論文No4054
Neutrophil-Mediated Inflammatory Plasminogen Degradation, Rather Than High Plasminogen-Activator Inhibitor-1, May Underly Failures and Inefficiencies of Intrapleural Fibrinolysis
Christopher D. Barrett,Peter K. Moore,Ernest E. Moore,...Ivor Douglas,Fredric M. Pieracci,Michael B. Yaffe
CHEST, Volume 167, Issue 1, p67-75, January 2025.

要約
この研究は、胸腔内感染症の治療においてなぜ線維素溶解剤(血栓を溶かす薬)が十分に効果を発揮できないのか、その原因を解明しようとするものです。

研究の結果、胸腔内の感染部位では、好中球という白血球が放出するエラスターゼという酵素が過剰に存在し、これが線維素溶解に重要なプラスミノーゲンというタンパク質を分解していることがわかりました。

つまり、エラスターゼがプラスミノーゲンを分解してしまうため、線維素溶解剤の効果が妨げられているというわけです。

さらに、この研究では、胸腔内に存在するPAI-1という、線維素溶解を阻害する物質の活性は、当初考えられていたほど高くないことも明らかになりました。

Take Home Message
胸腔内感染症における線維素溶解不全の原因: 胸腔内感染症では、好中球エラスターゼによるプラスミノーゲン分解が線維素溶解を阻害する主要な要因である可能性が高い。
PAI-1の役割: 従来考えられていたよりも、PAI-1は線維素溶解不全の主要な原因ではない。
治療への示唆: 胸腔内感染症の治療において、線維素溶解剤に加えて、エラスターゼの活性を抑制したり、プラスミノーゲンを補給したりするような新たな治療法の開発が期待される。

 

 

 

 



Background
Complex pleural space infections often require treatment with multiple doses of intrapleural tissue plasminogen activator (tPA) and deoxyribonuclease, with treatment failure frequently necessitating surgery. Pleural infections are rich in neutrophils, and neutrophil elastase degrades plasminogen, the target substrate of tPA, that is required to generate fibrinolysis. We hypothesized that pleural fluid from patients with pleural space infection would show high elastase activity, evidence of inflammatory plasminogen degradation, and low fibrinolytic potential in response to tPA that could be rescued with plasminogen supplementation.
Research Question
Does neutrophil elastase degradation of plasminogen contribute to intrapleural fibrinolytic failure?
Study Design and Methods
We obtained infected pleural fluid and circulating plasma from hospitalized adults (n = 10) with institutional review board approval from a randomized trial evaluating intrapleural fibrinolytics vs surgery for initial management of pleural space infection. Samples were collected before the intervention and on days 1, 2, and 3 after the intervention. Activity assays, enzyme-linked immunosorbent assays, and Western blot analysis were performed, and turbidimetric measurements of fibrinolysis were obtained from pleural fluid with and without exogenous plasminogen supplementation. Results are reported as median (interquartile range) or number (percentage) as appropriate, with an α value of .05.
Results
Pleural fluid elastase activity was more than fourfold higher (P = .02) and plasminogen antigen levels were more than threefold lower (P = .04) than their corresponding plasma values. Pleural fluid Western blot analysis demonstrated abundant plasminogen degradation fragments consistent with elastase degradation patterns. We found that plasminogen activator inhibitor 1 (PAI-1), the native tPA inhibitor, showed high antigen levels before the intervention, but the overwhelming majority of this PAI-1 (82%) was not active (P = .003), and all PAI-1 activity was lost by day 2 after the intervention in patients receiving intrapleural tPA and deoxyribonuclease. Finally, using turbidity clot lysis assays, we found that the pleural fluid of 9 of 10 patients was unable to generate a significant fibrinolytic response when challenged with tPA and that plasminogen supplementation rescued fibrinolysis in all patients.
Interpretation
Our findings suggest that inflammatory plasminogen deficiency, not high PAI-1 activity, is a significant contributor to intrapleural fibrinolytic failure.