Aseptic loosening of total hip replacement - Macrophase expression of inducible nitric oxide synthase and cyclo-oxygenase-2, together with peroxynitrite formation, as a possible mechanism for early prosthesis failure
Aseptic loosening of total hip replacement - Macrophase expression of inducible nitric oxide synthase and cyclo-oxygenase-2, together with peroxynitrite formation, as a possible mechanism for early prosthesis failure
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DOI：
10.1302/0301-620x.79b3.7469
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发表时间：
1997-05-01
影响因子：
--
通讯作者：
Polak, JM
中科院分区：
文献类型：
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作者：
Hukkanen, M;Corbett, SA;Polak, JM
无菌性松动是全髋关节置换术失败的主要原因，假体磨损颗粒引起的不良组织反应，以及细胞因子和前列腺素的激活，导致植入物周围的骨丢失。我们研究了骨-植入物界面假膜中巨噬细胞表达诱导型一氧化氮合酶（iNOS）和环氧合酶-2（考克斯-2）的可能性，我们还评估了膜中是否产生过氧亚硝酸盐，一种与细胞损伤相关的一氧化氮（NO）衍生的氧化剂。使用精氨酸-瓜氨酸测定技术和前列腺素E-2（PGE（2））测量iNOS的酶活性，作为考克斯-2活性的指标，使用酶免疫测定法测量。iNOS的细胞免疫反应性，硝基酪氨酸通过定量过氧化物酶免疫细胞化学评估过氧化亚硝酸盐诱导的细胞损伤的标志物）和考克斯-2，同时免疫荧光方法用于随后与CD 68（+）巨噬细胞的共定位研究。免疫细胞化学显示假体周围的CD 68（+）磨损碎片负载的巨噬细胞是对iNOS、硝基酪氨酸和考克斯-2免疫反应最显著的细胞类型，其他假体周围炎性细胞和驻留细胞类型也被发现免疫定位硝基酪氨酸，从而表明过氧亚硝酸盐诱导的蛋白质亚硝基化和细胞损伤不仅在NO产生的CD 68（+）这些数据表明，iNOS和考克斯-2都由界面膜中的CD 68（+）巨噬细胞表达，并且过氧亚硝酸盐诱导的细胞损伤在这样的组织中是明显的。如果高输出NO和过氧亚硝酸盐的产生将导致巨噬细胞死亡，这将导致吞噬的磨损碎片释放到细胞外基质中，然后，通过新募集的炎性细胞的进一步吞噬作用和随后的NO、过氧亚硝酸盐和前列腺素类合成，建立了有害的事件循环。由于NO和PGE（2）都参与了慢性炎症的诱导和维持，导致骨丢失，而过氧亚硝酸盐参与了疾病状态的发病机制，它们可能是无菌性松动发病机制的核心。
Aseptic loosening is a major cause of failure of total hip arthroplasty, The adverse tissue response to prosthetic wear particles, with activation of cytokine and prostanoid production, contributes to bone loss around the implants, We have investigated the possibility that inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2) are expressed in macrophages in the pseudomembrane at the bone-implant interface, thereby contributing to the periprosthetic bone resorption.We also assessed whether peroxynitrite, a nitric oxide (NO)-derived oxidant associated with cellular injury, is generated in the membrane, Enzymatic activity of iNOS was measured using the arginine-citrulline assay technique and prostaglandin E-2 (PGE(2)), as an indicator of COX-2 activity, was measured using an enzyme immunoassay.Cellular immunoreactivity for iNOS, nitrotyrosine (a marker of peroxynitrite-induced cellular injury) and COX-2 was assessed by quantitative peroxidase immunocytochemistry while immunofluorescence methods were used for subsequent co-localisation studies with CD68(+) macrophages.The presence of calcium-independent iNOS activity and PGE(2) production was confirmed in the homogenised interface membrane, Immunocytochemistry showed that periprosthetic CD68(+) wear-debris-laden macrophages were the most prominent cell type immunoreactive for iNOS, nitrotyrosine and COX-2, Other periprosthetic inflammatory and resident cell types were also found to immunolocalise nitrotyrosine thereby suggesting peroxynitrite-induced protein nitrosylation and cellular damage not only in NO-producing CD68(+) macrophages, but also in their neighbouring cells, These data indicate that both iNOS and COX-2 are expressed by CD68(+) macrophages in the interface membrane and peroxynitrite-induced cellular damage is evident in such tissue, If high-output NO and peroxynitrite generation were to cause macrophage cell death, this would result in the release of phagocytosed wear debris into the extracellular matrix, A detrimental cycle of events would then be established with further phagocytosis by newly-recruited inflammatory cells and subsequent NO, peroxynitrite and prostanoid synthesis, Since both NO and PGE(2) have been implicated in the induction and maintenance of chronic inflammation with resulting loss of bone, and peroxynitrite in the pathogenesis of disease states, they may be central to the pathogenesis of aseptic loosening.