Department of Anesthesiology, Intensive Care and Pain Medicine, and.
Institute of Medical Biochemistry, Centre for Molecular Biology of Inflammation, University of Münster, Münster, Germany.
Am J Respir Crit Care Med. 2022 Aug 15;206(4):488-500. doi: 10.1164/rccm.202201-0054OC.
Capillary leakage frequently occurs during sepsis and after major surgery and is associated with microvascular dysfunction and adverse outcome. Procalcitonin is a well-established biomarker in inflammation without known impact on vascular integrity. We determined how procalcitonin induces endothelial hyperpermeability and how targeting procalcitonin protects vascular barrier integrity. In a prospective observational clinical study, procalcitonin levels were assessed in 50 patients who underwent cardiac surgery and correlated to postoperative fluid and vasopressor requirements along with sublingual microvascular functionality. Effects of the procalcitonin signaling pathway on endothelial barrier and adherens junctional integrity were characterized and verified in mice. Inhibition of procalcitonin activation by dipeptidyl-peptidase 4 (DPP4) was evaluated in murine polymicrobial sepsis and clinically verified in cardiac surgery patients chronically taking the DPP4 inhibitor sitagliptin. Elevated postoperative procalcitonin levels identified patients with 2-fold increased fluid requirements ( < 0.01), 1.8-fold higher vasopressor demand ( < 0.05), and compromised microcirculation (reduction to 63.5 ± 2.8% of perfused vessels, < 0.05). Procalcitonin induced 1.4-fold endothelial and 2.3-fold pulmonary capillary permeability (both s < 0.001) by destabilizing VE-cadherin. Procalcitonin effects were dependent on activation by DPP4, and targeting the procalcitonin receptor or DPP4 during sepsis-induced hyperprocalcitonemia reduced capillary leakage by 54 ± 10.1% and 60.4 ± 6.9% (both s < 0.01), respectively. Sitagliptin before cardiac surgery was associated with augmented microcirculation (74.1 ± 1.7% vs. 68.6 ± 1.9% perfused vessels in non-sitagliptin-medicated patients, < 0.05) and with 2.3-fold decreased fluid ( < 0.05) and 1.8-fold reduced vasopressor demand postoperatively ( < 0.05). Targeting procalcitonin's action on the endothelium is a feasible means to preserve vascular integrity during systemic inflammation associated with hyperprocalcitonemia.
毛细血管渗漏在脓毒症和大手术后经常发生，与微血管功能障碍和不良预后有关。降钙素原是一种在炎症中得到充分证实的生物标志物，其对血管完整性没有已知的影响。我们确定了降钙素原如何诱导内皮通透性增加，以及靶向降钙素原如何保护血管屏障完整性。在一项前瞻性观察性临床研究中，评估了 50 名接受心脏手术的患者的降钙素原水平，并将其与术后液体和血管加压药需求以及舌下微血管功能相关联。研究还在小鼠中描述并验证了降钙素原信号通路对内皮屏障和黏附连接完整性的影响。评估了二肽基肽酶 4（DPP4）对降钙素原激活的抑制作用，在小鼠多微生物脓毒症中进行了评估，并在长期服用 DPP4 抑制剂西他列汀的心脏手术患者中进行了临床验证。术后升高的降钙素原水平可识别出液体需求增加 2 倍的患者（ < 0.01），血管加压药需求增加 1.8 倍（ < 0.05），并且微循环受损（灌注血管减少到 63.5 ± 2.8%， < 0.05）。降钙素原通过破坏 VE-钙粘蛋白，诱导内皮通透性增加 1.4 倍和肺毛细血管通透性增加 2.3 倍（均 s < 0.001）。降钙素原的作用依赖于 DPP4 的激活，在脓毒症诱导的高降钙素原血症期间，靶向降钙素原受体或 DPP4 可使毛细血管渗漏减少 54 ± 10.1%和 60.4 ± 6.9%（均 s < 0.01）。心脏手术前使用西他列汀与增强的微循环相关（与未使用西他列汀的患者相比，灌注血管增加 74.1 ± 1.7%， < 0.05），并且术后液体减少 2.3 倍（ < 0.05），血管加压药需求减少 1.8 倍（ < 0.05）。靶向降钙素原对内皮的作用是在与高降钙素原血症相关的全身炎症期间维持血管完整性的可行方法。
