ACTH Blocker Master Data Weaner2020 pub data.xlsx

The hypothalamic–pituitary–adrenal (HPA) axis controls the release of glucocorticoids, which regulate immune and inflammatory function by modulating cytokines, white blood cells and oxidative stress via glucocorticoid receptor (GR) signaling. Although the response to HPA activation is well characterized in many species, little is known about the impacts of HPA activation during extreme physiological conditions. Hence, we challenged 18 simultaneously fasting and developing elephant seal pups with daily intramuscular injections of adrenocorticotropin (ACTH), a GR antagonist (RU486), or a combination of the two (ACTH+RU486) for 4 days. We collected blood at baseline, 2 h and 4 days after the beginning of treatment ACTH and ACTH+RU486 elevated serum aldosterone and cortisol at 2 h, with effects diminishing at 4 days. RU486 alone induced a compensatory increase in aldosterone, but not cortisol, at 4 days. ACTH decreased neutrophils at 2 h, while decreasing lymphocytes and increasing the neutrophil:lymphocyte ratio at 4 days. These effects were abolished by RU486. Despite alterations in white blood cells, there was no effect of ACTH or RU486 on transforming growth factor-β or interleukin-6 levels; however, both cytokines decreased with the 4 day fasting progression. Similarly, ACTH did not impact protein oxidation, lipid peroxidation or antioxidant enzymes, but plasma isoprostanes and catalase activity decreased while glutathione peroxidase increased with fasting progression. These data demonstrate differential acute (2 h) and chronic (4 days) modulatory effects of HPA activation on white blood cells and that the chronic effect is mediated, at least in part, by GR. These results also underscore elephant seals’ extraordinary resistance to oxidative stress derived from repeated HPA activation.

下丘脑-垂体-肾上腺（hypothalamic–pituitary–adrenal, HPA）轴负责调控糖皮质激素的释放，而糖皮质激素可通过糖皮质激素受体（glucocorticoid receptor, GR）信号通路调节细胞因子、白细胞及氧化应激水平，进而调控免疫与炎症功能。尽管目前已在多个物种中明确了HPA轴激活后的应答特征，但人们对极端生理条件下HPA轴激活的影响仍知之甚少。
为此，本研究对18只处于禁食状态的发育中象海豹幼崽进行干预：每日肌肉注射促肾上腺皮质激素（adrenocorticotropin, ACTH）、糖皮质激素受体拮抗剂（RU486）或二者联合给药（ACTH+RU486），连续处理4天，并分别于处理开始时（基线）、处理后2小时及处理后4天采集血液样本。
结果显示，ACTH单独给药及ACTH+RU486联合给药均可在处理后2小时升高血清醛固酮与皮质醇水平，但该调控效应在处理4天后逐渐减弱。单独使用RU486则可在处理4天后引发醛固酮的代偿性升高，但对皮质醇水平无显著影响。ACTH给药可在处理后2小时降低中性粒细胞计数，在处理4天后降低淋巴细胞计数并升高中性粒细胞/淋巴细胞比值，上述效应均可被RU486阻断。尽管白细胞参数出现上述变化，但ACTH或RU486对转化生长因子-β（transforming growth factor-β, TGF-β）与白细胞介素-6（interleukin-6, IL-6）的水平均无显著影响；不过，两种细胞因子的表达水平均随4天禁食进程出现下降。
类似地，ACTH给药未对蛋白质氧化、脂质过氧化及抗氧化酶活性产生显著影响，但血浆异前列腺素水平与过氧化氢酶活性随禁食进程出现下降，而谷胱甘肽过氧化物酶活性则有所升高。
本研究数据表明，HPA轴激活对白细胞的调控存在急性（2小时）与慢性（4天）差异，且该慢性调控效应至少部分由GR信号通路介导。本研究结果同时凸显了象海豹在反复HPA轴激活状态下，对氧化应激的超强耐受性。