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Establishment of diffuse alveolar damage induced by hyperoxia exposure in mice and elucidation of its pathogenesis

小鼠高氧暴露引起弥漫性肺泡损伤的建立及其发病机制的阐明

基本信息

批准号：
17590574
负责人：
SHIMADA Ichiroh
金额：
$ 2.3万
依托单位：
University of Toyama
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

Under mechanical ventilation with high-inspired oxygen concentration, diffuse alveolar damage (DAD) was found to take place in some patients.To clarify the molecular pathophysiology of this condition we investigated the gene expression changes induced by hyperoxia exposure in mouse lung using cDNA microarrays. It revealed that 5 genes in 4277 genes analyzed were up-regulated, and 30 genes among those were down-regulated.Subsequently, we confirmed the time course of some selected genes using real-time quantitative polymerase chain reaction (real-time qPCR). It showed that mRNA levels of cysteine rich protein 61 (CYR61) and connective tissue growth factor (CTGF) were significantly up-regulated, while those of surfactant-associated protein C (SFTPC), cytochrome P450, 2F2 (CYP2F2), lysozyme (LYZS), P lysozyme structural (LZP-S), and genes of tight junction (Claudin 1, Claudin 18, Occludin, ZO-1) were significantly down-regulated. Increasing levels of mRNAs, each encoding CYR61 and CTGF, suggests a serious risk of fibrosing alveolitis. Decrease in levels of mRNAs for SFTPC, CYP2F2, LYZS, LZP-S, and genes of tight junction suggests alveolar dysfunction, disruption of the immune system, and exudation to alveolar space.Moreover we confirmed apoptotic conditions, such as significant up-regulations of mRNA levels in Galectin-3 and Myc using real-time qPCR. Hyperoxic condition probably yielded reactive oxygen species (ROS), which resulted in a malignant cycle of ROS production by Myc overexpression.

在高氧浓度机械通气条件下，部分患者出现弥漫性肺泡损伤（DAD），为了阐明DAD的分子病理生理机制，我们利用cDNA微阵列技术研究了高氧暴露诱导的小鼠肺组织基因表达的变化。结果表明，在4277个基因中，有5个基因表达上调，30个基因表达下调，并对其中的部分基因进行了实时定量PCR（real-time qPCR）分析。结果表明，在细胞周期中，富含半胱氨酸蛋白61（CYR 61）和结缔组织生长因子（CTGF）的mRNA水平显著上调，而细胞色素P450、2F 2（CYP 2F 2）、表面活性剂相关蛋白C（SFTPC）、溶菌酶（LYZS）、P溶菌酶结构蛋白（LZP-S）和紧密连接基因（Claudin 1、Claudin 18、Occludin、ZO-1）的mRNA水平显著下调。编码CYR 61和CTGF的mRNA水平的增加表明纤维化肺泡炎的严重风险。SFTPC、CYP 2F 2、LYZS、LZP-S和紧密连接基因的mRNA水平下降表明肺泡功能障碍、免疫系统破坏和肺泡腔渗出。此外，我们还证实了细胞凋亡情况，例如mRNA水平显着上调Galectin-3和Myc使用实时qPCR。高氧条件下可能产生活性氧（ROS），这导致了Myc过表达产生ROS的恶性循环。