Adrenomedullin and Adrenomedullin-Targeted Therapy As Treatment Strategies Relevant for Sepsis.
Adrenomedullin and Adrenomedullin-Targeted Therapy As Treatment Strategies Relevant for Sepsis.
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DOI：
10.3389/fimmu.2018.00292
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发表时间：
2018
影响因子：
7.3
通讯作者：
Pickkers P
中科院分区：
文献类型：
--
作者：
Geven C;Kox M;Pickkers P
脓毒症仍然是一个主要的医学挑战，除了支持性护理的改善外，在过去几十年中治疗没有发生相关变化。血管舒张和血管渗漏在感染性休克的发展中起关键作用，血管渗漏是由破坏的内皮完整性引起的。肾上腺髓质素（ADM）是一种参与调节内皮屏障功能和血管张力的游离循环肽，与脓毒症的病理生理有关。ADM水平在脓毒症期间增加，并且与血管舒张程度以及疾病严重程度和死亡率相关。体外和临床前体内数据显示，在脓毒症期间给予ADM对内皮屏障功能具有抗炎、抗菌和保护作用，但其他研究表明，它也可能降低血压，这可能对脓毒性休克患者有害。已经进行了工作，以否定ADM的假定的负面影响，同时保留甚至加强其有益的行动。临床前研究已经证明，使用与ADM的N-末端结合的抗体导致循环ADM水平的总体增加并改善脓毒症结果。使用ADM和ADM结合蛋白-1的共同给药获得了类似的有益效果。据推测，ADM结合的有益作用背后的机制涉及其半衰期的延长和ADM从氚到循环的转移。这反过来又导致血液隔室中ADM活性增加，在血液隔室中ADM发挥有益的内皮屏障稳定作用，而其在血管中的有害血管舒张作用降低。到目前为止，缺乏人体ADM靶向治疗的体内数据;然而，目前正在进行第一项针对脓毒症患者的N端抗体（Adrecizumab）研究。
Sepsis remains a major medical challenge, for which, apart from improvements in supportive care, treatment has not relevantly changed over the last few decades. Vasodilation and vascular leakage play a pivotal role in the development of septic shock, with vascular leakage being caused by disrupted endothelial integrity. Adrenomedullin (ADM), a free circulating peptide involved in regulation of endothelial barrier function and vascular tone, is implicated in the pathophysiology of sepsis. ADM levels are increased during sepsis, and correlate with extent of vasodilation, as well as with disease severity and mortality. In vitro and preclinical in vivo data show that administration of ADM exerts anti-inflammatory, antimicrobial, and protective effects on endothelial barrier function during sepsis, but other work suggests that it may also decrease blood pressure, which could be detrimental for patients with septic shock. Work has been carried out to negate ADMs putative negative effects, while preserving or even potentiating its beneficial actions. Preclinical studies have demonstrated that the use of antibodies that bind to the N-terminus of ADM results in an overall increase of circulating ADM levels and improves sepsis outcome. Similar beneficial effects were obtained using coadministration of ADM and ADM-binding protein-1. It is hypothesized that the mechanism behind the beneficial effects of ADM binding involves prolongation of its half-life and a shift of ADM from the interstitium to the circulation. This in turn results in increased ADM activity in the blood compartment, where it exerts beneficial endothelial barrier-stabilizing effects, whereas its detrimental vasodilatory effects in the interstitium are reduced. Up till now, in vivo data on ADM-targeted treatments in humans are lacking; however, the first study in septic patients with an N-terminus antibody (Adrecizumab) is currently being conducted.