Deficiency of tumour necrosis factor-α and interferon-γ in bone marrow cells synergistically inhibits neointimal formation following vascular injury
Deficiency of tumour necrosis factor-α and interferon-γ in bone marrow cells synergistically inhibits neointimal formation following vascular injury
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DOI：
10.1093/cvr/cvn250
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发表时间：
2008-11-01
影响因子：
10.8
通讯作者：
Ikeda, Uichi
中科院分区：
文献类型：
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作者：
Murayama, Hideki;Takahashi, Masafumi;Ikeda, Uichi
目的经皮冠状动脉介入治疗（PCI）后的新生内膜形成，称为再狭窄，限制了治疗性血运重建。由于现在已知血管损伤涉及炎症反应，我们研究了肿瘤坏死因子-α的作用，（TNF-α）和干扰素-γ方法和结果对照组（BALB/c），TNF-α缺陷组（Tnf（-/-）），IFN-γ缺陷组（Ifng（-/-）），或双缺陷（Tnf（-/-）Ifng（-/-））小鼠经受线介导的右股动脉血管损伤。与对照组、Tnf（-/-）和Ifng（-/-）小鼠相比，Tnf（-/-）Ifng（-/-）小鼠损伤后新生内膜形成显著减少。免疫组织化学分析显示，TNF-α和IFN-γ在对照小鼠的新生内膜病变中表达，但在相应细胞因子缺乏的小鼠中不表达。在这些组中未观察到再内皮化的显著差异。在Tnf（-/-）Ifng（-/-）小鼠中，新生内膜病变中增殖细胞核抗原的数量显著减少。骨髓移植实验显示，骨髓细胞中特异性TNF-α和IFN-γ的缺乏可显著抑制血管损伤后新生内膜的形成。结论骨髓细胞中TNF-α和IFN-γ的缺乏可协同抑制血管损伤后新生内膜的形成，从而为PCI术后再狭窄的机制提供新的见解。
Aims Neointimal formation after percutaneous coronary intervention (PCI), termed restenosis, limits therapeutic revascularization. Since it is now known that vascular injury involves an inflammatory response, we examined the role of tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the neointimal formation after injury.Methods and results Control (BALB/c), TNF-alpha-deficient (Tnf(-/-)), IFN-gamma-deficient Ifng(-/-)), or double-deficient (Tnf(-/-)Ifng(-/-)) mice were subjected to wire-mediated vascular injury of the right femoral artery. Neointimal formation after injury was significantly reduced after the injury in the Tnf(-/-)Ifng(-/-)) mice, compared to that in the control, Tnf(-/-), and Ifng(-/-) mice. Immunohistochemical analysis showed that TNF-alpha and IFN-gamma were expressed in neointimal lesions in the control mice, but not in mice with deficiency of the corresponding cytokine. No significant difference in re-endothelialization was observed among these groups. The number of proliferating cell nuclear antigen in the neointimal lesions was significantly decreased in the Tnf(-/-)Ifng(-/-) mice. Bone marrow transplantation experiments revealed that deficiency of TNF-alpha and IFN-gamma specifically in bone marrow cells significantly inhibited neointimal formation after vascular injury.Conclusion The absence of TNF-alpha and IFN-gamma in bone marrow cells synergistically inhibits neointimal formation following vascular injury, and thus, may provide new insights into the mechanisms underlying restenosis after PCI.