PDF(Pubmed)
Abstract：
UNASSIGNED: The contribution of the central nervous system to sepsis pathobiology is incompletely understood. In previous studies, administration of endotoxin to mice decreased activity of the vagus anti-inflammatory reflex. Treatment with the centrally-acting M1/M4 muscarinic acetylcholine (ACh) receptor (M1/M4AChR) attenuated this endotoxin-mediated change. We hypothesize that decreased M1/M4AChR-mediated activity contributes to inflammation following cecal ligation and puncture (CLP), a mouse model of sepsis.
UNASSIGNED: Basal forebrain cholinergic activity (immunostaining), serum cytokine/chemokine levels (ELISA) and splenocyte subtypes (flow cytometry) were examined at baseline and following CLP in male C57BL/6 male mice.
UNASSIGNED: At 48hrs. post-CLP, activity in basal forebrain cells expressing choline acetyltransferase (ChAT) was half of that observed at baseline. Lower activity was also noted in the hippocampus, which contains projections from ChAT-expressing basal forebrain neurons. Serum levels of TNFα, IL-1β, MIP-1α, IL-6, KC and G-CSF were higher post-CLP than at baseline. Post-CLP numbers of splenic macrophages and inflammatory monocytes, TNFa+ and ILb+ neutrophils and ILb+ monocytes were higher than baseline while numbers of central Dendritic Cells (cDCs), CD4+ and CD8+ T cells were lower. When, following CLP, mice were treated with xanomeline, a central-acting M1AChR agonist, activity in basal forebrain ChAT-expressing neurons and in the hippocampus was significantly higher than in untreated animals. Post-CLP serum concentrations of TNFα, IL-1β, and MIP-1α, but not of IL-6, KC and G-CSF, were significantly lower in xanomline-treated mice than in untreated mice. Post-CLP numbers of splenic neutrophils, macrophages, inflammatory monocytes and TNFα+ neutrophils also were lower in xanomeline-treated mice than in untreated animals. The effects of CLP on percentages of IL-1β+ neutrophils, IL-1β+ monocytes, cDCs, CD4+ T cells and CD8+ T cells were similar in xanomeline - treated and untreated post-CLP mice.
UNASSIGNED: Our findings indicate that M1/M4AChR-mediated responses modulate CLP-induced alterations in the distribution of some, but not all, leukocyte phenotypes and certain cytokines and chemokines.
UNASSIGNED: Basal forebrain cholinergic activity (immunostaining), serum cytokine/chemokine levels (ELISA) and splenocyte subtypes (flow cytometry) were examined at baseline and following CLP in male C57BL/6 male mice.
UNASSIGNED: At 48hrs. post-CLP, activity in basal forebrain cells expressing choline acetyltransferase (ChAT) was half of that observed at baseline. Lower activity was also noted in the hippocampus, which contains projections from ChAT-expressing basal forebrain neurons. Serum levels of TNFα, IL-1β, MIP-1α, IL-6, KC and G-CSF were higher post-CLP than at baseline. Post-CLP numbers of splenic macrophages and inflammatory monocytes, TNFa+ and ILb+ neutrophils and ILb+ monocytes were higher than baseline while numbers of central Dendritic Cells (cDCs), CD4+ and CD8+ T cells were lower. When, following CLP, mice were treated with xanomeline, a central-acting M1AChR agonist, activity in basal forebrain ChAT-expressing neurons and in the hippocampus was significantly higher than in untreated animals. Post-CLP serum concentrations of TNFα, IL-1β, and MIP-1α, but not of IL-6, KC and G-CSF, were significantly lower in xanomline-treated mice than in untreated mice. Post-CLP numbers of splenic neutrophils, macrophages, inflammatory monocytes and TNFα+ neutrophils also were lower in xanomeline-treated mice than in untreated animals. The effects of CLP on percentages of IL-1β+ neutrophils, IL-1β+ monocytes, cDCs, CD4+ T cells and CD8+ T cells were similar in xanomeline - treated and untreated post-CLP mice.
UNASSIGNED: Our findings indicate that M1/M4AChR-mediated responses modulate CLP-induced alterations in the distribution of some, but not all, leukocyte phenotypes and certain cytokines and chemokines.
摘要：
背景：中枢神经系统对脓毒症病理生物学的贡献尚不完全清楚。在以往的研究中,向小鼠施用内毒素会降低迷走神经抗炎反射的活性。用中枢作用的M1/M4毒蕈碱乙酰胆碱（ACh）受体（M1/M4AChR）治疗减弱了这种内毒素介导的变化。我们假设减少M1/M4AChR介导的活性有助于盲肠结扎和穿刺（CLP）后的炎症，脓毒症小鼠模型.方法：基底前脑胆碱能活性（免疫染色），在基线和CLP后,在雄性C57BL/6小鼠中检测血清细胞因子/趋化因子水平(ELISA)和脾细胞亚型(流式细胞术)。结果：在48小时。CLP后，表达胆碱乙酰转移酶(ChAT)的基底前脑细胞的活性是基线时的一半.海马区的活动也较低，其中包含来自表达ChAT的基底前脑神经元的投影。血清TNFα水平，IL-1β,MIP-1α,CLP后IL-6、KC和G-CSF高于基线。CLP后脾巨噬细胞和炎性单核细胞的数量，TNFa+和ILb+中性粒细胞和ILb+单核细胞高于基线，而中央树突状细胞（cDCs）的数量，CD4+和CD8+T细胞较低。When,在CLP之后，用xanomeline治疗小鼠，一种中枢作用的M1AChR激动剂，基底前脑ChAT表达神经元和海马的活性明显高于未经治疗的动物。CLP后血清TNFα浓度，IL-1β,和MIP-1α，但不是IL-6，KC和G-CSF，在xanomline处理的小鼠中明显低于未处理的小鼠。CLP后脾中性粒细胞数量，巨噬细胞，xanomeline治疗的小鼠的炎性单核细胞和TNFα+中性粒细胞也低于未治疗的动物.CLP对IL-1β+中性粒细胞百分比的影响，IL-1β+单核细胞,cDC,CD4+T细胞和CD8+T细胞在xanomeline处理和未处理的CLP后小鼠中相似。结论：我们的发现表明M1/M4AChR介导的反应调节CLP诱导的一些分布的改变，但不是全部,白细胞表型和某些细胞因子和趋化因子。
