Department of Plastic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, 1511 Jianghong Road, Hangzhou 310000, Zhejiang, China.
Clinical Research Center, The Second Affiliated Hospital Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou 310009, Zhejiang, China.
Burns. 2022 Feb;48(1):156-167. doi: 10.1016/j.burns.2021.04.013. Epub 2021 Apr 24.
Early acute kidney injury (AKI) after burn contributes to disastrous prognoses for severely burned patients. Burn-induced renal oxidative stress and secondary proinflammatory mediator release contribute to early AKI development, and Toll-like receptor (TLR) 4 regulates inflammation. Heme oxygenase-1 (HO-1) is a stress-responsive enzyme that plays a vital role in protecting against ischemia-induced organ injury via its antioxidant properties and regulation of inflammation. We investigated the potential effect of HO-1 induction in preventing burn-induced early AKI and its related mechanism.
A classic major-burn rat model was established using a 100 °C water bath, and hemin was injected intraperitoneally immediately after the injury to induce HO-1. Histological staining and blood tests were used to assess AKI progression based on structural changes and function. Renal levels of HO-1, oxidative stress, proinflammatory mediators and TLR4-related signals were detected using ELISA, immunostaining, qRT-PCR, and western blotting. The selective TLR4 inhibitor TAK242 and TLR4 inducer LPS were introduced to determine the roles of HO-1 in burn-related renal inflammation and the TLR4 pathway.
Hemin improved burn-induced renal histological damage and dysfunction, and this beneficial effect was related to reduced renal oxidative stress and the release of proinflammatory mediators, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6 and intracellular adhesion molecule-1 (ICAM-1). Hemin downregulated the expression of TLR4 and the subsequent phosphorylation of IKKα/β, IκBα, and NF-κB p65;. TAK242 exerted an effect similar to but weaker than hemin; and LPS reversed the antiinflammatory effect of hemin and the regulation of TLR4 signals. These results suggested that the TLR4 signaling pathway mediated the HO-1-facilitated regulation of renal inflammation after burn.
The present study demonstrated that HO-1 induction prevented burn-induced early AKI by targeting renal inflammation, which was mediated via regulation of the TLR4/NF-κB signaling pathway.
烧伤后早期急性肾损伤（AKI）导致严重烧伤患者预后不良。烧伤诱导的肾氧化应激和继发性促炎介质释放导致早期 AKI 的发展，而 Toll 样受体（TLR）4 调节炎症。血红素加氧酶-1（HO-1）是一种应激反应酶，通过其抗氧化特性和炎症调节，在保护缺血性器官损伤方面发挥重要作用。我们研究了诱导 HO-1 预防烧伤诱导的早期 AKI 的潜在作用及其相关机制。
使用 100°C 水浴建立经典的大烧伤大鼠模型，损伤后立即腹腔内注射血红素诱导 HO-1。组织学染色和血液检查用于根据结构变化和功能评估 AKI 进展。使用 ELISA、免疫染色、qRT-PCR 和 Western blot 检测肾 HO-1、氧化应激、促炎介质和 TLR4 相关信号的水平。引入选择性 TLR4 抑制剂 TAK242 和 TLR4 诱导剂 LPS 以确定 HO-1 在烧伤相关肾炎症和 TLR4 途径中的作用。
血红素改善了烧伤引起的肾组织学损伤和功能障碍，这种有益作用与减少肾氧化应激和促炎介质的释放有关，如肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-1β、IL-6 和细胞间黏附分子-1（ICAM-1）。血红素下调 TLR4 的表达以及随后 IKKα/β、IκBα 和 NF-κB p65 的磷酸化；TAK242 发挥的作用与血红素相似但较弱；LPS 逆转了血红素的抗炎作用和 TLR4 信号的调节。这些结果表明，TLR4 信号通路介导了烧伤后 HO-1 促进的肾炎症调节。
本研究表明，HO-1 诱导通过靶向肾炎症来预防烧伤引起的早期 AKI，这是通过调节 TLR4/NF-κB 信号通路实现的。
