Diverse stage-dependent effects of glucocorticoids in a murine model of viral myocarditis.
Diverse stage-dependent effects of glucocorticoids in a murine model of viral myocarditis.
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DOI：
10.1016/j.jjcc.2012.11.006
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发表时间：
2013-03
影响因子：
2.5
通讯作者：
Hiroshi Nakamura;I. Kunitsugu;K. Fukuda;M. Matsuzaki;M. Sano
中科院分区：
文献类型：
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作者：
Hiroshi Nakamura;I. Kunitsugu;K. Fukuda;M. Matsuzaki;M. Sano
背景糖皮质激素治疗病毒性心肌炎的疗效存在争议。为探讨柯萨奇B3病毒(CVB3)诱导的小鼠急性病毒性心肌炎模型是否存在糖皮质激素治疗的“机会窗”，将小鼠随机分为4组：(1)病毒感染不给予地塞米松(DEX)治疗；(2)病毒感染前每日0.75 mg/kg，连续5天；(3)病毒感染后立即给予0.75 mg/kg，ip，DEX治疗5天；(4)0.75 mg/kg，从感染后第7天开始，连续5天ip地塞米松。结果病毒感染前或感染后即刻给予地塞米松可提高小鼠的存活率，减轻感染后心脏的左室扩张、收缩功能障碍、纤维化和免疫细胞的浸润。相反，晚期服用地塞米松降低了存活率(在第14天确定)，并与心脏肿瘤坏死因子-α和干扰素-γ水平的持续增加有关。早期给予地塞米松对小鼠存活的有利作用可被选择性环氧合酶-2抑制剂(NS-398，每天5 mg/kg，P.O.)完全抵消。值得注意的是，地塞米松显著抑制了感染后心脏中的病毒滴度，但在病毒感染时联合应用NS-398可消除地塞米松的抑制作用，事实上，增加病毒滴度。结论早期应用地塞米松对治疗暴发型病毒性心肌炎是有益的，而晚期应用地塞米松是有害的。同时给予选择性COX-2抑制剂可完全消除DEX对生存的有利影响。因此，我们推测，地塞米松对心肌细胞的直接作用，而不是地塞米松对免疫细胞的抗炎作用，赋予了对病毒感染引起的心肌损伤的抵抗。
BACKGROUNDThe effects of glucocorticoids on viral myocarditis are contentious. The aim of the present study was to determine whether there is a “window of opportunity” for glucocorticoid treatment in a mouse model of acute viral myocarditis induced by Coxsackie group B3 virus (CVB3).METHODSA/J (H-2a) mice were randomly assigned to one of four experimental groups: (1) viral infection without dexamethasone (DEX) treatment; (2) treatment with 0.75mg/kg, i.p., DEX each day for 5 days prior to viral infection; (3) 0.75mg/kg, i.p., DEX treatment for 5 days immediately after viral infection; and (4) 0.75mg/kg, i.p., DEX treatment for 5 days starting on day 7 after infection.RESULTSDEX administration before or immediately after viral infection improved survival and attenuated left ventricular dilatation, systolic dysfunction, fibrosis, and infiltration of immune cells in the post-infectious heart. In contrast, late administration of DEX reduced survival (as determined on day 14), and was associated with sustained increases in cardiac tumor necrosis factor-α and interferon-γ levels. The beneficial effects of early DEX administration on survival were completely abrogated by coadministration of a selective cyclooxygenase (COX)-2 inhibitor (NS-398; 5mg/kg per day, p.o.). Notably, the virus titer in the post-infectious heart was significantly suppressed by DEX, but coadministration of NS-398 at the time of viral infection abolished the suppressive effects of DEX and, in fact, increased virus titers.CONCLUSIONSEarly administration of DEX is beneficial in the treatment of fulminant viral myocarditis, whereas late administration of DEX is harmful. The beneficial effects of DEX on survival were completely abolished by simultaneous administration of a selective COX-2 inhibitor. Hence, we speculate that a direct action of DEX on cardiomyocytes, rather than anti-inflammatory effects of DEX on immune cells, confers resistance to myocardial damage induced by viral infection.