PREDOMINANT ROLE OF NEUTROPHILS IN THE INACTIVATION OF ALPHA-2-MACROGLOBULIN IN ARTHRITIC JOINTS
PREDOMINANT ROLE OF NEUTROPHILS IN THE INACTIVATION OF ALPHA-2-MACROGLOBULIN IN ARTHRITIC JOINTS
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DOI：
10.1002/art.1780340910
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发表时间：
1991-09-01
影响因子：
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通讯作者：
HACK, CE
中科院分区：
文献类型：
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作者：
ABBINK, JJ;KAMP, AM;HACK, CE
我们研究了82例患有几种类型关节炎的患者（包括52例类风湿性关节炎和11例骨关节炎）的α-2-巨球蛋白（α-2M）（软骨降解蛋白酶的重要抑制剂）与中性粒细胞活化的关系。 用对i-alpha-2 M具有特异性的单克隆抗体测量总的无活性alpha-2 M（i-alpha-2 M）的水平，该无活性alpha-2 M包括与蛋白酶复合的alpha-2 M和通过氧化或水解失活的alpha-2 M。 此外，采用特定试验定量与蛋白酶复合的α-2M水平。 通过测量弹性蛋白酶-α-1-抗胰蛋白酶复合物和乳铁蛋白来评估中性粒细胞活化。 在82名受试患者中，83%的患者滑液（SF）与血浆i-α-2M比值超过1，表明关节内生成。 i-alpha-2 M水平与中性粒细胞数量（P < 0.0005）以及弹性蛋白酶-alpha-1-抗胰蛋白酶复合物和乳铁蛋白水平（均P < 0.00001）显著相关。 此外，部分i-α-2M由与弹性蛋白酶样和胰凝乳蛋白酶样蛋白酶复合的α-2M组成，推测分别为中性粒细胞弹性蛋白酶和组织蛋白酶G。 然而，i-α-2M的量比与这些蛋白酶复合的量大约10倍。 在体外，激活的中性粒细胞对α-2 M的失活仅可被弹性蛋白酶和组织蛋白酶G的特异性抑制剂eglin C部分抑制。 活性氧的释放可能是α-2M额外失活的原因，因为eglin C完全消除了活化中性粒细胞的无细胞上清液对α-2M的失活。 因此，我们的研究结果表明，中性粒细胞在炎症性关节疾病患者SF中α-2M失活中起着主导作用。 然而，这种失活只能部分解释为嗜酸性蛋白酶的释放。 我们认为SF中α-2M的失活是由于活性氧和溶酶体蛋白酶的协同作用。
We studied the state of alpha-2-macroglobulin (alpha-2M), an important inhibitor of cartilage-degrading proteinases, in relation to activation of neutrophils in 82 patients with several types of arthritis, including 52 with rheumatoid arthritis and 11 with osteoarthritis. Levels of total inactive alpha-2M (i-alpha-2M), which comprises alpha-2M complexed to proteinases and alpha-2M inactivated by oxidation or hydrolysis, were measured with a monoclonal antibody specific for i-alpha-2M. In addition, levels of alpha-2M complexed to proteinases were quantitated with specific assays. Neutrophil activation was assessed by measuring elastase-alpha-1-antitrypsin complexes and lactoferrin. In 83% of the 82 patients tested, the synovial fluid (SF) to plasma ratio of i-alpha-2M exceeded 1, indicating an intraarticular generation. Levels of i-alpha-2M significantly correlated with neutrophil numbers (P < 0.0005) and with levels of elastase-alpha-1-antitrypsin complexes and of lactoferrin (P < 0.00001 for both). Moreover, part of i-alpha-2M consisted of alpha-2M complexed to elastase-like and chymotrypsin-like proteinases, presumably, neutrophil elastase and cathepsin G, respectively. However, the amount of i-alpha-2M was approximately 10-fold larger than the amount complexed to these proteinases. In vitro inactivation of alpha-2M by activated neutrophils was only partly inhibitable by eglin C, a specific inhibitor of both elastase and cathepsin G. Release of reactive oxygen species was presumably responsible for the additional inactivation of alpha-2M, because eglin C completely abolished the inactivation of alpha-2M by cell-free supernatant of activated neutrophils. Thus, our results suggest a predominant role of neutrophils in the inactivation of alpha-2M in the SF of patients with inflammatory joint diseases. However, this inactivation could be explained only in part by the release of neutrophilic proteinases. We propose that the inactivation of alpha-2M in SF was due to the concerted action of both reactive oxygen species and lysosomal proteinases.