Department of Vascular and Endovascular Surgery, Heinrich-Heine-University University Medical Center, Moorenstraße.5, 40225, Düsseldorf, Germany.
Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany.
Sci Rep. 2018 Jul 3;8(1):10006. doi: 10.1038/s41598-018-28331-y.
Sepsis is a systemic inflammatory disorder with organ dysfunction and represents the leading cause of mortality in non-coronary intensive care units. A key player in septic shock is Tumor Necrosis Factor-alpha (TNF-α). Phospholipase (PL)D1 is involved in the regulation of TNF-α upon ischemia/reperfusion injury in mice. In this study we analyzed the impact of PLD1 in the regulation of TNF-α, inflammation and organ damage in experimental sepsis. PLD1 deficiency increased survival of mice and decreased vital organ damage after LPS injections. Decreased TNF-α plasma levels and reduced migration of leukocytes and platelets into lungs was associated with reduced apoptosis in lung and liver tissue of PLD1 deficient mice. PLD1 deficient platelets contribute to preserved outcome after LPS-induced sepsis because platelets exhibit an integrin activation defect suggesting reduced platelet activation in PLD1 deficient mice. Furthermore, reduced thrombin generation of PLD1 deficient platelets might be responsible for reduced fibrin formation in lungs suggesting reduced disseminated intravascular coagulation (DIC). The analysis of Pld1-PF4-Cre mice revealed that migration of neutrophils and cell apoptosis in septic animals is not due to platelet-mediated processes. The present study has identified PLD1 as a regulator of innate immunity that may be a new target to modulate sepsis.
脓毒症是一种全身炎症性疾病，伴有器官功能障碍，是非冠状动脉重症监护病房死亡的主要原因。肿瘤坏死因子-α（TNF-α）是感染性休克的关键因子。在小鼠的缺血/再灌注损伤中，磷酸酯酶（PL）D1 参与 TNF-α的调节。在本研究中，我们分析了 PLD1 在实验性脓毒症中对 TNF-α、炎症和器官损伤的调节作用。PLD1 缺乏可增加 LPS 注射后小鼠的存活率，并减少重要器官的损伤。PLD1 缺乏小鼠的 TNF-α 血浆水平降低，白细胞和血小板向肺部的迁移减少，与肺和肝组织中细胞凋亡减少有关。PLD1 缺乏的血小板有助于 LPS 诱导的脓毒症后的良好预后，因为血小板表现出整合素激活缺陷，提示 PLD1 缺乏小鼠中血小板激活减少。此外，PLD1 缺乏血小板的凝血酶生成减少可能导致肺部纤维蛋白形成减少，提示弥散性血管内凝血（DIC）减少。对 Pld1-PF4-Cre 小鼠的分析表明，脓毒症动物中性粒细胞的迁移和细胞凋亡不是由于血小板介导的过程。本研究确定了 PLD1 是先天免疫的调节剂，可能是调节脓毒症的新靶点。
