Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina (R.K.S., S.D., S.P., D.D., S.C.); School of Science, Technology, Engineering and Mathematics (STEM), Dillard University, New Orleans, Louisiana (S.I., J.B.R.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina (D.F.); and Division of Gastroenterology, Duke University, Durham, North Carolina (G.A.M., A.M.D.).
Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina (R.K.S., S.D., S.P., D.D., S.C.); School of Science, Technology, Engineering and Mathematics (STEM), Dillard University, New Orleans, Louisiana (S.I., J.B.R.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina (D.F.); and Division of Gastroenterology, Duke University, Durham, North Carolina (G.A.M., A.M.D.)
J Pharmacol Exp Ther. 2015 Jan;352(1):77-89. doi: 10.1124/jpet.114.218131. Epub 2014 Oct 27.
Activation of M1 macrophages in nonalcoholic steatohepatitis (NASH) is produced by several external or endogenous factors: inflammatory stimuli, oxidative stress, and cytokines are known. However, any direct role of oxidative stress in causing M1 polarization in NASH has been unclear. We hypothesized that CYP2E1-mediated oxidative stress causes M1 polarization in experimental NASH, and that nitric oxide (NO) donor administration inhibits CYP2E1-mediated inflammation with concomitant attenuation of M1 polarization. Because CYP2E1 takes center stage in these studies, we used a toxin model of NASH that uses a ligand and a substrate of CYP2E1 for inducing NASH. Subsequently, we used a methionine and choline-deficient diet-induced rodent NASH model where the role of CYP2E1 in disease progression has been shown. Our results show that CYP2E1 causes M1 polarization bias, which includes a significant increase in interleukin-1β (IL-1β) and IL-12 in both models of NASH, whereas CYP2E1-null mice or diallyl sulfide administration prevented it. Administration of gadolinium chloride (GdCl3), a macrophage toxin, attenuated both the initial M1 response and the subsequent M2 response, showing that the observed increase in cytokine levels is primarily from macrophages. Based on the evidence of an adaptive NO increase, the NO donor administration in vivo that mechanistically inhibited CYP2E1 catalyzed the oxidative stress during the entire study in NASH-abrogated M1 polarization and NASH progression. The results obtained show the association of CYP2E1 in M1 polarization, and that inhibition of CYP2E1 catalyzed oxidative stress by an NO donor (DETA NONOate [(Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate]) can be a promising therapeutic strategy in NASH.
非酒精性脂肪性肝炎 (NASH) 中 M1 巨噬细胞的激活是由几种外部或内源性因素产生的：已知炎症刺激物、氧化应激和细胞因子。然而，氧化应激在 NASH 中导致 M1 极化的确切作用尚不清楚。我们假设 CYP2E1 介导的氧化应激导致实验性 NASH 中的 M1 极化，并且一氧化氮 (NO) 供体给药抑制 CYP2E1 介导的炎症，同时减弱 M1 极化。由于 CYP2E1 在这些研究中占据中心位置，我们使用了一种 NASH 的毒素模型，该模型使用 CYP2E1 的配体和底物来诱导 NASH。随后，我们使用蛋氨酸和胆碱缺乏饮食诱导的啮齿动物 NASH 模型，其中已经显示 CYP2E1 在疾病进展中的作用。我们的结果表明，CYP2E1 导致 M1 极化偏向，这包括两种 NASH 模型中白细胞介素-1β (IL-1β) 和 IL-12 的显着增加，而 CYP2E1 缺失小鼠或二烯丙基二硫化物给药可预防这种情况。给予钆氯化物 (GdCl3)，一种巨噬细胞毒素，可减弱初始 M1 反应和随后的 M2 反应，表明观察到的细胞因子水平增加主要来自巨噬细胞。基于适应性 NO 增加的证据，体内给予 NO 供体可在整个 NASH 研究中机械地抑制 CYP2E1 催化的氧化应激，从而阻断 M1 极化和 NASH 进展。所得结果表明 CYP2E1 与 M1 极化有关，并且 NO 供体抑制 CYP2E1 催化的氧化应激（通过[Z]-1-[N-(2-氨基乙基）-N-(2-氨乙基)氨基]二氮烯-1-基-1,2-二醇酸盐（DETA NONOate））可能是 NASH 的一种有前途的治疗策略。
