Roald Dahl Haemostasis and Thrombosis Centre, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, UK.
Crit Care. 2011 Aug 11;15(4):R195. doi: 10.1186/cc10356.
Activated protein C (APC) induces release of microparticles (MP) from primary physiological cells, which are found in patients undergoing treatment with recombinant human APC (rhAPC) for severe sepsis. We hypothesised that APC on these circulating MPs activate endothelial protease-activated receptor 1 (PAR1) to induce anti-apoptotic and anti-inflammatory properties that can improve patient outcome.
This was an experimental study on clinical samples in an intensive care setting, and included patients with severe sepsis who fulfilled criteria for treatment with rhAPC. The number of CD13+ MPs from the patients were analysed to determine their origin. They were also quantified for endothelial protein C receptor (EPCR) and APC expression. Clinical relevance of these MPs were ascertained by comparing survival between the group receiving rhAPC (n = 25) and a control group of untreated patients (n = 25). MPs were also incubated with endothelial cells to analyse apoptotic gene expression, cytoprotection and anti-inflammatory effects.
rhAPC treatment induced a significant increase in circulating MP-associated EPCR by flow cytometry (P < 0.05) and by quantitative ELISA (P < 0.005). APC expression also showed significant increases (P < 0.05). Numerically, CD13+ MPs were higher in rhAPC-treated survivors versus non-survivors. However, the number of non-survivors was low and this was not significantly different. APC on MPs was demonstrated to induce anti-apoptotic and endothelial barrier effects through the activation of endothelial PAR1.
rhAPC treatment in patients with sepsis significantly increases circulating EPCR + MPs. These MPs were noted to express APC, which has specific anti-apoptotic and anti-inflammatory effects, with a non-significant correlative trend towards survival. This suggests that MPs could disseminate APC function and activate endothelial PAR1 at distal vascular sites.
活化蛋白 C（APC）可诱导原发性生理细胞释放微粒（MP），这些细胞存在于接受重组人 APC（rhAPC）治疗严重败血症的患者中。我们假设这些循环 MPs 上的 APC 激活内皮蛋白酶激活受体 1（PAR1），以诱导抗凋亡和抗炎特性，从而改善患者的预后。
这是一项在重症监护环境中进行的临床样本的实验研究，包括符合 rhAPC 治疗标准的严重败血症患者。分析患者的 CD13+ MPs 数量以确定其来源。还对其内皮细胞蛋白 C 受体（EPCR）和 APC 表达进行了定量分析。通过比较接受 rhAPC 治疗组（n=25）和未接受治疗的对照组患者（n=25）的生存率来确定这些 MPs 的临床相关性。还将 MPs 与内皮细胞孵育，以分析凋亡基因表达、细胞保护和抗炎作用。
rhAPC 治疗通过流式细胞术（P < 0.05）和定量 ELISA（P < 0.005）显著增加了循环 MP 相关的 EPCR。APC 表达也显著增加（P < 0.05）。数值上，rhAPC 治疗的幸存者的 CD13+ MPs 高于非幸存者。然而，非幸存者的数量较少，且无显著差异。实验表明，MPs 上的 APC 通过激活内皮 PAR1 诱导抗凋亡和内皮屏障作用。
败血症患者接受 rhAPC 治疗后，循环 EPCR+ MPs 明显增加。这些 MPs 被发现表达 APC，具有特定的抗凋亡和抗炎作用，与生存率呈非显著相关性趋势。这表明 MPs 可以传播 APC 功能并在远处的血管部位激活内皮 PAR1。
