Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, China.
Br J Pharmacol. 2024 Dec;181(23):4845-4858. doi: 10.1111/bph.17321. Epub 2024 Sep 4.
Skin flaps are among the most important means of wound repair in clinical settings. However, partial or even total distal necrosis may occur after a flap operation, with severe consequences for both patients and doctors. This study investigated whether tert-butylhydroquinone (TBHQ), a known agonist of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), and an antioxidant, could promote skin flap survival.
McFarlane skin flap models were established in male Sprague-Dawley rats and then randomly divided into control, low-dose TBHQ, and high-dose TBHQ treatment groups. On postoperative day 7, the survival and blood flow of the skin flaps were assessed. Using flap tissue samples, angiogenesis, inflammation, apoptosis, autophagy, and Nrf2/haem oxygenase 1 (HO-1) signalling pathway activity were measured with immunohistochemical techniques and western blotting.
TBHQ dose-dependently stimulated the Nrf2/HO-1 signalling pathway, inducing autophagy through the up-regulation of LC3B and beclin 1 and concurrently suppressing p62 expression. Additionally, TBHQ hindered apoptosis by enhancing Bcl-2 expression while inhibiting the expression of Bax. It suppressed inflammation by inhibiting the expression of interleukin 1β, interleukin 6, and tumour necrosis factor-α and enhanced angiogenesis by promoting the expression of vascular endothelial growth factor.
In summary, TBHQ promoted flap survival in rats by up-regulating the Nrf2/HO-1 signalling pathway. As TBHQ is already widely used as a food additive, it could offer an acceptable means of improving clinical outcomes following skin flap surgery in patients.
皮瓣是临床创面修复的重要手段之一。但皮瓣术后可能会出现部分或全部远端坏死，给医患双方带来严重后果。本研究旨在探讨 tert-butylhydroquinone（TBHQ）——一种已知的转录因子核因子红细胞 2 相关因子 2（Nrf2）激动剂和抗氧化剂——是否能促进皮瓣存活。
建立雄性 Sprague-Dawley 大鼠 McFarlane 皮瓣模型，随机分为对照组、低剂量 TBHQ 组和高剂量 TBHQ 组。术后第 7 天，评估皮瓣的存活和血流情况。采用免疫组化技术和 Western blot 法检测皮瓣组织中血管生成、炎症、细胞凋亡、自噬以及 Nrf2/血红素加氧酶 1（HO-1）信号通路的活性。
TBHQ 呈剂量依赖性地刺激 Nrf2/HO-1 信号通路，通过上调 LC3B 和 beclin 1 并同时抑制 p62 的表达来诱导自噬。此外，TBHQ 通过增强 Bcl-2 的表达同时抑制 Bax 的表达来抑制细胞凋亡。它通过抑制白细胞介素 1β、白细胞介素 6 和肿瘤坏死因子-α 的表达来抑制炎症，通过促进血管内皮生长因子的表达来促进血管生成。
综上所述，TBHQ 通过上调 Nrf2/HO-1 信号通路促进大鼠皮瓣存活。由于 TBHQ 已广泛用作食品添加剂，因此它可能为改善患者皮瓣手术后的临床结局提供一种可接受的方法。
