Department of Intensive Medicine, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China.
Immun Inflamm Dis. 2021 Sep;9(3):991-999. doi: 10.1002/iid3.458. Epub 2021 Jun 1.
Here, by using the lipopolysaccharide (LPS)-induced mice sepsis model, we treated septic wild-type (WT) mice or MEK1 mice with rigosertib to evaluate its prospective effects on sepsis.
We also generated macrophages derived from bone marrow from WT or MEK1 mice. These macrophages were pretreated with rigosertib and then induced with LPS or poly I:C.
Rigosertib suppressed LPS or poly I:C-induced expression of inflammatory cytokines (tumor necrosis factor-alpha [TNF-α] and interleukin-6 [IL-6], and IL-23) in WT bone marrow-derived macrophages while failed to affect the upregulation of TNF-α and IL-6 in LPS-treated bone marrow-derived macrophages from MEK1 mice. Rigosertib promoted survival rate, ameliorated lung injury, and reduced inflammatory cytokine levels in serum of WT septic mice.
In contrast, the effects of rigosertib on sepsis were abrogated in septic MEK1 mice, which had inducible constitutive activation of MEK1 signaling. Rigosertib alleviated LPS-induced sepsis inhibits MEK1/ERK signaling pathway.
在这里，我们使用脂多糖 (LPS) 诱导的小鼠脓毒症模型，用 rigosertib 治疗脓毒症野生型 (WT) 小鼠或 MEK1 小鼠，以评估其对脓毒症的潜在影响。
我们还从 WT 或 MEK1 小鼠的骨髓中生成巨噬细胞。这些巨噬细胞先用 rigosertib 预处理，然后用 LPS 或 poly I:C 诱导。
Rigosertib 抑制 LPS 或 poly I:C 诱导的 WT 骨髓来源巨噬细胞中炎症细胞因子（肿瘤坏死因子-α [TNF-α]和白细胞介素-6 [IL-6]和 IL-23）的表达，而对 LPS 处理的 MEK1 小鼠骨髓来源巨噬细胞中 TNF-α和 IL-6 的上调没有影响。Rigosertib 提高了 WT 脓毒症小鼠的存活率，改善了肺损伤，并降低了血清中炎症细胞因子的水平。
相比之下，在可诱导组成性激活 MEK1 信号的脓毒症 MEK1 小鼠中，rigosertib 对脓毒症的作用被消除。Rigosertib 减轻 LPS 诱导的脓毒症抑制 MEK1/ERK 信号通路。
