Platelet- mast cell interactions as determinants of the vascular pathology in septic shock.

摘要： 脓毒症中休克的发展定义了临床状态的急剧恶化，并与严重的 发病率和死亡率上升。然而，细胞和分子机制决定的， 感染性休克的血管病理学仍不明确。 我们过去的工作建立了肥大细胞（MC）作为血管病理学的关键效应细胞，在不同的血管病变中， 疾病背景。因为MC产物在休克时的血浆中被发现，而在败血症时则没有，这支持了 MC激活是导致感染性休克的中心事件。采用最先进的技术，如 动态光声成像的微血管，我们提供了第一个证据表明，MC形状的关键特征 脓毒症休克的危险因素：全身性低血压、血管渗漏和微血管灌注异常。在 此外，我们阐明，在败血症中，MCs，这是位于近腔侧的相对 不可渗透的内皮细胞受到血小板的刺激，血小板可以在血小板聚集后在其附近聚集。 炎症触发器 基于这些观察，我们假设血小板之间的特定信号相互作用， 血管周围的MC和内皮驱动败血性休克的血管病理学。我们的工作目标是 首先全面定义脓毒症中MC介导的血管病理学机制，其次， 阐明血小板触发MC反应和导致的血管病理学的具体机制 最后，在一组脓毒症患者中建立我们研究结果的临床相关性。 总之，该项目是实现我们长期目标的关键一步，即建立MC响应， 脓毒症生物学的生物标志物，并开发可直接靶向 脓毒症疾病进展的机制。

Abstract: Development of shock in sepsis defines a dramatic deterioration of clinical status and is linked to a significant increase in morbidity and mortality rates. However, the cellular and molecular mechanisms determining the vascular pathology of septic shock remain undefined. Our past work established mast cells (MC) as key effector cells of vascular pathology in different disease contexts. Because MC products are found in the plasma in shock but not during sepsis, this supports that MC activation is a central event leading to septic shock. Employing state-of-the- art technologies such as dynamic photoacoustic imaging of the microvasculature, we provide first evidence that MCs shape key features of shock in sepsis: systemic hypotension, vascular leakage and microvascular perfusion abnormalities. In addition, we elucidate that in sepsis MCs, which are located on the abluminal side of a relatively impermeable endothelium, are stimulated by platelets, which can aggregate in their close proximity following inflammatory triggers. Based on these observations, we hypothesize that specific signaling interactions between platelets, perivascular MCs and the endothelium drive the vascular pathology of septic shock. The objective of our work is first to comprehensively define the mechanisms of MC-mediated vascular pathology in sepsis, second to elucidate the specific mechanism by which platelets trigger MC responses and resultant vascular pathology and lastly, to establish the clinical relevance of our findings in a cohort of septic patients. Together, this project constitutes a key step towards our long-term goal to establish MC responses as a biomarker of sepsis biology and to develop novel therapeutic strategies that may directly target the mechanisms of disease progression in sepsis.