合物具有产生ROS的特殊功能，从而为氧化爆发提供燃料。有趣的是，最近在易患关节炎的大鼠身上进行的实验发现，这种复合物的亚基之一Ncf1的形式发生改变，减少了ROS的产生，这些动物对关节炎的易感性也更大。这一发现令人惊讶，因为自由基通常与炎症和对细胞的长期损害有关，因此，ROS的减少可能会降低对类风湿关节炎等炎症性疾病的易感性。由于许多自身免疫性炎症疾病（如类风湿性关节炎）患者对目前可用的治疗方法没有反应，新的治疗方法值得研究。基于观察到的ROS减少与关节炎易感性增加之间的联系，研究人员想要找出一种通过NADPH氧化酶复合物增加ROS产生的化合物治疗是否会导致关节炎的改善。研究人员在易患关节炎的老鼠身上测试了一种叫做叶绿醇的化合物，看看它是如何影响炎症的。众所周知，在这些大鼠身上注射一种叫做pristane的油可以诱发关节炎。研究人员发现，叶绿醇在实验室培养的人粒细胞细胞中引起强烈的氧化爆发，但不会引起大鼠关节炎；而引起关节炎的嘌呤，在粒细胞中引起较低的氧化破裂。然后他们研究了叶绿醇是否能预防大鼠关节炎。他们发现，注射叶绿醇的大鼠在随后注射普利斯坦后免受关节炎的侵害。鉴于这一结果，他们想知道叶绿醇是否会像在实验室细胞培养中那样增加大鼠体内的活性氧。他们研究了用叶绿醇处理过的大鼠的粒细胞，发现这些细胞的氧化爆发确实增加了，并且在处理后的几周内仍然增加。他们继续测试叶绿醇作为活动性关节炎的治疗方法，发现给患有急性前列腺素诱导关节炎的大鼠服用叶绿醇可以显著减少关节肿胀和软骨破坏。叶绿醇的有益作用不仅在Ncf1产生异常低ROS的大鼠中被发现，而且在粒细胞产生正常氧化爆发的大鼠中也被发现。当（在大鼠中）与获准用于类风湿性关节炎的药物（依那西普和甲氨蝶呤）进行比较时，叶绿醇似乎至少是一样有效的。叶绿醇抗关节炎的活性被证明与T淋巴细胞有关，因为注射叶绿醇可以抑制前列腺素诱导的关节炎与这些细胞的转移。这些实验提出了一种治疗自身免疫性疾病的全新模式的有趣可能性；即通过药物来增加ROS的产生。这项研究提出了一些实际的和科学的问题。例如，目前尚不清楚产生活性氧的能力降低是否是人类类风湿性关节炎的一个重要因素。此外，ROS（由粒细胞产生）和自身免疫性关节炎（涉及T淋巴细胞的活动）之间的联系仍有待澄清。最后，通常与自由基相关的破坏性影响（如对DNA的破坏和血管阻塞）可能会使这种方法在人类中的应用复杂化，并且像任何新药一样，那些增加ROS产生的药物可能会有其他意想不到的副作用。然而，无论药物开发的结果如何，这项研究都很好地提醒我们，生物化学没有“好”或“坏”之分——在复杂的细胞代谢中，一切都是平衡的问题。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.0030348访问这些网站。关节炎基金会：类风湿关节炎页面医学炎症研究页面（R. Holmdahl研究组）维基百科类风湿关节炎章节（注：维基百科是任何人都可以编辑的免费网络百科全书）维基百科活性氧章节（注：维基百科是任何人都可以编辑的免费网络百科全书）
Despite recent successes with biological agents as therapy for autoimmune inflammatory diseases such as rheumatoid arthritis (RA), many patients fail to respond adequately to these treatments, making a continued search for new therapies extremely important. Recently, the prevailing hypothesis that reactive oxygen species (ROS) promote inflammation was challenged when polymorphisms in Ncf1, that decrease oxidative burst, were shown to increase disease severity in mouse and rat arthritis models. Based on these findings we developed a new therapy for arthritis using oxidative burst-inducing substances. Treatment of rats with phytol (3,7,11,15-tetramethyl-2-hexadecene-1-ol) increased oxidative burst in vivo and thereby corrected the effect of the genetic polymorphism in arthritis-prone Ncf1 DA rats. Importantly, phytol treatment also decreased the autoimmune response and ameliorated both the acute and chronic phases of arthritis. When compared to standard therapies for RA, anti-tumour necrosis factor-α and methotrexate, phytol showed equally good or better therapeutic properties. Finally, phytol mediated its effect within hours of administration and involved modulation of T cell activation, as injection prevented adoptive transfer of disease with arthritogenic T cells. Treatment of arthritis with ROS-promoting substances such as phytol targets a newly discovered pathway leading to autoimmune inflammatory disease and introduces a novel class of therapeutics for treatment of RA and possibly other chronic inflammatory diseases. Treatment of arthritis in rats with phytol, a reactive oxygen species promoting substance, suggests a novel pathway of autoimmune inflammatory disease and possibly a novel therapeutic strategy. Rheumatoid arthritis (RA) is a chronic illness that affects between 0.3% and 1% of people worldwide, causing pain and swelling in joints, tendons, and other tissues, and frequently leading to permanent deformity and disability. RA involves an abnormal attack by cells of the immune system against the body's own connective tissues (so-called autoimmunity). Current drugs for RA work by counteracting the molecules that cause the pain and swelling (inflammation). By reducing the severity of autoimmune inflammation, these drugs may also reduce the disease's long-term damage to joints. Inflammation is not always abnormal, but in fact plays an important part in the body's defense against infection. As part of their activity against disease-causing bacteria, the white blood cells known as granulocytes generate reactive oxygen species (ROS), sometimes known as “free radicals.” After engulfing invading bacteria, neutrophils release an “oxidative burst” of ROS—essentially the subcellular equivalent of pouring hydrogen peroxide on a wound to disinfect it. A complex of molecules known collectively as the NADPH oxidase complex has the specific function of generating ROS to fuel the oxidative burst. Interestingly, recent experiments in arthritis-prone