Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, Wuchang, 238 Liberation Road, Hubei Province, China.
Department of Anesthesiology, Bao'an Maternity & Child Health Hospital, Shenzhen 518100, Baoan, 56 Yulv Road, Guangdong Province, China.
Cytokine. 2020 Apr;128:155019. doi: 10.1016/j.cyto.2020.155019. Epub 2020 Feb 1.
Previous studies showed that GTS-21, a selective alpha 7 nAchR agonist, can trigger anti-inflammatory effects and improve the survival of septic animals. However, whether GTS-21 affects autophagy responses remains unclear. Here, we tested the hypothesis that GTS-21 ameliorates sepsis-induced hepatic injury by modulating autophagy in mice.
C57BL/6 male mice were randomly separated and categorized into four groups: the sham group, and CLP group subjected to caecal ligation and puncture (CLP, a model of polymicrobial sepsis). The CLP + GTS-21 group was administered GTS-21 immediately after CLP challenge. α-Bungarotoxin (an alpha 7 nAchR antagonist) was injected before CLP was performed, and then, after CLP challenge, GTS-21 was administered to α-BGT + CLP + GTS-21 group. The hepatic tissue and blood samples were harvested 6 h after the operation.
CLP challenge increased TNF-α and IL-6 production, and hepatic enzyme alanine aminotransferase and aspartate transaminase levels. CLP also elevated the expression of hepatic LC3-II, sequestosome-1/p62, Atg7 and Atg5. The administration of GTS-21 inhibited pro-inflammatory cytokine production and hepatic enzymatic marker expression, promoted the expression of LC3-II, Atg7, Atg5, and decreased the expression of p62, which could be reversed by α-BGT treatment.
Our findings suggested that α7nAchR is involved in diminishing hepatic damage by inhibiting inflammatory responses and improving autophagy in mice with polymicrobial sepsis.
先前的研究表明，GTS-21（一种选择性α7 nAChR 激动剂）可引发抗炎作用并提高脓毒症动物的存活率。然而，GTS-21 是否影响自噬反应尚不清楚。在这里，我们检验了这样一个假设，即 GTS-21 通过调节小鼠的自噬来改善脓毒症引起的肝损伤。
将 C57BL/6 雄性小鼠随机分为四组：假手术组和盲肠结扎穿刺术（CLP，一种多微生物脓毒症模型）组。CLP+GTS-21 组在 CLP 后立即给予 GTS-21。α-银环蛇毒素（α7 nAChR 拮抗剂）在进行 CLP 前注射，然后在 CLP 后给予 GTS-21，给予 GTS-21 至α-BGT+CLP+GTS-21 组。术后 6 小时采集肝组织和血液样本。
CLP 刺激增加了 TNF-α和 IL-6 的产生以及肝酶丙氨酸氨基转移酶和天冬氨酸氨基转移酶的水平。CLP 还增加了 LC3-II、自噬相关蛋白 1（sequestosome-1）/p62、Atg7 和 Atg5 的表达。GTS-21 的给药抑制了促炎细胞因子的产生和肝酶标志物的表达，促进了 LC3-II、Atg7、Atg5 的表达，并降低了 p62 的表达，而 α-BGT 处理则逆转了这些表达。
我们的研究结果表明，α7 nAChR 通过抑制炎症反应和改善多微生物脓毒症小鼠的自噬来减轻肝损伤。
