环氧化酶-2抑制剂在狼疮性肾炎中的作用及其研究进展
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摘要
系统性红斑狼疮(systemic lupus erythematosus，SLE)是一种由多种因素(环境因素、机体遗传背景及性激素影响等)引起机体免疫失调，产生一系列自身抗体所导致的多系统、多器官受累的自身免疫性综合征。其免疫异常最终导致B细胞活化，过度增生并产生大量自身抗体。形成的循环免疫复合物沉积于肾小球或在肾小球内形成原位免疫复合物，激活补体，造成炎性细胞浸润、凝血因子活化及各种炎症介质释放，导致肾小球内细胞增殖及基质合成增多，引起肾损害。严重的肾脏损害增加了SLE的病残率及病死率。狼疮性肾炎(lupus nephritis，LN)是我国最常见也是最重要的继发性肾小球疾病。随着SLE发病率的增高，LN所致的终末期肾功能衰竭发病率随之升高。故积极有效控制LN的恶化、防止其向终末期进展尤为重要。环氧化酶-2(cyclooxgenase-2，COX-2)是近年的研究热点，作用广泛，参与机体的炎症反应、免疫调节、呼吸道、心血管、神经系统及肿瘤等多种疾病的病理生理过程。
郑州人学2004届临床医学硕_卜专业毕业论文环软化酶一2抑制剂在狼疮性肾炎中的作用及其研究进展
环氧化酶(cyclooxgenase，COX)是前列腺素生物合成的限速酶，有2种亚
型，结构型酶cOX一1和诱导型酶COX一2。COX一1在大多数组织中表达，促进
生理需要的前列腺素合成，调节外周血管阻力，维持肾血流量，保护胃勃膜
及调节血小板聚集。COX一2在生理情况下，大多数组织和细胞中检测不到，
当细胞受到各种刺激时，巨噬细胞、血管内皮细胞、滑膜细胞中COX一2迅速
合成，表达增加，是炎症过程中一个重要的诱导酶。在肾脏中主要表达于致
密斑(maeula densa)、皮质髓拌升支粗段(eortieal thiek asending lime or Henle，
cTALH)和肾髓质的间质细胞。cox一2与肾血流动力学及水盐代谢关系密切，
对于肾脏的正常发育和正常肾脏结构和功能的保持亦有较为重要的作用。而
病理生理条件下，炎症刺激物激活转录因子NF一沼，使COX一2的表达增加，进
而PGEZ增加，诱导粘液分泌、引起血管舒张和水肿等炎症反应。COX代谢物
亦参与肾小球和小管一间质炎性疾病中的功能和结构改变。系膜细胞是肾小球
中主要存在的具有免疫调节作用的细胞，担负着许多像巨噬细胞样的功能。
LN中，’肾小球的系膜细胞常被激活，是炎症反应的关键调控物，分泌炎症介
质(一氧化氮和环氧化酶产物)，从而使局部的炎症反应更为持久。在人和
鼠LN中，COX一2的表达增加，前列腺素(PGS)的生成发生变化，能增加肾
小球滤过率，具有血管扩张作用的PGEZ和PGIZ减少，而TXAZ增加。PGE:、
PGI:的肾脏效应与肾脏血管张力、系膜和肾小球功能及水盐的代谢调节有
关;也可通过影响其它血管活性物质作用(如促进肾素释放)而发挥其生物
功能。TXA:具有收缩血管和促使系膜细胞收缩的作用，在病理生理状态下，
参与肾脏血流动力学的改变，导致肾血流(RBF)和肾小球滤过率(GFR)
显著下降。与PGEZ、PG12的抑制作用相反，TXAZ可以促进系膜细胞的增殖
郑州人学2004届临床医学硕卜专业毕业论文环氧化酶一2抑制剂在狼疮性肾炎中的作用及其研究进展
和细胞外基质的合成。在鼠LN和人类活动性LN中，TXAZ作为一个主要介质
参与起病，’肾脏中TXAZ的生成增加，与蛋白尿和肾脏病理改变的严重程度成
正相关。应用COX一2抑制剂，可下调COX一2表达，阻断TXAZ合成，从而改变
肾小球炎症损伤的自然病程，减轻蛋白尿和肾脏病理改变程度。自19“年起，
非选择性NSAIDS己广泛应用于SLE的治疗。有效缓解SLE的一些临床症状，
诸如骨关节肌肉的疼痛、浆膜炎、发热、头痛和疲劳。但其潜在增加过敏反
应、肾和胃肠毒性大，而应用COX一2抑制剂治疗上述症状，疗效好，副作用
相对较轻。COX一2抑制剂在LN中的治疗作用己被动物实验证实。LN肾脏血
流中TxB:(TXAZ的水解产物)产生增加，应用COx一2抑制剂治疗可显著改
善其肾脏功能和结构损伤，并在一定程度上延迟蛋白尿发生和延长动物生存
时间。
目前的一些实验研究证实选择性COX一2抑制剂可防止LN进展，期待其日
后广泛应用于临床，减少终末期肾脏疾病的发生，从而使LN的预后得到进一
步的改善。
Lupus nephritis (immune-mediated nephritis) is a common complication of systemic lupus erythematosus (SLE). It is now clear that multiple and independent mechanisms contribute to disease onset and pathogenesis, which may explain the remarkable phenotypic and histopathological heterogeneity observed in human SLE. Identification and characterization of disease-relevant autoantibodies, cellular effectors, and soluble immune elements have provided crucial insight into the immunologic interactions that promote renal immune injury. It is now clear that nephritogenic autoantibodies of diverse specificity localize to the kidney by a variety of mechanisms. They are accompanied by activated macrophages and T cells recruited in part through enhanced and abnormal production of macrophage growth factors and cytokines. These pathways provide novel targets for therapeutic intervention to prevent or ameliorate
