Effect of phospholipase A2 inhibitory peptide on inflammatory arthritis in a TNF transgenic mouse model: a time-course ultrastructural study.
Effect of phospholipase A2 inhibitory peptide on inflammatory arthritis in a TNF transgenic mouse model: a time-course ultrastructural study.
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DOI：
10.1186/ar1179
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发表时间：
2004
影响因子：
4.9
通讯作者：
Gopalakrishnakone P
中科院分区：
文献类型：
--
作者：
Thwin MM;Douni E;Aidinis V;Kollias G;Kodama K;Sato K;Satish RL;Mahendran R;Gopalakrishnakone P
我们评估了分泌型磷脂酶A2（sPLA 2）抑制肽在细胞水平上对关节侵蚀，软骨破坏和滑膜炎的人肿瘤坏死因子（TNF）转基因小鼠关节炎模型的治疗效果。对4周龄的Tg 197小鼠（N = 18）或野生型小鼠（N = 10）给予腹膜内剂量（7.5 mg/kg）的选择性sPLA 2抑制肽P-NT.II或乱序P-NT.II（阴性对照），每周三次，持续4周。包括未处理的Tgl 97小鼠（N = 10）作为对照。通过关节炎评分和组织学检查每周监测发病机制，持续4周。组织学分析显示，P-NT.II治疗后，滑膜炎，骨侵蚀，特别是软骨破坏显着减少。在关节软骨细胞（空泡化的细胞质和细胞核的损失）和滑膜细胞（崩解的细胞核和空泡，滑膜粘连）的未处理或scrambled-P-NT. II-处理的Tg 197小鼠中观察到的明显的超微结构改变在P-NT. II-处理的Tg 197组中不存在。组织学评分和超微结构证据表明，软骨细胞似乎是TNF转基因小鼠模型中关节炎进展期间主要受肽保护的靶细胞。这是第一次超微结构评价这个模型已经提出。在8周龄时未处理的Tg 197小鼠中检测到的高水平循环sPLA 2通过肽处理降低至基础水平。脂多糖和TNF诱导的P-NT从培养的巨噬细胞释放前列腺素E2的衰减。II表明，肽可能会影响类风湿性关节炎中的胰高血糖素介导的炎症反应，通过限制花生四烯酸的生物利用度通过sPLA 2抑制。
We evaluated the therapeutic effect of secretory phospholipase A2 (sPLA2)-inhibitory peptide at a cellular level on joint erosion, cartilage destruction, and synovitis in the human tumor necrosis factor (TNF) transgenic mouse model of arthritis. Tg197 mice (N = 18) or wild-type (N = 10) mice at 4 weeks of age were given intraperitoneal doses (7.5 mg/kg) of a selective sPLA2 inhibitory peptide, P-NT.II, or a scrambled P-NT.II (negative control), three times a week for 4 weeks. Untreated Tg197 mice (N = 10) were included as controls. Pathogenesis was monitored weekly for 4 weeks by use of an arthritis score and histologic examinations. Histopathologic analysis revealed a significant reduction after P-NT.II treatment in synovitis, bone erosion, and cartilage destruction in particular. Conspicuous ultrastructural alterations seen in articular chondrocytes (vacuolated cytoplasm and loss of nuclei) and synoviocytes (disintegrating nuclei and vacuoles, synovial adhesions) of untreated or scrambled-P-NT.II-treated Tg197 mice were absent in the P-NT.II-treated Tg197 group. Histologic scoring and ultrastructural evidence suggest that the chondrocyte appears to be the target cell mainly protected by the peptide during arthritis progression in the TNF transgenic mouse model. This is the first time ultrastructural evaluation of this model has been presented. High levels of circulating sPLA2 detected in untreated Tg197 mice at age 8 weeks of age were reduced to basal levels by the peptide treatment. Attenuation of lipopolysaccharide- and TNF-induced release of prostaglandin E2 from cultured macrophage cells by P-NT.II suggests that the peptide may influence the prostaglandin-mediated inflammatory response in rheumatoid arthritis by limiting the bioavailability of arachidonic acid through sPLA2 inhibition.
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DOI：
10.1007/s00281-003-0125-3
发表时间：
2003-08-01
期刊：
SPRINGER SEMINARS IN IMMUNOPATHOLOGY
影响因子：
--
作者：
Li, P;Schwarz, EM
通讯作者：
Schwarz, EM
影响因子：
11.4
作者：
KEFFER, J;PROBERT, L;KOLLIAS, G
通讯作者：
KOLLIAS, G
影响因子：
27.4
作者：
Jamal, OS;Conaghan, PG;Scott, KF
通讯作者：
Scott, KF
影响因子：
4.4
作者：
Bidgood, MJ;Jamal, OS;Scott, KF
通讯作者：
Scott, KF
影响因子：
5.1
作者：
Lin, MKS;Katz, A;Pruzanski, W
通讯作者：
Pruzanski, W