Pharmaceutical Biology ( IF 3.8 ) Pub Date : 2021-06-22 , DOI: 10.1080/13880209.2021.1933083 Yee Han Chan 1 , Nazmi Firdaus Musa 1 , Yi Joong Chong 1 , Siti Arfah Saat 1 , Faizul Hafiz 1 , Khozirah Shaari 2, 3 , Daud Ahmad Israf 1 , Chau Ling Tham 1
Abstract
Context
Lipopolysaccharide (LPS) exacerbates systemic inflammatory responses and causes excessive fluid leakage. 2,4,6-Trihydroxy-3-geranyl acetophenone (tHGA) has been revealed to protect against LPS-induced vascular inflammation and endothelial hyperpermeability in vitro.
Objective
This study assesses the in vivo protective effects of tHGA against LPS-induced systemic inflammation and vascular permeability in endotoxemic mice.
Materials and methods
BALB/c mice were intraperitoneally pre-treated with tHGA for 1 h, followed by 6 h of LPS induction. Evans blue permeability assay and leukocyte transmigration assay were performed in mice (n = 6) pre-treated with 2, 20 and 100 mg/kg tHGA. The effects of tHGA (20, 40 and 80 mg/kg) on LPS-induced serum TNF-α secretion, lung dysfunction and lethality were assessed using ELISA (n = 6), histopathological analysis (n = 6) and survivability assay (n = 10), respectively. Saline and dexamethasone were used as the negative control and drug control, respectively.
Results
tHGA significantly inhibited vascular permeability at 2, 20 and 100 mg/kg with percentage of inhibition of 48%, 85% and 86%, respectively, in comparison to the LPS control group (IC50=3.964 mg/kg). Leukocyte infiltration was suppressed at 20 and 100 mg/kg doses with percentage of inhibition of 73% and 81%, respectively (IC50=17.56 mg/kg). However, all tHGA doses (20, 40 and 80 mg/kg) failed to prevent endotoxemic mice from lethality because tHGA could not suppress TNF-α overproduction and organ dysfunction.
Discussion and conclusions
tHGA may be developed as a potential therapeutic agent for diseases related to uncontrolled vascular leakage by combining with other anti-inflammatory agents.
中文翻译:
2,4,6-三羟基-3-香叶基苯乙酮抑制脂多糖诱导的内毒素血症小鼠血管渗漏和白细胞浸润
摘要
语境
脂多糖 (LPS) 会加剧全身炎症反应并导致过多的液体渗漏。2,4,6-Trihydroxy-3-geranyl acetophenone (tHGA) 已被证明可以在体外防止 LPS 诱导的血管炎症和内皮细胞渗透性过高。
客观的
本研究评估了tHGA 对内毒素血症小鼠 LPS 诱导的全身炎症和血管通透性的体内保护作用。
材料和方法
BALB/c 小鼠用 tHGA 腹腔内预处理 1 小时,然后进行 6 小时的 LPS 诱导。在 用 2、20 和 100 mg/kg tHGA 预处理的小鼠 ( n = 6)中进行伊文思蓝渗透性测定和白细胞迁移测定。使用 ELISA ( n = 6)、组织病理学分析 ( n = 6) 和存活率测定 ( n = 10),分别。生理盐水和地塞米松分别用作阴性对照和药物对照。
结果
与 LPS 对照组相比,tHGA 在 2、20 和 100 mg/kg 时显着抑制血管通透性,抑制百分比分别为 48%、85% 和 86% (IC 50 =3.964 mg/kg)。白细胞浸润在 20 和 100 mg/kg 剂量下被抑制,抑制百分比分别为 73% 和 81% (IC 50 =17.56 mg/kg)。然而,所有 tHGA 剂量(20、40 和 80 mg/kg)均未能防止内毒素血症小鼠致死,因为 tHGA 不能抑制 TNF-α 过度产生和器官功能障碍。
讨论和结论
通过与其他抗炎剂结合,tHGA 可能被开发为与不受控制的血管渗漏相关的疾病的潜在治疗剂。