Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom.
Shock. 2023 Aug 1;60(2):172-180. doi: 10.1097/SHK.0000000000002158. Epub 2023 Jun 30.
Key underlying pathological mechanisms contributing to sepsis are hemostatic dysfunction and overwhelming inflammation. Platelet aggregation is required for hemostasis, and platelets are also separately involved in inflammatory responses that require different functional attributes. Nevertheless, P2Y receptor activation of platelets is required for this dichotomy of function. The aim of this study was to elucidate whether P2YR-dependent hemostatic and inflammatory functions were altered in platelets isolated from sepsis patients, compared with patients with mild sterile inflammation. Platelets from patients undergoing elective cardiac surgery (20 patients, 3 female) or experiencing sepsis after community-acquired pneumonia (10 patients, 4 female) were obtained through the IMMunE dysfunction and Recovery from SEpsis-related critical illness in adults (IMMERSE) Observational Clinical Trial. In vitro aggregation and chemotaxis assays were performed with platelets after stimulation with ADP and compared with platelets isolated from healthy control subjects (7 donors, 5 female). Cardiac surgery and sepsis both induced a robust inflammatory response with increases in circulating neutrophil counts with a trend toward decreased circulating platelet counts being observed. The ability of platelets to aggregate in response to ex vivo ADP stimulation was preserved in all groups. However, platelets isolated from patients with sepsis lost the ability to undergo chemotaxis toward N -formylmethionyl-leucyl-phenylalanine, and this suppression was evident at admission through to and including discharge from hospital. Our results suggest that P2Y 1 -dependent inflammatory function in platelets is lost in patients with sepsis resulting from community-acquired pneumonia. Further studies will need to be undertaken to determine whether this is due to localized recruitment to the lungs of a platelet responsive population or loss of function as a result of dysregulation of the immune response.
导致脓毒症的关键潜在病理机制包括止血功能障碍和炎症过度。血小板聚集是止血所必需的，血小板也分别参与需要不同功能特性的炎症反应。然而，血小板 P2Y 受体的激活是这种功能二分法所必需的。本研究旨在阐明与轻度无菌性炎症患者相比，从脓毒症患者中分离的血小板中是否存在依赖于 P2YR 的止血和炎症功能改变。通过 IMMunE 功能障碍和恢复脓毒症相关危重病成年人（IMMERSE）观察性临床试验，从接受择期心脏手术的患者（20 例，女性 3 例）或社区获得性肺炎后发生脓毒症的患者（10 例，女性 4 例）中获得血小板。用 ADP 刺激后，对血小板进行体外聚集和趋化性测定，并与从健康对照者（7 名供体，女性 5 名）中分离的血小板进行比较。心脏手术和脓毒症均引起强烈的炎症反应，循环中性粒细胞计数增加，循环血小板计数呈下降趋势。所有组的血小板对体外 ADP 刺激的聚集能力均得到保留。然而，从脓毒症患者中分离的血小板丧失了对 N -甲酰基 - 甲硫氨酸 - 亮氨酸 - 苯丙氨酸趋化的能力，这种抑制在入院时即可观察到，并持续到出院。我们的研究结果表明，由社区获得性肺炎引起的脓毒症患者的血小板中 P2Y 1 依赖性炎症功能丧失。需要进一步的研究来确定这是否是由于对肺部的血小板反应性人群的局部募集，还是由于免疫反应失调导致的功能丧失。
