Department of Toxicology, School of Public Health, Anhui Medical University, No. 81 Meishan Road, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, School of Public Health, Anhui Medical University, Hefei 230022, China.
School of Health Management, Anhui Medical University, No.81, MeiShan Road, Hefei 230032, Anhui, China.
J Control Release. 2021 Mar 10;331:350-363. doi: 10.1016/j.jconrel.2021.01.025. Epub 2021 Jan 19.
Acetaminophen (APAP) induced liver injury is the most common drug-induced liver injury, accounting for the top cause of acute liver failure in the United State, however the therapeutic options for it is very limited. Excess generation of reactive oxygen species (ROS) and the subsequent inflammatory responses are the major factors of the liver injury. Carbon monoxide (CO) is an important gaseous molecule with versatile functions including anti-oxidation and anti-inflammation, and we previous reported the therapeutic potential of a nano-designed CO donor SMA/CORM2 in a dextran sulphate sodium (DSS) induced mouse colitis model. In this context, we investigated the effect of SMA/CORM2 in an APAP-induced mouse acute liver injury model and tackled the mechanisms involved. We found upregulation of heme oxygenase-1 (HO-1, endogenous CO generating enzyme) and the dynamic changes of macrophage polarization (pro-inflammatory M1/anti-inflammatory M2), which played important roles in the process of live injury. SMA/CORM2 treatment remarkably increased the CO levels in the liver and circulation, by which oxidative stresses in the liver were significantly reduced, and more importantly, it remarkably suppressed the expression of M1 macrophages but alternatively increased M2 polarization. Consequently the liver injury was significantly ameliorated, and the proliferation and regeneration were greatly promoted through the Pi3k/Akt/mTOR signaling pathway. The shift of macrophage polarization accompanied with the downregulated hypoxia-inducible factor-1α (HIF-1α) level. These findings suggested CO released from SMA/CORM2 manipulated the macrophage reprogramming toward M2 phenotype by inhibiting HIF-1α, which subsequently protected liver against inflammatory injury and benefited tissue repair. Moreover, compared to native CORM2, SMA/CORM2 exhibited superior bioavailability and protective effect. We thus anticipate the application of SMA/CORM2 as a therapeutic regimen for APAP induced liver injury as well as other inflammatory diseases and disorders.
对乙酰氨基酚（APAP）诱导的肝损伤是最常见的药物性肝损伤，占美国急性肝衰竭的首要原因，但目前的治疗选择非常有限。活性氧（ROS）的过度产生和随后的炎症反应是肝损伤的主要因素。一氧化碳（CO）是一种重要的气体分子，具有多种功能，包括抗氧化和抗炎作用，我们之前报道了纳米设计的 CO 供体 SMA/CORM2 在葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎模型中的治疗潜力。在这种情况下，我们研究了 SMA/CORM2 在 APAP 诱导的小鼠急性肝损伤模型中的作用，并探讨了相关机制。我们发现血红素加氧酶-1（HO-1，内源性 CO 生成酶）的上调和巨噬细胞极化的动态变化（促炎 M1/抗炎 M2），在肝损伤过程中发挥重要作用。SMA/CORM2 治疗显著增加了肝和循环中的 CO 水平，从而显著降低了肝中的氧化应激，更重要的是，它显著抑制了 M1 巨噬细胞的表达，而是增加了 M2 极化。因此，肝损伤明显改善，通过 Pi3k/Akt/mTOR 信号通路极大地促进了增殖和再生。巨噬细胞极化的转变伴随着缺氧诱导因子-1α（HIF-1α）水平的下调。这些发现表明，SMA/CORM2 释放的 CO 通过抑制 HIF-1α来操纵巨噬细胞向 M2 表型的重编程，从而保护肝脏免受炎症损伤，并有利于组织修复。此外，与天然 CORM2 相比，SMA/CORM2 具有更好的生物利用度和保护作用。因此，我们期望 SMA/CORM2 可作为治疗对乙酰氨基酚诱导的肝损伤以及其他炎症性疾病和障碍的治疗方案。
