Degradation of C1-Inhibitor by Plasmin: Implications for the Control of Inflammatory Processes
Degradation of C1-Inhibitor by Plasmin: Implications for the Control of Inflammatory Processes
复制标题
纤溶酶降解 C1 抑制剂：对控制炎症过程的影响
作者：
E. Wallace;S. Perkins;Robert B Sim;A. Willis;C. Feighery;J. Jackson
背景蛋白酶和抑制剂活性之间的正确平衡对于维持体内平衡至关重要;酶途径的过度激活经常与炎症性疾病相关。纤溶酶是一种在炎症性疾病中广泛激活的酶，C1-抑制剂（C1-Inh）是蛋白酶活性的关键抑制剂，其在调节血浆中产生的酶级联反应中特别重要。纤溶酶和C1-Inh之间的相互作用的性质是知之甚少understanded.Materials和MethodsC 1-Inh的免疫吸附从血浆中的正常人（n = 21），从患者的系统性红斑狼疮（n = 18）或成人呼吸窘迫综合征（n = 9），并从血浆和滑液的类风湿性关节炎患者（n = 18）。由于纤溶酶是负责C1-Inh降解的假定酶，因此使用SDS-PAGE检查纤溶酶与C1-Inh之间的相互作用。此外，通过纤溶酶从C1-Inh切割的肽被分离和测序，并且从已知的C1-Inh的一级序列确定精确的切割位点。同源模型的C1-Inh，然后constructed.Resultsincreased水平的裂解和灭活C1-Inh被发现在每个炎性疾病检查。SDS-PAGE分析表明，纤溶酶在体外能迅速降解C1-Inh。在炎症性疾病患者体内观察到的C1-Inh裂解模式与纤溶酶孵育后体外产生的C1-Inh裂解模式非常相似。同源模型的C1-Inh表明，大多数的纤溶酶裂解位点是相邻的inhibitors.ConclusionsThis研究表明，局部C1-Inh降解纤溶酶可能是一个中心和关键的事件，在炎症过程中的蛋白酶抑制的损失。这些发现对我们理解炎症的致病机制和开发更有效的靶向治疗方案具有重要意义。这些发现也可以解释抗纤溶酶药物治疗C1-Inh缺乏状态的疗效，因为它们可以减少纤溶酶介导的C1-Inh降解。
BackgroundA correct balance between protease and inhibitor activity is critical in the maintenance of homoeostasis; excessive activation of enzyme pathways is frequently associated with inflammatory disorders. Plasmin is an enzyme ubiquitously activated in inflammatory disorders, and C1-inhibitor (C1-Inh) is a pivotal inhibitor of protease activity, which is particularly important in the regulation of enzyme cascades generated in plasma. The nature of the interaction between plasmin and C1-Inh is poorly understood.Materials and MethodsC1-Inh was immunoadsorbed from the plasma of normal individuals (n = 21), from that of patients with systemic lupus erythematosus (n = 18) or adult respiratory distress syndrome (n = 9), and from the plasma and synovial fluid of patients with rheumatoid arthritis (n = 18). As plasmin is a putative enzyme responsible for C1-Inh degradation, the interaction between plasmin and C1-Inh was examined using SDS-PAGE. In addition, peptides cleaved from C1-Inh by plasmin were isolated and sequenced and the precise cleavage sites determined from the known primary sequence of C1-Inh. Homology models of C1-Inh were then constructed.ResultsIncreased levels of cleaved and inactivated C1-Inh were found in each of the inflammatory disorders examined. Through SDS-PAGE analysis it was shown that plasmin rapidly degraded C1-Inh in vitro. The pattern of C1-Inh cleavage seen in vivo in patients with inflammatory disorders and that produced in vitro following incubation with plasmin were very similar. Homology models of C1-Inh indicate that the majority of the plasmin cleavage sites are adjacent to the reactive site of the inhibitor.ConclusionsThis study suggests that local C1-Inh degradation by plasmin may be a central and critical event in the loss of protease inhibition during inflammation. These findings have important implications for our understanding of pathogenic mechanisms in inflammation and for the development of more effectively targeted therapeutic regimes. These findings may also explain the efficacy of anti-plasmin agents in the treatment of C1-Inh deficiency states, as they may diminish plasmin-mediated C1-Inh degradation.
遗传性血管神经性水肿患者纯化的功能失调 C1(-) 抑制剂蛋白的变异性。
DOI：
10.1172/jci111664
发表时间：
1985
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
Donaldson,VH;Harrison,RA;Rosen,FS;Bing,DH;Kindness,G;Canar,J;Wagner,CJ;Awad,S
通讯作者：
Awad,S
人多形核白细胞弹性蛋白酶对 α2-纤溶酶抑制剂和 C1 灭活剂进行蛋白水解裂解和灭活。
DOI：
--
发表时间：
1982
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Brower,MS;Harpel,PC
通讯作者：
Harpel,PC
影响因子：
2.9
作者：
BOCK, SC;SKRIVER, K;MAGNUSSON, S
通讯作者：
MAGNUSSON, S