Mast cells play a critical role in the pathogenesis of viral myocarditis
Mast cells play a critical role in the pathogenesis of viral myocarditis
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DOI：
10.1161/circulationaha.107.741595
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发表时间：
2008-07-22
期刊：
影响因子：
37.8
通讯作者：
Matsumori, Akira
中科院分区：
文献类型：
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作者：
Higuchi, Hirokazu;Hara, Masatake;Matsumori, Akira
背景-肥大细胞是多种细胞因子和化学介质的强大产生者，在各种心血管疾病的发病机制中发挥着关键作用。我们使用 2 种肥大细胞缺陷型小鼠，检查了肥大细胞在病毒性心肌炎所致心力衰竭小鼠模型中的作用。 方法和结果 - 两种肥大细胞缺陷型小鼠品系 WBB6F1-Kit(W)/Kit(W-v) (W/W-V) 和 WCB6F1-Kitl(Sl)/Kitl(Sl-d) (Sl/Sl(d)) 接种腹腔内注入10个脑心肌炎病毒空斑形成单位。接种后第 14 天，W/W-V 小鼠的存活率显着高于对照同窝小鼠（77% 对比 31%；P = 0.03；n = 13）。在第 7 天的组织学检查中，W/W-V 和 Sl/Sl(d) 小鼠的心肌坏死和细胞浸润明显低于其对照同窝小鼠（浸润面积，7.6 +/- 3.5% 对比 29.3 +/- 15.6%；P = 0.002；坏死面积，7.6 +/- 3.5% 对比 30.0 +/- 17.2%；P = 0.003；n = 10)。组织学检查显示，重建的肥大细胞比未重建的 W/W-V 和 Sl/Sld 小鼠的肥大细胞变化更严重。肥大细胞蛋白酶的基因表达在病毒性心肌炎的急性期上调，并在心力衰竭的亚急性期进一步升高。它们的激活与心肌坏死和纤维化的发展同时发生，并与基质金属蛋白酶-9 基因表达的上调相关。组胺 H1 受体拮抗剂贝托斯汀可改善脑心肌炎和病毒性心肌炎。结论 - 这些观察结果表明，肥大细胞参与与急性病毒性心肌炎相关的急性炎症反应和心室重塑的发生，并且抑制其功能可能对该疾病具有治疗作用。
Background - Mast cells are powerful producers of multiple cytokines and chemical mediators playing a pivotal role in the pathogenesis of various cardiovascular diseases. We examined the role of mast cells in murine models of heart failure due to viral myocarditis, using 2 strains of mast cell - deficient mice.Methods and Results - Two strains of mast cell - deficient mice, WBB6F1-Kit(W)/Kit(W-v) (W/W-V) and WCB6F1- Kitl(Sl)/Kitl(Sl-d) (Sl/Sl(d)), were inoculated with 10 plaque-forming units of the encephalomyocarditis virus intraperitoneally. On day 14 after inoculation, survival of W/W-V mice was significantly higher than that of their control littermates (77% versus 31%; P = 0.03; n = 13). On histological examination on day 7, myocardial necrosis and cellular infiltration were significantly less pronounced in W/W-V and Sl/ Sl(d) mice than in their control littermates (area of infiltration, 7.6 +/- 3.5% versus 29.3 +/- 15.6%; P = 0.002; area of necrosis, 7.6 +/- 3.5% versus 30.0 +/- 17.2%; P = 0.003; n = 10). Histological examination showed more severe changes in mast cell - reconstituted than in - nonreconstituted W/W-V and Sl/ Sld mice. The gene expressions of mast cell proteases were upregulated in the acute phase of viral myocarditis and rose further in the subacute phase of heart failure. Their activation coincided with the development of myocardial necrosis and fibrosis and correlated with the upregulation of gene expression of matrix metalloproteinase-9. The histamine H1- receptor antagonist bepotastine improved encephalomyocarditis viral myocarditis.Conclusions - These observations suggest that mast cells participate in the acute inflammatory reaction and the onset of ventricular remodeling associated with acute viral myocarditis and that the inhibition of their function may be therapeutic in this disease.