Effects of exogenous ghrelin administration and ghrelin receptor blockade, in combination with alcohol, on peripheral inflammatory markers in heavy-drinking individuals: Results from two human laboratory studies.
Effects of exogenous ghrelin administration and ghrelin receptor blockade, in combination with alcohol, on peripheral inflammatory markers in heavy-drinking individuals: Results from two human laboratory studies.
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外源性生长素释放肽给药和生长素释放肽受体阻断与酒精联合对重度饮酒个体外周炎症标志物的影响：两项人体实验室研究的结果。
DOI：
10.1016/j.brainres.2020.146851
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发表时间：
2020-08-01
期刊：
影响因子：
2.9
通讯作者：
Leggio L
中科院分区：
文献类型：
--
作者：
Farokhnia M;Portelli J;Lee MR;McDiarmid GR;Munjal V;Abshire KM;Battista JT;Browning BD;Deschaine SL;Akhlaghi F;Leggio L
生长激素释放肽系统因其在不同神经精神疾病中的作用而引起人们的兴趣，包括酒精使用障碍（AUD）。因此，靶向生长素释放肽系统作为一种潜在的新的治疗方法正在研究中。虽然酒精会引起免疫系统和炎症反应，但ghrelin具有有效的免疫调节和抗炎特性。本研究的目的是阐明生长激素释放肽和炎症之间的"串扰"，通过检查外源性生长激素释放肽管理和生长激素释放肽受体阻断剂对外周炎症标志物的影响，在两个人类实验室研究的背景下，酒精管理。非寻求治疗，酗酒的酒精依赖者，其中大多数是非洲裔美国男性，入组。在第一项随机、交叉、双盲、安慰剂对照的人体实验室研究中，参与者接受了两种实验范式-静脉内酒精自我给药（IV-ASA）和静脉内酒精钳夹（IV-AC）-每种都包括两个平衡阶段（生长激素释放肽，安慰剂）。给予负荷剂量的静脉内生长激素释放肽（3 mcg/kg）或安慰剂，随后连续输注生长激素释放肽（16.9 ng/kg/min）或安慰剂。在第二项剂量递增、单盲、安慰剂对照的人体实验室1b期研究中，受试者口服胃饥饿素受体阻滞剂（PF-5190457），并接受口服酒精挑战。重复采集血液样本，并测量以下炎症标志物的血浆浓度：C-反应蛋白（CRP）、白细胞介素（IL）-6、IL-10、IL-18和肿瘤坏死因子α（TNF-α）。在IV-ASA实验中，观察到IL-6的显著药物×时间相互作用效应（F3，36 = 3.345，p = 0.030）和IL-10（F3，53.2 = 4.638，p = 0.006），表明与安慰剂相比，生长素释放肽显著降低促炎细胞因子IL-6的血液浓度，同时增加抗炎细胞因子IL-10的血液浓度。在IV-AC实验期间未观察到显著的药物×时间相互作用效应，可能是因为其持续时间短得多和/或样本量小。与安慰剂相比，PF-5190457治疗对研究的炎症标志物无显著影响。总之，超生理药理学挑战与外源性生长激素释放肽在大量饮酒的个人产生的背景下，静脉注射酒精的抗炎作用。相反，胃饥饿素受体阻断剂没有导致本研究中包括的炎症标志物的任何变化。机制研究需要更好地了解生长激素释放肽，酒精和炎症过程之间的相互作用。
The ghrelin system has been garnering interest for its role in different neuropsychiatric disorders, including alcohol use disorder (AUD). Accordingly, targeting the ghrelin system is under investigation as a potential novel therapeutic approach. While alcohol provokes the immune system and inflammatory responses, ghrelin has potent immunomodulatory and anti-inflammatory properties. The present study aimed to shed light on the “crosstalk” between ghrelin and inflammation by examining the effects of exogenous ghrelin administration andghrelin receptor blockade on peripheral inflammatory markers in the context of two human laboratory studies with alcohol administration. Non-treatment-seeking, heavy-drinking individuals with alcohol dependence, the majority of whom were African American males, were enrolled. In the first randomized, crossover, double-blind, placebo-controlled human laboratory study, participants underwent two experimental paradigms – an intravenous alcohol self-administration (IV-ASA) and an intravenous alcohol clamp (IV-AC) – each consisting of two counterbalanced sessions (ghrelin, placebo). A loading dose of intravenous ghrelin (3 mcg/kg) or placebo, followed by a continuous ghrelin (16.9 ng/kg/min) or placebo infusion was administered. In the second dose-escalating, single-blind, placebo-controlled human laboratory phase 1b study, participants were dosed with an oral ghrelin receptor blocker (PF-5190457) and underwent an oral alcohol challenge. Repeated blood samples were collected, and plasma concentrations of the following inflammatory markers were measured: C-reactive protein (CRP), interleukin (IL)-6, IL-10, IL-18, and tumor necrosis factor alpha (TNF-α). During the IV-ASA experiment, significant drug × time interaction effects were observed for IL-6 (F3,36 = 3.345, p = 0.030) and IL-10 (F3,53.2 = 4.638, p = 0.006), indicating that ghrelin, compared to placebo, significantly reduced blood concentrations of the proinflammatory cytokine IL-6, while increasing blood concentrations of the anti-inflammatory cytokine IL-10. No significant drug × time interaction effects were observed during the IV-AC experiment, possibly because of its much shorter duration and/or smaller sample. Treatment with PF-5190457, compared to placebo, had no significant effect on the inflammatory markers investigated. In conclusion, a supraphysiologic pharmacological challenge with exogenous ghrelin in heavy-drinking individuals produced anti-inflammatory effects in the context of intravenous alcohol administration. On the contrary, ghrelin receptor blockade did not lead to any change in the inflammatory markers included in this study. Mechanistic studies are required to better understand the interaction between ghrelin, alcohol, and inflammatory processes.
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影响因子：
9.8
作者：
Calissendorff, Jan;Danielsson, Olle;Rojdmark, Sven
通讯作者：
Rojdmark, Sven
影响因子：
11.1
作者：
Bell S;Mehta G;Moore K;Britton A
通讯作者：
Britton A
影响因子：
15.9
作者：
Chuang, Jen-Chieh;Perello, Mario;Zigman, Jeffrey M.
通讯作者：
Zigman, Jeffrey M.
影响因子：
4.2
作者：
Costello, E. Jane;Copeland, William E.;Angold, Adrian
通讯作者：
Angold, Adrian
DOI：
10.1111/aji.12512
发表时间：
2016-06
期刊：
American journal of reproductive immunology (New York, N.Y. : 1989)
影响因子：
--
作者：
Aldo P;Marusov G;Svancara D;David J;Mor G
通讯作者：
Mor G