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Molecular pathophysiology of pulmonary fibrosis in oxygen poisoning

氧中毒肺纤维化的分子病理生理学

基本信息

批准号：
22590630
负责人：
SHIMADA Ichiroh
金额：
$ 2.91万
依托单位：
University of Fukui
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2012
项目状态：
已结题

项目摘要

Eight-week-old mice (C57BL/6J) were bred as follows. In the 100 % oxygen-exposure experiment, the parameters were duplicated. Twenty male mice weighing 21-24 g were randomly divided into four groups as follows: (1) five mice for the control group were kept in atmospheric oxygen; (2) another fifteen mice to be used as the hyperoxia-exposure group were kept in a metallic chamber for 1 day, 2 days, and 3 days, respectively, into which oxygen flowed at a rate of 0.8 liter / min. The oximeter (JKO-25LJII, JIKCO Ltd, Japan), which was connected with the chamber, indicated 95-100 % oxygen concentration. In the 75 % oxygen-exposure experiment, ten male mice were randomly divided into two groups as follows: (1) five mice for the control group were kept in atmospheric oxygen; (2) another five mice to be used as the hyperoxia-exposure group were kept in a metallic chamber for 9 days, respectively.In the 60 % oxygen- and 40 % oxygen-exposure experiments, ten male mice were randomly divided into tw … More o groups as follows: (1) five mice for the control group were kept in atmospheric oxygen; (2) another five mice to be used as the hyperoxia-exposure group were kept in a metallic chamber for 4 weeks, respectively. In the 6 % oxygen-exposure experiment, ten male mice were randomly divided into two groups as follows: (1) five mice for the control group were kept in atmospheric oxygen; (2) another five mice to be used as the hypoxia-exposure group were kept in a metallic chamber for 3 days, respectively. In these experiment, we could not establish marked pulmonary fibrosis in mice. We have already elucidated transcript profiling of diffuse alveolar damage (DAD) induced by hyperoxia exposure in mice and showed that the mRNA level of surfactant-associated protein C (SP-C) is significantly down-regulated, while that of c-Myc is significantly up-regulated (Int J Legal Med 2008;122:373-83). To confirm the molecular pathophysiology of this alveolar dysfunction more precisely, other surfactant-associated genes and apoptosis-related genes were examined in this Grants-in-Aid for Scientific Research (C). Our study showed that: (1) hyperoxia induces a marked increase in protein levels of 4-hydroxy-2-nonenal (HNE)-amino acid Michael adduct and c-Myc; and (2) mRNA levels of surfactant-associated protein A (SP-A) and surfactant-associated protein C (SP-C) are significantly down-regulated, while those of c-Myc and Bax are significantly up-regulated in hyperoxia exposure. These results suggest that: (1) c-Myc and Bax overexpression means progression of apoptosis, which brings about a malignant cycle of reactive oxygen species (ROS) production; and (2) multiple apoptotic pathways seem to be involved in decreases in levels of mRNAs for SP-A and SP-C, in turn causing the serious risk for pulmonary collapse. Less

如下饲养八周龄小鼠(C57BL/6J)。在 100% 氧气暴露实验中，参数被重复。雄性小鼠20只，体重21-24g，随机分为四组：(1)对照组5只，常氧饲养。 (2)将另外15只小鼠作为高氧暴露组，分别在金属室中饲养1天、2天和3天，其中氧气以0.8升/分钟的速率流入。与室连接的血氧计（JKO-25LJII，JIKCO Ltd，日本）显示95-100%的氧气浓度。 75%氧暴露实验中，将10只雄性小鼠随机分为两组，如下：（1）5只为对照组，5只保持在常压氧气中；（2）5只为对照组。 (2)另5只小鼠作为高氧暴露组，分别在金属室中饲养9天。在60%氧气和40%氧气暴露实验中，将10只雄性小鼠随机分为两组，如下：(1)对照组5只小鼠在常压氧气中饲养； (2)另5只小鼠作为高氧暴露组，分别在金属室中饲养4周。 6%氧暴露实验中，将10只雄性小鼠随机分为两组，如下：（1）5只为对照组，5只置于常压氧气中； (2)另取5只小鼠作为缺氧组，分别在金属室中饲养3天。在这些实验中，我们无法在小鼠中建立明显的肺纤维化。我们已经阐明了小鼠高氧暴露引起的弥漫性肺泡损伤 (DAD) 的转录谱，并表明表面活性剂相关蛋白 C (SP-C) 的 mRNA 水平显着下调，而 c-Myc 的 mRNA 水平显着上调 (Int J Legal Med 2008;122:373-83)。为了更准确地确认这种肺泡功能障碍的分子病理生理学，本次科学研究补助金 (C) 中检查了其他表面活性剂相关基因和凋亡相关基因。我们的研究表明：（1）高氧诱导4-羟基-2-壬烯醛（HNE）-氨基酸迈克尔加合物和c-Myc的蛋白质水平显着增加； (2)高氧环境下表面活性剂相关蛋白A(SP-A)和表面活性剂相关蛋白C(SP-C)的mRNA水平显着下调，而c-Myc和Bax的mRNA水平显着上调。这些结果表明：（1）c-Myc和Bax过表达意味着细胞凋亡的进展，从而导致活性氧（ROS）产生的恶性循环； (2)多种细胞凋亡途径似乎与 SP-A 和 SP-C mRNA 水平的降低有关，进而导致肺塌陷的严重风险。较少的