School of Kinesiology, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, China; Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, Shanghai, China.
Department of Physiology, Navy Medical University, Shanghai, China.
J Surg Res. 2023 Jan;281:264-274. doi: 10.1016/j.jss.2022.08.003. Epub 2022 Oct 8.
Persistent lung inflammation is a characteristic of sepsis-induced lung injury. Matrine, the active ingredient from Sophora flavescens, has exhibited anti-inflammatory activities. This study investigated the effects of prophylactic administration of matrine on macrophage polarization, apoptosis, and tissue injury in a cecal ligation and puncture (CLP)-induced murine lung injury model.
Mice were randomly allocated into four groups: Sham, CLP, Sham + Matrine, and CLP + Matrine. Lung tissues were collected at 24 h post-CLP. Histopathology and immunofluorescence analysis were performed to evaluate lung injury and macrophage infiltration in the lung, respectively. Caspase-3 activities, TUNEL staining, and anti-apoptotic proteins were examined to assess apoptosis. To determine the mechanism of action of matrine, protein levels of Sirtuin 1 (SIRT1), nuclear factor κB (NF-κB), p53 and the messenger RNA levels of p53-mediated proapoptotic genes were examined to elucidate the associated signaling pathways.
Histopathological evaluation showed that matrine prophylaxis attenuated sepsis-induced lung injury. Matrine prophylaxis attenuated sepsis-induced infiltration of the total population of macrophages in the lung. Matrine inhibited M1 macrophage infiltration, but increased M2 macrophage infiltration, thus resulting in a decrease in the proportion of M1 to M2 macrophages in septic lung. Sepsis-induced lung injury was associated with apoptotic cell death as evidenced by increases in caspase-3 activity, TUNEL-positive cells, and decreases in antiapoptotic proteins, all of which were reversed by matrine prophylaxis. Matrine restored sepsis-induced downregulation of SIRT1 and deacetylation of NF-κB p65 subunit and p53, thus inactivating NF-κB pathway and suppressing p53-induced proapoptotic pathway in septic lung.
In summary, this study demonstrated that matrine exhibited pro-M2 macrophage polarization and antiapoptotic effects in sepsis-induced lung injury, which might be, at least partly, due to the modulation of SIRT1/NF-κB and SIRT1/p53 pathways.
持续性肺部炎症是脓毒症性肺损伤的特征。苦参碱是苦参中的一种活性成分，具有抗炎作用。本研究旨在探讨预防性给予苦参碱对盲肠结扎穿孔（CLP）诱导的小鼠肺损伤模型中巨噬细胞极化、凋亡和组织损伤的影响。
将小鼠随机分为四组：假手术组（Sham）、盲肠结扎穿孔组（CLP）、假手术+苦参碱组（Sham+Matrine）和盲肠结扎穿孔+苦参碱组（CLP+Matrine）。CLP 后 24 小时采集肺组织。通过组织病理学和免疫荧光分析分别评估肺损伤和肺内巨噬细胞浸润。通过检测 caspase-3 活性、TUNEL 染色和抗凋亡蛋白来评估细胞凋亡。为了确定苦参碱的作用机制，检测了 Sirtuin 1（SIRT1）、核因子κB（NF-κB）、p53 的蛋白水平以及 p53 介导的促凋亡基因的信使 RNA 水平，以阐明相关的信号通路。
组织病理学评估表明，苦参碱预防可减轻脓毒症引起的肺损伤。苦参碱预防可减轻脓毒症引起的肺内总巨噬细胞浸润。苦参碱抑制 M1 巨噬细胞浸润，但增加 M2 巨噬细胞浸润，从而导致脓毒症肺中 M1 与 M2 巨噬细胞的比例降低。脓毒症引起的肺损伤与凋亡细胞死亡有关，表现为 caspase-3 活性增加、TUNEL 阳性细胞增加以及抗凋亡蛋白减少，这些变化均被苦参碱预防所逆转。苦参碱恢复了脓毒症引起的 SIRT1 下调和 NF-κB p65 亚基及 p53 的去乙酰化，从而使 NF-κB 通路失活并抑制脓毒症肺中 p53 诱导的促凋亡通路。
综上所述，本研究表明，苦参碱在脓毒症性肺损伤中表现出促 M2 巨噬细胞极化和抗凋亡作用，这可能至少部分归因于 SIRT1/NF-κB 和 SIRT1/p53 通路的调节。
