Murine gammaherpesvirus-68 infection causes multi-organ fibrosis and alters leukocyte trafficking in interferon-γ receptor knockout mice
Murine gammaherpesvirus-68 infection causes multi-organ fibrosis and alters leukocyte trafficking in interferon-γ receptor knockout mice
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DOI：
10.1016/s0002-9440(10)64683-4
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发表时间：
2001-06-01
影响因子：
6
通讯作者：
Nash, AA
中科院分区：
文献类型：
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作者：
Ebrahimi, B;Dutia, BM;Nash, AA
小鼠γ -疱疹病毒68 （MHV-68）感染干扰素- γ受体敲除小鼠(ifn - γ - mar（-)/(-)）导致脾纤维化和脾细胞过度损失，在我们目前的研究中，我们发现MHV-68感染ifn - γ - mar(-)/(-)小鼠还导致纵隔淋巴结纤维化和萎缩，间质性肺纤维化和肝脏纤维化改变。ifn - γ -(-)/(-)脾脏的萎缩和细胞耗竭不是细胞死亡增加的结果。ifn - γ -(-)/(-)小鼠脾细胞的损失在感染后第23天最为明显，这与外周血白细胞数量的增加有关。感染后第23天，在白细胞增多的高峰期，感染的ifn - γ -(-)/(-)小鼠外周血细胞不能通过ifn - γ -(-)/(-)小鼠的纤维化脾脏，但能够进入野生型小鼠的脾脏。这表明白细胞增多在一定程度上是由于脾脏细胞的迁出和随后在纤维化高度时排除了它们的再入。ifn - γ -(-)/(-)小鼠脾脏细胞因子和趋化因子发生显著变化。感染后第14天，ifn - γ、肿瘤坏死因子- α (tnf - α)、tnf - β、白细胞介素-1 β (IL-1 β)、转化生长因子-pr （tgf - β）、淋巴趋化素和MIP-1 β升高，趋化因子IP-10和MIG显著降低。这些变化提示细胞因子和趋化因子失调在严重器官特异性纤维化中的作用，与免疫介导的纤维化疾病有关。
Murine gammaherpesvirus-68 (MHV-68) infection in interferon-gamma receptor knockout mice (IFN-gammaR(-)/(-)) results in splenic fibrosis and excessive loss of splenocytes, In our present study we found that MHV-68 infection in IFN-gammaR(-)/(-) mice also resulted in fibrosis and atrophy of the mediastinal lymph nodes, interstitial pulmonary fibrosis and fibrotic changes in the Liver. Atrophy and cellular depletion of the spleen in IFN-gammaR(-)/(-) was not the result of increased cell death. The loss of splenocytes in IFN-gammaR(-)/(-) mice, which was most evident on day 23 after infection, correlated with an increase in the number of leukocytes in peripheral blood. At the peak of leukocytosis, on day 23 after infection, peripheral blood cells from infected IFN-gammaR(-)/(-) mice were unable to traffic through the fibrosed spleens of IFN-gammaR(-)/(-) mice but were able to enter the spleens of wild-type mice. This indicates that leukocytosis was in part the result of emigration of cells from the spleen and their subsequent exclusion of re-entry at the height of fibrosis. Significant cytokine and chemokine changes were observed in spleens of IFN-gammaR(-)/(-) mice. IFN-gamma, tumor necrosis factor-alpha (TNF-alpha), TNF-beta, interleukin-1 beta (IL-1 beta), transforming growth factor-pr (TGF-beta1), lymphotactin, and MIP-1 beta were elevated on day 14 after infection whereas chemokines IP-10 and MIG were significantly reduced. These changes suggest a role for dysregulated cytokines and chemokines in severe organ-specific fibrosis with implications for immune-mediated fibrotic disorders.