Bomalaski J S, Fallon M, Turner R A, Crooke S T, Meunier P C, Clark M A
Veterans Administration Medical Center, Medical College of Pennsylvania, Philadelphia.
J Lab Clin Med. 1990 Dec;116(6):814-25.
Eicosanoids are important mediators of the destructive arthropathy observed in rheumatoid arthritis. The rate-limiting step in the eicosanoid synthesis pathway is the availability of free arachidonic acid. The phospholipase enzymes release arachidonic acid from membrane phospholipids and thus play an important role in the regulation of eicosanoid production. We have previously demonstrated enhanced phospholipase A2 and C enzyme activities in cells from patients with rheumatoid arthritis and have also described a phospholipase A2 activating protein (PLAP) in mammalian cell lines. In an attempt to determine the biochemical basis of enhanced phospholipase A2 activity found in patients with inflammatory joint disease, we examined synovial fluid from patients with rheumatoid arthritis for PLAP. To determine whether PLAP was specific for rheumatoid disease, we assayed specimens from patients with other arthropathies. Histologic examination of rheumatoid joint tissue, with the use of immunohistochemical techniques, demonstrated high concentration of PLAP in monocytes, macrophages, chondrocytes, vascular smooth muscle, and endothelial cells. Human PLAP could be biochemically isolated from synovial fluid from patients with rheumatoid arthritis and was found to be similar to PLAP previously isolated from murine and bovine sources. To determine whether PLAP could directly mediate any aspect of inflammatory disease, purified PLAP was injected into rabbit knee joints. This resulted in an acute inflammatory arthritis with synovial cell proliferation and synovial fluid leukocytosis. Purified PLAP also induced eicosanoid formation both in vivo and in vitro. With enzyme-linked immunosorbent assays, we found more PLAP in synovial fluid specimens from patients with rheumatoid arthritis compared with samples from patients with other inflammatory arthropathies as well as osteoarthritis, a noninflammatory arthropathy. These data suggest that PLAP may be responsible, at least in part, for some aspects of the destructive inflammatory arthropathy that is observed in patients with rheumatoid arthritis.
类二十烷酸是类风湿关节炎中所见破坏性关节病的重要介质。类二十烷酸合成途径中的限速步骤是游离花生四烯酸的可利用性。磷脂酶可从膜磷脂中释放花生四烯酸，因此在类二十烷酸生成的调节中起重要作用。我们先前已证明类风湿关节炎患者细胞中磷脂酶A2和C酶活性增强，并且还在哺乳动物细胞系中描述了一种磷脂酶A2激活蛋白（PLAP）。为了确定炎性关节病患者中磷脂酶A2活性增强的生化基础，我们检测了类风湿关节炎患者滑液中的PLAP。为了确定PLAP是否对类风湿病具有特异性，我们检测了其他关节病患者的标本。使用免疫组织化学技术对类风湿关节组织进行组织学检查，结果显示单核细胞、巨噬细胞、软骨细胞、血管平滑肌和内皮细胞中PLAP浓度很高。人PLAP可从类风湿关节炎患者的滑液中进行生化分离，并且发现其与先前从鼠源和牛源分离的PLAP相似。为了确定PLAP是否能直接介导炎症性疾病的任何方面，将纯化的PLAP注入兔膝关节。这导致了急性炎症性关节炎，伴有滑膜细胞增殖和滑液白细胞增多。纯化的PLAP在体内和体外均能诱导类二十烷酸的形成。通过酶联免疫吸附测定，我们发现与其他炎性关节病患者以及骨关节炎（一种非炎性关节病）患者的样本相比，类风湿关节炎患者滑液标本中的PLAP更多。这些数据表明，PLAP可能至少部分地导致了类风湿关节炎患者中所见的破坏性炎性关节病的某些方面。
