Department of Medicine, Section of Internal and Cardiovascular Medicine, University of Perugia, Centro didattico - Edificio B piano 1 - Strada vicinale, Via delle Corse, 06132 Perugia, Italy.
Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, Room 5.06 Franklin-Wilkins Building, Waterloo Campus, King's College London, London SE1 9NH, UK.
Thromb Res. 2018 Dec;172:110-118. doi: 10.1016/j.thromres.2018.10.019. Epub 2018 Oct 25.
Platelets participate in inflammatory disorders through a variety of different functional responses, including chemotaxis, platelet-leukocyte complex formation and facilitation of leukocyte recruitment that are thought to be distinct from platelet aggregation. This may account for why classical anti-platelet drugs have failed to ameliorate inflammatory disorders where platelets are known to participate, suggesting that distinct pathways may control inflammatory and haemostatic functions of platelets. In the present study, we have therefore investigated the effect of different stimuli on several different functions of platelets preferentially involved either in haemostasis or in inflammation.
Human platelets were stimulated with either inflammatory (fMLP, histamine, IL-1β, LPS, MDC/CCL22, SDF-1α/CXCL12 and 5-HT) or haemostatic (ADP, collagen, convulxin, epinephrine, TRAP-6 and U46619) stimuli. Aggregation, platelet-leukocyte complex formation, platelet migration and platelet protein phosphorylation were assessed.
Haemostatic stimuli induced platelet aggregation, whilst inflammatory agonists induced platelet migration. The haemostatic stimuli, with the exception of epinephrine, and some of the inflammatory stimuli induced platelet-leukocyte complex formation, even if to a different extent. Furthermore, inflammatory stimuli induced a shorter lasting profile of platelet protein phosphorylation compared with haemostatic stimuli.
Stimulation of platelets with inflammatory stimuli triggers the activation of non haemostatic functions different from those induced by haemostatic stimuli, supporting the existence of alternative platelet responses depending on the stimulus (haemostatic or inflammatory). A deeper understanding of the biochemical pathways behind these functional differences may lead to the development of novel therapeutic options targeting the inflammatory actions of platelets, without affecting their critical role in haemostasis.
血小板通过多种不同的功能反应参与炎症性疾病，包括趋化作用、血小板-白细胞复合物的形成以及促进白细胞募集，这些反应被认为与血小板聚集不同。这可能解释了为什么经典的抗血小板药物未能改善已知与血小板参与有关的炎症性疾病，这表明控制血小板炎症和止血功能的途径可能不同。在本研究中，我们因此研究了不同刺激物对几种不同功能的血小板的影响，这些功能优先涉及止血或炎症。
用人血小板分别用炎症（fMLP、组胺、IL-1β、LPS、MDC/CCL22、SDF-1α/CXCL12 和 5-HT）或止血（ADP、胶原、凝血酶、肾上腺素、TRAP-6 和 U46619）刺激物刺激。评估了聚集、血小板-白细胞复合物的形成、血小板迁移和血小板蛋白磷酸化。
止血刺激物诱导血小板聚集，而炎症激动剂诱导血小板迁移。除肾上腺素外，止血刺激物和一些炎症刺激物诱导血小板-白细胞复合物的形成，尽管程度不同。此外，与止血刺激物相比，炎症刺激物诱导的血小板蛋白磷酸化的持续时间更短。
用炎症刺激物刺激血小板会触发与止血刺激物诱导的非止血功能不同的激活，这支持了根据刺激物（止血或炎症）存在替代血小板反应的存在。对这些功能差异背后的生化途径的更深入了解可能会导致开发针对血小板炎症作用的新型治疗选择，而不会影响其在止血中的关键作用。
