Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Pharmacy, Inner Mongolia Autonomous Region People's Hospital, Hohhot, China.
Anesthesiology. 2024 Dec 1;141(6):1119-1138. doi: 10.1097/ALN.0000000000005206.
Acute liver injury is a disease characterized by severe liver dysfunction, caused by significant infiltration of immune cells and extensive cell death with a high mortality. Previous studies demonstrated that the α7 nicotinic acetylcholine receptor (α7nAChR) played a crucial role in various liver diseases. The hypothesis of this study was that activating α7nAChR could alleviate acute liver injury and investigate its possible mechanisms.
Acute liver injury was induced by intraperitoneal injection of lipopolysaccharide (LPS)/D-galactosamine (D-Gal) in wild type, α7nAChR knockout (α7nAChR-/-) and stimulator of interferon gene (STING) mutation (Stinggt/gt) mice in the presence or absence of a pharmacologic selective α7nAChR agonist (PNU-282987). The effects of α7nAChR on hepatic injury, inflammatory response, mitochondrial damage, necroptosis, and infiltration of immune cells during acute liver injury were assessed.
The expression of α7nAChR in liver tissue was increased in LPS/D-Gal-induced acute liver injury mice. Compared to the age-matched wild-type mice, α7nAChR deficiency decreased the survival rate, exacerbated the hepatic injury accompanied with enhanced inflammatory response and oxidative stress, and aggravated hepatic mitochondrial damage and necroptosis. Conversely, pharmacologic activation of α7nAChR by PNU-282987 displayed the opposite trends. Furthermore, PNU-282987 significantly reduced the proportion of infiltrating monocyte-derived macrophages (CD45+CD11bhiF4/80int), M1 macrophages (CD45+CD11b+F4/80+CD86hiCD163low), and Ly6Chi monocytes (CD45+CD11b+MHC [major histocompatibility complex] ⅡlowLy6Chi), but increased the resident Kupffer cells (CD45+CD11bintF4/80hiTIM4hi) in the damaged hepatic tissues caused by LPS/D-Gal. Interestingly, α7nAChR deficiency promoted the STING signaling pathway under LPS/D-Gal stimulation, while PNU-282987 treatment significantly prevented its activation. Finally, it was found that Sting mutation abolished the protective effects against hepatic injury by activating α7nAChR.
The authors' study revealed that activating α7nAChR could protect against LPS/D-Gal-induced acute liver injury by inhibiting hepatic inflammation and necroptosis possibly via regulating immune cells infiltration and inhibiting STING signaling pathway.
急性肝损伤是一种以严重肝功能障碍为特征的疾病，其发生与大量免疫细胞浸润、广泛细胞死亡有关，死亡率较高。先前的研究表明，α7 型烟碱型乙酰胆碱受体（α7nAChR）在多种肝脏疾病中发挥着关键作用。本研究假设激活 α7nAChR 可以减轻急性肝损伤，并探讨其可能的机制。
在野生型、α7nAChR 敲除（α7nAChR-/-）和干扰素基因刺激因子（STING）突变（Stinggt/gt）小鼠中，通过腹腔注射脂多糖（LPS）/D-半乳糖胺（D-Gal）诱导急性肝损伤，观察在有无药理学选择性 α7nAChR 激动剂（PNU-282987）的情况下，α7nAChR 对急性肝损伤时肝损伤、炎症反应、线粒体损伤、坏死性凋亡和免疫细胞浸润的影响。
LPS/D-Gal 诱导的急性肝损伤小鼠肝组织中 α7nAChR 的表达增加。与同龄野生型小鼠相比，α7nAChR 缺失降低了生存率，加重了肝损伤，伴有增强的炎症反应和氧化应激，并加重了肝线粒体损伤和坏死性凋亡。相反，PNU-282987 通过药理学激活 α7nAChR 则呈现出相反的趋势。此外，PNU-282987 显著降低了浸润的单核细胞衍生巨噬细胞（CD45+CD11bhiF4/80int）、M1 巨噬细胞（CD45+CD11b+F4/80+CD86hiCD163low）和 Ly6Chi 单核细胞（CD45+CD11b+MHC[主要组织相容性复合体]ⅡlowLy6Chi）的比例，但增加了 LPS/D-Gal 损伤肝组织中驻留的枯否细胞（CD45+CD11bintF4/80hiTIM4hi）。有趣的是，α7nAChR 缺失促进了 LPS/D-Gal 刺激下的 STING 信号通路，而 PNU-282987 处理显著阻止了其激活。最后发现，激活 α7nAChR 引起的 STING 突变消除了对肝损伤的保护作用。
本研究表明，激活 α7nAChR 通过抑制肝脏炎症和坏死性凋亡，可能通过调节免疫细胞浸润和抑制 STING 信号通路，来抵抗 LPS/D-Gal 诱导的急性肝损伤。