the aggressive autoimmune nephritis that characterizes SLE.
The enzyme cyclooxygenase ( COX ) catalyzes the first step of the synthesis of prostanoids by converting arachidonic acid into prostaglandin H2, which is the common substrate for specific prostaglandin synthases. COX consists of two distinct isoforms: constitutive COX-1, constitutively expressed as a "housekeeping" enzyme in most tissues, mediates physiological responses (e.g., cytoprotection of the stomach, platelet aggregation) and inducible COX-2, expressed by cells that are involved in inflammation(e.g., macrophages, monocytes, synoviocytes), which can be up-regulated by various proinflammatory agents, including lipopolysaccharide, cytokines, and growth factors. In renal cortex, COX-2 expression is localized in the macula densa and the cortical thick ascending limb of Henle (cTALH) cells. COX-2 plays a role in physiological renal functions. It regulates glomerular blood flow and rennin release and becomes up-regulated by sodium restriction. In kidneies of patients with active lupus nephritis, the expression of COX-2 isoenzyme is selectively up-regulated. Glomerular mesangial cells are key modulators of the inflammatory response in lupus nephritis. When activated, these cells secrete inflammatory mediators including NO and products of cyclooxygenase perpetuating the local inflammatory response. Alterations in PG production are known to occur in human and murine lupus nephritis. PGE2 and PGI2, vasodilators that increase glomerular filtration rate (GFR),
are decreased in lupus nephritis, whereas thromboxane A2 which reduces GFR, is elevated. Thromboxane A2 (TXA2) has been implicated as a major mediator in that in mice as well as in patients with active lupus nephritis, renal TXA2 production increased and correlated with both proteinuria and the severity of renal pathological changes. This discloses a novel pathway of inflammatory injury in LN. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been commonly used to manage joint and muscle pain, fatigue, serositis, fevers and headache in patients with SLE since 1966. But for their potential heightened allergic responses, renal and GI toxicity, patients with SLE can be safely and effectively treated with COX-2 inhibitor. The rationale of using the COX-2 inhibitor is offered by findings of an increased production of TXB2 in kidney homogenate. The treatment of the COX-2 inhibitor remarkably affords preservation of renal function and structural injury, and delays the onset of proteinuria and ameliorats animal sur
vival.