rats found that animals with an altered form of one of the subunits of this complex, Ncf1, that decreased the production of ROS also had greater susceptibility to arthritis. This finding was surprising because free radicals have generally been associated with inflammation and long-term damage to cells, so that a reduction in ROS might have been expected to decrease susceptibility to an inflammatory disease like RA. Because many patients with autoimmune inflammatory illnesses like RA do not respond to currently available therapies, new approaches to treatment merit investigation. Based on the observed association between reduced ROS and increased susceptibility to arthritis, the researchers wanted to find out whether treatment with a compound that increases ROS production by the NADPH oxidase complex would cause an improvement in arthritis. The researchers tested a compound called phytol in arthritis-prone rats to see how it affected inflammation. It is known that arthritis can be induced in these rats by injecting them with an oil called pristane. The researchers found that phytol caused a strong oxidative burst in human granulocyte cells grown in the laboratory, but did not cause arthritis in rats; whereas pristane, which does cause arthritis, caused a lower oxidative burst in the granulocytes. They then studied whether phytol prevented arthritis in rats. They found that rats injected with phytol were protected from arthritis following a later injection of pristane. Given this result, they wanted to know if phytol increased ROS in the rats as it did in laboratory cell cultures. Studying granulocytes taken from rats that had been treated with phytol, they found that the oxidative burst of these cells was indeed increased, and remained increased for several weeks after treatment. They went on to test phytol as a treatment for active arthritis, and found that it dramatically reduced swollen joints and destruction of cartilage when given to rats with acute pristane-induced arthritis. The beneficial effects of phytol were seen not only in rats bred with a form of Ncf1 that produces abnormally low amounts of ROS, but also in rats whose granulocytes produce normal oxidative bursts. When compared (in rats) to drugs licensed for RA (etanercept and methotrexate), phytol appeared to be at least as effective. The activity of phytol against arthritis was shown to involve T lymphocytes, as injection of phytol inhibited transfer of pristane-induced arthritis with these cells. These experiments raise the intriguing possibility of an entirely new modality for treating autoimmune diseases; namely, through drugs designed to increase the production of ROS. This study raises a number of practical and scientific issues. For example, it is not known whether reduced capacity to produce ROS is a significant factor in human RA. Also, the connection between ROS production (by granulocytes) and autoimmune arthritis (which involves activity by T lymphocytes) remains to be clarified. Finally, the destructive effects typically associated with free radicals (such as damage to DNA and blockage of blood vessels) could complicate the use of this approach in humans, and like any new drugs, those that increase ROS production might have other, unanticipated side effects. Whatever the outcome of drug development efforts, however, this study is an excellent reminder that there are no “good” or “evil” biochemicals—in the intricacies of cellular metabolism, it's all a matter of balance. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030348. The Arthritis Foundation: Rheumatoid Arthritis pages Medical Inflammation Research pages (R. Holmdahl research group) Wikipedia chapter on Rheumatoid Arthritis (note: Wikipedia is a free Internet encyclopedia that anyone can edit) Wikipedia chapter on Reactive Oxygen Species (note: Wikipedia is a free Internet encyclopedia that anyone can edit)
登录
查看更多内容
影响因子：
30.8
作者：
Horikawa, Y;Oda, N;Bell, GI
通讯作者：
Bell, GI
影响因子：
30.5
作者：
Jackson, SH;Devadas, S;Williams, MS
通讯作者：
Williams, MS
影响因子：
9.8
作者：
Lesage, S;Zouali, H;Hugot, JP
通讯作者：
Hugot, JP
影响因子：
32.4
作者：
Hildeman, DA;Mitchell, T;Marrack, PC
通讯作者：
Marrack, PC
影响因子：
5.3
作者：
Gringhuis, SI;Papendrecht-van der Voort, EAM;Verweij, CL
通讯作者：
Verweij, CL