Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi, 214122, Jiangsu, People's Republic of China.
Food Science and Technology, Jiangnan University, 1800 Lihu Avenue, Wuxi, 214122, Jiangsu, People's Republic of China.
Inflamm Res. 2023 Jun;72(6):1133-1145. doi: 10.1007/s00011-023-01733-z. Epub 2023 May 11.
Pulmonary fibrosis (PF) is a chronic and refractory interstitial lung disease with limited therapeutic options. 4-octyl itaconate (4-OI), a cell-permeable derivative of itaconate, has been shown to have anti-oxidative and anti-inflammatory properties. However, the effect and the underlying mechanism of 4-OI on PF are still unknown.
WT or Nrf2 knockout (Nrf2) mice were intratracheally injected with bleomycin (BLM) to establish PF model and then treated with 4-OI. The mechanism study was performed by using RAW264.7 cells, primary macrophages, and conditional medium-cultured MLE-12 cells.
4-OI significantly alleviated BLM-induced PF and EMT process. Mechanism studies have found that 4-OI can not only directly inhibit EMT process, but also can reduce the production of TGF-β1 by restraining macrophage M2 polarization, which in turn inhibits EMT process. Moreover, the effect of 4-OI on PF and EMT depends on Nrf2.
4-OI ameliorates BLM-induced PF in an Nrf2-dependent manner, and its role in alleviating PF is partly due to the direct inhibition on EMT, and partly through indirect inhibition of M2-mediated EMT. These findings suggested that 4-OI has great clinical potential to develop as a new anti-fibrotic agent for PF therapy.
肺纤维化（PF）是一种慢性、难治性的间质性肺疾病，治疗选择有限。4-辛烯酸（4-OI）是衣康酸的一种细胞可渗透衍生物，具有抗氧化和抗炎特性。然而，4-OI 对 PF 的作用和潜在机制尚不清楚。
WT 或 Nrf2 敲除（Nrf2）小鼠经气管内注射博来霉素（BLM）建立 PF 模型，然后用 4-OI 治疗。通过 RAW264.7 细胞、原代巨噬细胞和条件培养基培养的 MLE-12 细胞进行机制研究。
4-OI 显著减轻 BLM 诱导的 PF 和 EMT 过程。机制研究发现，4-OI 不仅可以直接抑制 EMT 过程，还可以通过抑制巨噬细胞 M2 极化来减少 TGF-β1 的产生，从而抑制 EMT 过程。此外，4-OI 对 PF 和 EMT 的作用依赖于 Nrf2。
4-OI 以 Nrf2 依赖的方式改善 BLM 诱导的 PF，其在缓解 PF 中的作用部分归因于对 EMT 的直接抑制，部分归因于通过间接抑制 M2 介导的 EMT。这些发现表明，4-OI 具有很大的临床潜力，可以开发为治疗 PF 的新型抗纤维化药物。