Approaches to the treatment of lupus nephritis include immunosuppressants associated with anti-inflammatory drugs, mainly steroids, which, however, cause major side effects. COX-2 inhibitor will be effective in preventing progressive nephritis in LN. So COX-2 inhibitor can be an effective treatment of LN, with the obvious advantage of avoiding steroid-related toxicity.
郑州人学2004届临床医学硕_卜专业毕业论文环软化酶一2抑制剂在狼疮性肾炎中的作用及其研究进展
环氧化酶(cyclooxgenase，COX)是前列腺素生物合成的限速酶，有2种亚
型，结构型酶cOX一1和诱导型酶COX一2。COX一1在大多数组织中表达，促进
生理需要的前列腺素合成，调节外周血管阻力，维持肾血流量，保护胃勃膜
及调节血小板聚集。COX一2在生理情况下，大多数组织和细胞中检测不到，
当细胞受到各种刺激时，巨噬细胞、血管内皮细胞、滑膜细胞中COX一2迅速
合成，表达增加，是炎症过程中一个重要的诱导酶。在肾脏中主要表达于致
密斑(maeula densa)、皮质髓拌升支粗段(eortieal thiek asending lime or Henle，
cTALH)和肾髓质的间质细胞。cox一2与肾血流动力学及水盐代谢关系密切，
对于肾脏的正常发育和正常肾脏结构和功能的保持亦有较为重要的作用。而
病理生理条件下，炎症刺激物激活转录因子NF一沼，使COX一2的表达增加，进
而PGEZ增加，诱导粘液分泌、引起血管舒张和水肿等炎症反应。COX代谢物
亦参与肾小球和小管一间质炎性疾病中的功能和结构改变。系膜细胞是肾小球
中主要存在的具有免疫调节作用的细胞，担负着许多像巨噬细胞样的功能。
LN中，’肾小球的系膜细胞常被激活，是炎症反应的关键调控物，分泌炎症介
质(一氧化氮和环氧化酶产物)，从而使局部的炎症反应更为持久。在人和
鼠LN中，COX一2的表达增加，前列腺素(PGS)的生成发生变化，能增加肾
小球滤过率，具有血管扩张作用的PGEZ和PGIZ减少，而TXAZ增加。PGE:、
PGI:的肾脏效应与肾脏血管张力、系膜和肾小球功能及水盐的代谢调节有
关;也可通过影响其它血管活性物质作用(如促进肾素释放)而发挥其生物
功能。TXA:具有收缩血管和促使系膜细胞收缩的作用，在病理生理状态下，
参与肾脏血流动力学的改变，导致肾血流(RBF)和肾小球滤过率(GFR)
显著下降。与PGEZ、PG12的抑制作用相反，TXAZ可以促进系膜细胞的增殖
郑州人学2004届临床医学硕卜专业毕业论文环氧化酶一2抑制剂在狼疮性肾炎中的作用及其研究进展
和细胞外基质的合成。在鼠LN和人类活动性LN中，TXAZ作为一个主要介质
参与起病，’肾脏中TXAZ的生成增加，与蛋白尿和肾脏病理改变的严重程度成
正相关。应用COX一2抑制剂，可下调COX一2表达，阻断TXAZ合成，从而改变
肾小球炎症损伤的自然病程，减轻蛋白尿和肾脏病理改变程度。自19“年起，
非选择性NSAIDS己广泛应用于SLE的治疗。有效缓解SLE的一些临床症状，
诸如骨关节肌肉的疼痛、浆膜炎、发热、头痛和疲劳。但其潜在增加过敏反
应、肾和胃肠毒性大，而应用COX一2抑制剂治疗上述症状，疗效好，副作用
相对较轻。COX一2抑制剂在LN中的治疗作用己被动物实验证实。LN肾脏血
流中TxB:(TXAZ的水解产物)产生增加，应用COx一2抑制剂治疗可显著改
善其肾脏功能和结构损伤，并在一定程度上延迟蛋白尿发生和延长动物生存
时间。
目前的一些实验研究证实选择性COX一2抑制剂可防止LN进展，期待其日
后广泛应用于临床，减少终末期肾脏疾病的发生，从而使LN的预后得到进一
步的改善。
Lupus nephritis (immune-mediated nephritis) is a common complication of systemic lupus erythematosus (SLE). It is now clear that multiple and independent mechanisms contribute to disease onset and pathogenesis, which may explain the remarkable phenotypic and histopathological heterogeneity observed in human SLE. Identification and characterization of disease-relevant autoantibodies, cellular effectors, and soluble immune elements have provided crucial insight into the immunologic interactions that promote renal immune injury. It is now clear that nephritogenic autoantibodies of diverse specificity localize to the kidney by a variety of mechanisms. They are accompanied by activated macrophages and T cells recruited in part through enhanced and abnormal production of macrophage growth factors and cytokines. These pathways provide novel targets for therapeutic intervention to prevent or ameliorate
the aggressive autoimmune nephritis that characterizes SLE.
