Department of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, 37 Yiyuan Street, Nangang District, Harbin 150001, China.
Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin 150001, China.
Int Immunopharmacol. 2019 Apr;69:95-102. doi: 10.1016/j.intimp.2019.01.019. Epub 2019 Jan 25.
Previous studies have shown that ghrelin, a peptide produced in the stomach, attenuates acute lung injury (ALI) in various animal models, and that some of these effects are associated with inhibition of the nuclear factor κB signaling pathway. This study investigated whether ghrelin exerts beneficial effects on hemorrhagic shock (HS)-induced ALI by modulating nuclear factor κB inhibitor kinase/nuclear factor κB inhibitor/nuclear factor κB (IKK/IκBα/NF-κB) pathway activity. HS was induced in male SD rats by withdrawing blood to a mean arterial pressure (MAP) of 40 mm Hg for 1 h; rats then received ghrelin (10 nmol/kg) or vehicle intravenously and were resuscitated with the shed blood and an equal volume of Ringer lactate solution followed by observation for 2 h. After resuscitation, samples were collected and analyzed for lung histopathology, wet to dry weight ratio (W/D), bronchoalveolar lavage fluid (BALF) protein, neutrophil infiltration, plasma inflammatory cytokines (TNF-α and IL-6), and cytoplasmic phosphorylated IKKβ, IκBα, phosphorylated IκBα and nuclear NF-κB expression. Compared to those in the two sham groups, lung injury, W/D, BALF protein, neutrophil infiltration, plasma TNF-α and IL-6 levels, and IKK/IκBα/NF-κB pathway activation were significantly increased in HS rats. After ghrelin administration, all parameters analyzed were decreased compared to those without ghrelin in HS rats. Moreover, ghrelin alleviated the decreased MAP after resuscitation compared to that in HS rats. Exogenous ghrelin attenuates the inflammatory response and acute lung injury after HS. These beneficial effects appear to be mediated through inhibition of IKK/IκBα/NF-κB signaling.
先前的研究表明，胃中产生的肽 ghrelin 可减轻各种动物模型中的急性肺损伤 (ALI)，其中一些作用与核因子 κB 信号通路的抑制有关。本研究通过调节核因子 κB 抑制剂激酶/核因子 κB 抑制剂/核因子 κB（IKK/IκBα/NF-κB）途径的活性，研究了 ghrelin 是否通过调节核因子 κB 抑制剂激酶/核因子 κB 抑制剂/核因子 κB（IKK/IκBα/NF-κB）途径的活性对失血性休克（HS）诱导的 ALI 产生有益作用。通过将雄性 SD 大鼠的平均动脉压（MAP）降至 40mmHg 1 小时来诱导 HS；然后大鼠接受 ghrelin（10nmol/kg）或载体静脉内给药，并通过输注失血和等量的林格乳酸溶液进行复苏，然后观察 2 小时。复苏后，收集样本并进行肺组织病理学、湿干重比（W/D）、支气管肺泡灌洗液（BALF）蛋白、中性粒细胞浸润、血浆炎性细胞因子（TNF-α 和 IL-6）和细胞质磷酸化 IKKβ、IκBα、磷酸化 IκBα 和核 NF-κB 表达分析。与两个假手术组相比，HS 大鼠的肺损伤、W/D、BALF 蛋白、中性粒细胞浸润、血浆 TNF-α 和 IL-6 水平以及 IKK/IκBα/NF-κB 途径的激活明显增加。与 HS 大鼠中没有 ghrelin 相比，ghrelin 给药后所有分析参数均降低。此外，与 HS 大鼠相比，ghrelin 减轻了复苏后 MAP 的降低。外源性 ghrelin 可减轻 HS 后的炎症反应和急性肺损伤。这些有益作用似乎是通过抑制 IKK/IκBα/NF-κB 信号转导介导的。
