Procalcitonin Exerts a Mediator Role in Septic Shock Through the Calcitonin Gene-Related Peptide Receptor
Procalcitonin Exerts a Mediator Role in Septic Shock Through the Calcitonin Gene-Related Peptide Receptor
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DOI：
10.1097/ccm.0000000000004731
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发表时间：
2021-01-01
影响因子：
8.8
通讯作者：
Keller, Johannes
中科院分区：
文献类型：
--
作者：
Baranowsky, Anke;Appelt, Jessika;Keller, Johannes
结论：临床上，降钙素原是全球范围内最广泛使用的脓毒症生物标志物，迄今为止其病理生理学意义尚不清楚。药理学上，降钙素原被证明是通过降钙素受体和降钙素基因相关肽受体在体外的信号，但其生物学相关受体的身份仍然unknow.Design：前瞻性随机动物调查和体外人血studies.SETTING：研究实验室的一所大学hospital.SUBJECTS：C57 BL/6 J小鼠和创伤后sepsis.INTERVENTIONS患者：降钙素原缺陷小鼠被用来破译一个潜在的调解人的作用，在实验性脓毒性休克和识别降钙素原的相关受体。采用盲肠结扎穿孔和内毒素血症模型观察感染性休克。通过生存分析、组织学、蛋白质组分析、基因表达和流式细胞术评估疾病进展。用培养的巨噬细胞、树突状细胞和γ δ T细胞进行机制研究。主要研究结果证实了创伤后sepsis.MEASUREMENTS和主要结果：降钙素原缺陷小鼠的血清样本中受到保护，从脓毒性休克，并显示减少肺部炎症。从机制上讲，降钙素原增强先天免疫细胞中的促炎细胞因子表达，这是γ δ T细胞中白细胞介素-17 A表达所需的。在创伤后脓毒症患者中，降钙素原与全身白细胞介素-17A水平呈正相关。在患有内毒素血症的小鼠中，白细胞介素-17A的免疫中和抑制降钙素原对疾病结果的有害作用。虽然降钙素受体的表达是无关的疾病进展，非肽降钙素基因相关肽受体拮抗剂olcegepant，目前推出的抗偏头痛药物的原型，抑制降钙素原信号转导，并增加生存时间在脓毒性shock.CONCLUSIONS：我们的实验数据表明，降钙素原发挥了温和的，但有害的影响，在实验性脓毒性休克的疾病进展。此外，该研究指出降钙素基因相关肽受体与降钙素原信号传导相关，并表明降钙素基因相关肽受体抑制剂在脓毒症中的潜在治疗应用，这需要进一步的临床研究。
OBJECTIVES:Clinically, procalcitonin represents the most widely used biomarker of sepsis worldwide with unclear pathophysiologic significance to date. Pharmacologically, procalcitonin was shown to signal through both calcitonin receptor and calcitonin gene-related peptide receptor in vitro, yet the identity of its biologically relevant receptor remains unknown.DESIGN:Prospective randomized animal investigations and in vitro human blood studies.SETTING:Research laboratory of a university hospital.SUBJECTS:C57BL/6J mice and patients with post-traumatic sepsis.INTERVENTIONS:Procalcitonin-deficient mice were used to decipher a potential mediator role in experimental septic shock and identify the relevant receptor for procalcitonin. Cecal ligation and puncture and endotoxemia models were employed to investigate septic shock. Disease progression was evaluated through survival analysis, histology, proteome profiling, gene expression, and flow cytometry. Mechanistic studies were performed with cultured macrophages, dendritic cells, and gamma delta T cells. Main findings were confirmed in serum samples of patients with post-traumatic sepsis.MEASUREMENTS AND MAIN RESULTS:Procalcitonin-deficient mice are protected from septic shock and show decreased pulmonary inflammation. Mechanistically, procalcitonin potentiates proinflammatory cytokine expression in innate immune cells, required for interleukin-17A expression in gamma delta T cells. In patients with post-traumatic sepsis, procalcitonin positively correlates with systemic interleukin-17A levels. In mice with endotoxemia, immunoneutralization of interleukin-17A inhibits the deleterious effect of procalcitonin on disease outcome. Although calcitonin receptor expression is irrelevant for disease progression, the nonpeptide calcitonin gene-related peptide receptor antagonist olcegepant, a prototype of currently introduced antimigraine drugs, inhibits procalcitonin signaling and increases survival time in septic shock.CONCLUSIONS:Our experimental data suggest that procalcitonin exerts a moderate but harmful effect on disease progression in experimental septic shock. In addition, the study points towards the calcitonin gene-related peptide receptor as relevant for procalcitonin signaling and suggests a potential therapeutic application for calcitonin gene-related peptide receptor inhibitors in sepsis, which warrants further clinical investigation.