Department of Emergency, Xingtai People's Hospital of Hebei Province, No. 16 Hongxing Street, Xingtai, 054031, Hebei, China.
Department of Reproductive Medicine, Xingtai People's Hospital of Hebei Province, No. 16 Hongxing Street, Xingtai, 054031, Hebei, China.
Inflammation. 2021 Apr;44(2):549-557. doi: 10.1007/s10753-020-01352-4. Epub 2020 Oct 7.
Sepsis is an inflammatory disease characterized by dysregulation of inflammation. Macrophage-mediated inflammation has been implicated in the pathophysiology of sepsis. Itaconate is a metabolite produced in activated macrophages which has anti-inflammatory activities. In the present study, we investigated the potential effects of a cell-permeable itaconate derivative dimethyl itaconate on inflammation in sepsis. We established a lipopolysaccharide (LPS)-induced septic mouse model and administered dimethyl itaconate to the septic mice. The survival rate, serum level of pro-inflammatory cytokines, and lung pathology were evaluated. We also administered dimethyl itaconate to LPS-treated bone marrow-derived macrophages (BMDMs), and measured the cytokine production and Nrf2 expression. We also evaluated the effects of dimethyl itaconate on Nrf2-deficient mice. Administration of dimethyl itaconate enhanced survival rate, decreased serum level of TNF-α and IL-6, and ameliorated lung injury in septic mice. Dimethyl itaconate also suppressed LPS-induced production of TNF-α, IL-6, and NOS2 in BMDMs. Dimethyl itaconate activated Nrf2 and promoted the expression of Nrf2 and its downstream factor HO-1 and NQO-1. The regulatory activities of dimethyl itaconate on inflammatory cytokine production, mouse survival rate were abolished in septic Nrf2 mice. Dimethyl itaconate suppressed the inflammatory responses of macrophages in sepsis.
脓毒症是一种以炎症失调为特征的炎症性疾病。巨噬细胞介导的炎症反应参与了脓毒症的病理生理学过程。衣康酸是一种在活化的巨噬细胞中产生的代谢产物，具有抗炎活性。在本研究中，我们研究了一种可渗透细胞的衣康酸衍生物-二甲基衣康酸对脓毒症炎症的潜在作用。我们建立了脂多糖（LPS）诱导的脓毒症小鼠模型，并给脓毒症小鼠施用二甲基衣康酸。评估了存活率、血清促炎细胞因子水平和肺病理。我们还将二甲基衣康酸给予 LPS 处理的骨髓来源巨噬细胞（BMDM），并测量细胞因子产生和 Nrf2 表达。我们还评估了二甲基衣康酸对 Nrf2 缺陷型小鼠的影响。二甲基衣康酸的施用提高了存活率，降低了脓毒症小鼠血清中 TNF-α和 IL-6 的水平，并改善了肺损伤。二甲基衣康酸还抑制了 LPS 诱导的 BMDM 中 TNF-α、IL-6 和 NOS2 的产生。二甲基衣康酸激活了 Nrf2，并促进了 Nrf2 及其下游因子 HO-1 和 NQO-1 的表达。在脓毒症 Nrf2 小鼠中，二甲基衣康酸对炎症细胞因子产生和小鼠存活率的调节作用被消除。二甲基衣康酸抑制了脓毒症中巨噬细胞的炎症反应。
