Exacerbation of established pulmonary fibrosis in a murine model by gammaherpesvirus
Exacerbation of established pulmonary fibrosis in a murine model by gammaherpesvirus
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DOI：
10.1164/rccm.200708-1184oc
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发表时间：
2008-04-01
影响因子：
24.7
通讯作者：
Toewsl, Galen B.
中科院分区：
文献类型：
--
作者：
McMillan, Tracy R.;Moore, Bethany B.;Toewsl, Galen B.
原理：特发性肺纤维化是一种进行性疾病，死亡率高。虽然大多数患者的病程缓慢，但有些患者会出现功能急性恶化或急性加重，预后不良。在某些情况下，急性恶化与感染有关。疱疹病毒与这种疾病有关。纤维细胞也已被证明是重要的肺fibrosis.Objectives的发病机制：建立一个小鼠模型，为感染性恶化的预先存在的纤维化，并提供机制洞察疱疹病毒在纤维化diseases.Methods的作用：我们使用了荧光素异硫氰酸酯诱导的小鼠肺纤维化的模型。在建立肺纤维化时给予鼠γ疱疹病毒感染。在峰值裂解病毒replication.Measurements和主要结果：我们表明，感染γ疱疹病毒可以加剧建立异硫氰酸荧光素诱导的纤维化证明增加总肺胶原，急性肺损伤的组织学变化，肺功能下降。在Th 1细胞因子环境和缺乏Th 2细胞因子的情况下，γ-疱疹病毒可加重预先存在的纤维化。在野生型小鼠中，γ-疱疹病毒增加了纤维细胞向肺的募集，而不是CCR 2（-/-）小鼠，部分原因是病毒感染上调了CCL 2和CCL 12的产生，CCL 2和CCL 12是对纤维细胞募集重要的趋化因子。与此相反，小鼠腺病毒感染并没有加剧Collagendeposition.Conclusions：这些数据提供了一个新的模型，γ疱疹病毒加重已建立的肺纤维化。病毒感染期间趋化因子的上调和随后纤维细胞向肺的募集可能有助于肺纤维化的增强。
Rationale: Idiopathic pulmonary fibrosis is a progressive disease with high mortality. Although most patients have a slow, progressive course, some patients will have an acute deterioration in function or acute exacerbation, which carries a poor prognosis. In some cases, acute deterioration is associated with infection. Herpesviruses have been associated with this disease. Fibrocytes have also been shown to be important in the pathogenesis of pulmonary fibrosis.Objectives: To develop a murine model for infectious exacerbation of preexisting fibrosis, and provide mechanistic insight into the role of herpesviruses in fibrotic disease.Methods: We used a model of fluorescein isothiocyanate-induced pulmonary fibrosis in mice. Infection with a murine gammaherpesvirus was given at time of established lung fibrosis. Measurements were made at the time of peak lytic viral replication.Measurements and Main Results: We demonstrate that infection with gammaherpesvirus can exacerbate established fluorescein isothiocyanate-induced fibrosis evidenced by increased total lung collagen, histologic changes of acute lung injury, and diminished lung function. Gammaherpesvirus can exacerbate preexisting fibrosis in a Th1 cytokine environment and in the absence of Th2 cytokines. Gammaherpesvirus increases fibrocyte recruitment to the lung in wild-type, but not CCR2(-/-) mice, in part because viral infection up-regulates production of CCL2 and CCL12, chemokines important for fibrocyte recruitment. In contrast, mouse adenovirus infection did not exacerbate Collagen deposition.Conclusions: These data provide a new model for gammaherpesvirus exacerbation of established pulmonary fibrosis. The up-regulation of chemokines during viral infection and subsequent recruitment of fibrocytes to the lung likely contribute to augmentation of pulmonary fibrosis.