The enzyme cyclooxygenase ( COX ) catalyzes the first step of the synthesis of prostanoids by converting arachidonic acid into prostaglandin H2, which is the common substrate for specific prostaglandin synthases. COX consists of two distinct isoforms: constitutive COX-1, constitutively expressed as a "housekeeping" enzyme in most tissues, mediates physiological responses (e.g., cytoprotection of the stomach, platelet aggregation) and inducible COX-2, expressed by cells that are involved in inflammation(e.g., macrophages, monocytes, synoviocytes), which can be up-regulated by various proinflammatory agents, including lipopolysaccharide, cytokines, and growth factors. In renal cortex, COX-2 expression is localized in the macula densa and the cortical thick ascending limb of Henle (cTALH) cells. COX-2 plays a role in physiological renal functions. It regulates glomerular blood flow and rennin release and becomes up-regulated by sodium restriction. In kidneies of patients with active lupus nephritis, the expression of COX-2 isoenzyme is selectively up-regulated. Glomerular mesangial cells are key modulators of the inflammatory response in lupus nephritis. When activated, these cells secrete inflammatory mediators including NO and products of cyclooxygenase perpetuating the local inflammatory response. Alterations in PG production are known to occur in human and murine lupus nephritis. PGE2 and PGI2, vasodilators that increase glomerular filtration rate (GFR),
are decreased in lupus nephritis, whereas thromboxane A2 which reduces GFR, is elevated. Thromboxane A2 (TXA2) has been implicated as a major mediator in that in mice as well as in patients with active lupus nephritis, renal TXA2 production increased and correlated with both proteinuria and the severity of renal pathological changes. This discloses a novel pathway of inflammatory injury in LN. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been commonly used to manage joint and muscle pain, fatigue, serositis, fevers and headache in patients with SLE since 1966. But for their potential heightened allergic responses, renal and GI toxicity, patients with SLE can be safely and effectively treated with COX-2 inhibitor. The rationale of using the COX-2 inhibitor is offered by findings of an increased production of TXB2 in kidney homogenate. The treatment of the COX-2 inhibitor remarkably affords preservation of renal function and structural injury, and delays the onset of proteinuria and ameliorats animal sur
vival.
Approaches to the treatment of lupus nephritis include immunosuppressants associated with anti-inflammatory drugs, mainly steroids, which, however, cause major side effects. COX-2 inhibitor will be effective in preventing progressive nephritis in LN. So COX-2 inhibitor can be an effective treatment of LN, with the obvious advantage of avoiding steroid-related toxicity.
引文
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