Aggravation of Bleomycin-Induced Pulmonary Inflammation and Fibrosis in Mice Lacking Peroxiredoxin I
Aggravation of Bleomycin-Induced Pulmonary Inflammation and Fibrosis in Mice Lacking Peroxiredoxin I
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DOI：
10.1165/rcmb.2010-0137oc
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发表时间：
2011-09-01
影响因子：
6.4
通讯作者：
Hizawa, Nobuyuki
中科院分区：
文献类型：
--
作者：
Kikuchi, Norihiro;Ishii, Yukio;Hizawa, Nobuyuki
氧化应激在急性肺损伤和肺纤维化的发病机制中起重要作用。Peroxiredoxin（Prx）I是在应激条件下诱导的细胞抗氧化酶。在本研究中，使用Prx I缺陷小鼠研究Prx I对博来霉素诱导的急性肺部炎症和肺纤维化的发展的保护作用。博来霉素给药后Prx I缺陷小鼠的存活率显著低于野生型小鼠，这与增强的急性肺部炎症和纤维化相对应。博来霉素给药后，Prx I缺陷小鼠支气管肺泡灌洗液中炎性细胞因子和趋化因子（如TNF-α、巨噬细胞炎性蛋白-2和单核细胞趋化蛋白-1）的水平显著升高。此外，8-异前列烷，氧化应激标志物，和浓度和肺泡巨噬细胞表达的巨噬细胞迁移抑制因子的水平升高后，博莱霉素给药的Prx I缺陷小鼠的肺。用N-乙酰-L-半胱氨酸（一种自由基清除剂）或（S，R）-3-（4-羟基苯基）-4，5-二氢-5-异恶唑乙酸甲酯（一种巨噬细胞迁移抑制因子的互变异构酶抑制剂）治疗可抑制Prx I缺陷小鼠中博来霉素诱导的肺部炎症和纤维化的加重。这些发现表明，缺乏Prx I的小鼠对博莱霉素诱导的肺部炎症和纤维化高度敏感，因为肺氧化剂水平和巨噬细胞迁移抑制因子活性响应博莱霉素而增加。
Oxidative stress plays an important role in the pathogenesis of acute lung injury and pulmonary fibrosis. Peroxiredoxin (Prx) I is a cellular antioxidant enzyme induced under stress conditions. In the present study, the protective effects of Prx I on the development of bleomycin-induced acute pulmonary inflammation and pulmonary fibrosis were investigated using Prx I-deficient mice. Survival of Prx I-deficient mice after bleomycin administration was significantly lower than that of wild-type mice, corresponding with enhanced acute pulmonary inflammation and fibrosis. The level of inflammatory cytokines and chemokines, such as TNF-alpha, macrophage inflammatory protein-2, and monocyte chemotactic protein-1, was significantly elevated in the bronchoalveolar lavage fluid of Prx I-deficient mice after bleomycin administration. Furthermore, the level of 8-isoprostane, an oxidative stress marker, and the concentration and alveolar macrophage expression of macrophage migration inhibitory factor were elevated in the lungs of Prx I-deficient mice after bleomycin administration. The exacerbation of bleomycin-induced pulmonary inflammation and fibrosis in Prx I-deficient mice was inhibited by treatment with N-acetyl-L-cysteine, a radical scavenger, or with (S, R)-3-(4-hydroxyphenyl)- 4,5-dihydro-5-isoxazole acetic acid methyl ester, a tautomerase inhibitor of macrophage migration inhibitory factor. These findings suggest that mice lacking Prx I are highly susceptible to bleomycin-induced pulmonary inflammation and fibrosis because of increases in pulmonary oxidant levels and macrophage migration inhibitory factor activity in response to bleomycin.