Melanocortins protect against multiple organ dysfunction syndrome in mice
Melanocortins protect against multiple organ dysfunction syndrome in mice
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DOI：
10.1111/j.1476-5381.2010.01098.x
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发表时间：
2011-02-01
影响因子：
7.3
通讯作者：
Squadrito, Francesco
中科院分区：
文献类型：
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作者：
Bitto, Alessandra;Polito, Francesca;Squadrito, Francesco
黑皮质素通过对抗全身炎症反应和激活迷走神经介导的胆碱能抗炎通路来逆转循环休克和提高生存率。为了深入了解黑皮质素对全身炎症反应后多器官损伤的潜在治疗价值，我们研究了黑皮质素类似物[Nle 4，D-Phe 7] α-MSH的作用在广泛使用的多器官功能障碍综合征（MODS）的鼠模型中观察NDP-α-MSH（NDP-α-MSH）。实验方法通过单次腹膜内注射脂多糖在小鼠中诱导MODS，6天后（=第0天），通过酵母聚糖。在MODS或假MODS诱导后，将动物随机接受腹膜内NDP-α-MSH（340 μ g中心点/kg-1天）或生理盐水长达16天。另外的MODS小鼠组同时用黑皮质素MC 4受体拮抗剂HS 024或烟碱乙酰胆碱受体拮抗剂氯异达明和NDP-α-MSH治疗。关键词在第7天，在肝和肺中，NDP-α-MSH显著降低肿瘤坏死因子-α的mRNA表达。（TNF-α），增加白细胞介素-10的mRNA表达，改善组织学图片，以及降低TNF-α血浆水平;此外，如在整个16天观察期中所评估的，NDP-α-MSH剂量依赖性地增加存活率。HS 024和chlorisondamine防止所有有益的影响，NDP-α-MSH在MODS mice.CONCLUSIONS AND IMPLICATIONS这些数据表明，NDP-α-MSH保护对实验性MODS通过抵消全身炎症反应，可能通过脑MC 4受体触发激活的胆碱能抗炎通路。这些发现揭示了以前未描述的黑皮质素的影响，并可能在MODS设置的临床意义。
BACKGROUND AND PURPOSEMelanocortins reverse circulatory shock and improve survival by counteracting the systemic inflammatory response, and through the activation of the vagus nerve-mediated cholinergic anti-inflammatory pathway. To gain insight into the potential therapeutic value of melanocortins against multiple organ damage following systemic inflammatory response, here we investigated the effects of the melanocortin analogue [Nle4, D-Phe7]alpha-MSH (NDP-alpha-MSH) in a widely used murine model of multiple organ dysfunction syndrome (MODS).EXPERIMENTAL APPROACHMODS was induced in mice by a single intraperitoneal injection of lipopolysaccharide followed, 6 days later (= day 0), by zymosan. After MODS or sham MODS induction, animals were randomized to receive intraperitoneally NDP-alpha-MSH (340 mu g center dot kg-1 day) or saline for up to 16 days. Additional groups of MODS mice were concomitantly treated with the melanocortin MC4 receptor antagonist HS024, or the nicotinic acetylcholine receptor antagonist chlorisondamine, and NDP-alpha-MSH.KEY RESULTSAt day 7, in the liver and lung NDP-alpha-MSH, significantly reduced mRNA expression of tumour necrosis factor-alpha (TNF-alpha), increased mRNA expression of interleukin-10 and improved the histological picture, as well as reduced TNF-alpha plasma levels; furthermore, NDP-alpha-MSH dose-dependently increased survival rate, as assessed throughout the 16 day observation period. HS024 and chlorisondamine prevented all the beneficial effects of NDP-alpha-MSH in MODS mice.CONCLUSIONS AND IMPLICATIONSThese data indicate that NDP-alpha-MSH protects against experimental MODS by counteracting the systemic inflammatory response, probably through brain MC4 receptor-triggered activation of the cholinergic anti-inflammatory pathway. These findings reveal previously undescribed effects of melanocortins and could have clinical relevance in the MODS setting.