Yamada Tadaaki, Iwasaki Yoshinobu, Nagata Kazuhiro, Fushiki Shinji, Nakamura Hajime, Marunaka Yoshinori, Yodoi Junji
Department of Respiratory Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Pulm Pharmacol Ther. 2007;20(6):650-9. doi: 10.1016/j.pupt.2006.07.004. Epub 2006 Sep 1.
The mechanisms of hyperoxia-induced lung injury remain poorly defined. Thioredoxin-1 (TRX-1) is a small ubiquitous protein that acts as an important radical scavenger. We investigated the effect of TRX-1 on apoptosis in hyperoxia-induced lung injury.
Mice were exposed to 98% O(2) to produce a model of hyperoxia-induced lung injury. Using transgenic mice overexpressing human TRX-1 (hTRX-1), we assessed lung structure (n=4 per group), immunohistochemical staining for 8-hydroxy-deoxyguanosine (n=4 per group), TUNEL staining (n=5 per group), cytokine (n=5 per group) of IL-1beta and IL-6, and protein (n=6 per group) and m-RNA levels (n=4 per group) (or both) of cytochrome c, Bcl-2, Bax, p21, and p53 in the lungs.
After exposure to hyperoxia, hTRX-1 transgenic mice had significantly decreased alveolar damage. The apoptotic index was significantly lower in hTRX-1 transgenic mice than in wild-type (WT) mice after exposure to hyperoxia. Protein expression of cytochrome c in the lung was significantly lower in hTRX-1 transgenic mice than in WT mice after exposure to hyperoxia. Protein expression and m-RNA levels of Bcl-2 in the lung were significantly higher in hTRX-1 transgenic mice than in WT mice after exposure to hyperoxia. TRX-1 had no effect on the protein and m-RNA levels of Bax and p21. The protein and m-RNA levels of p53 was unaffected by hyperoxia in hTRX-1 transgenic mice. The cytokine level of IL-6 was significantly higher in hTRX-1 transgenic mice than in WT mice after exposure to hyperoxia. TRX-1 had no effect on cytokine level of IL-1beta.
These findings suggest that overexpression of hTRX-1 protects against hyperoxia-induced apoptosis in cells of the alveolar walls. The up-regulating Bcl-2 protein is considered to be one of antiapoptotic effects of TRX-1 in hyperoxia-induced lung injury.
高氧诱导肺损伤的机制仍未完全明确。硫氧还蛋白-1（TRX-1）是一种广泛存在的小分子蛋白质，作为一种重要的自由基清除剂发挥作用。我们研究了TRX-1对高氧诱导肺损伤中细胞凋亡的影响。
将小鼠暴露于98%氧气中以建立高氧诱导肺损伤模型。使用过表达人TRX-1（hTRX-1）的转基因小鼠，我们评估了肺结构（每组4只）、8-羟基脱氧鸟苷的免疫组化染色（每组4只）、TUNEL染色（每组5只）、白细胞介素-1β和白细胞介素-6的细胞因子（每组5只），以及肺中细胞色素c、Bcl-2、Bax、p21和p53的蛋白质（每组6只）和mRNA水平（每组4只）（或两者）。
暴露于高氧后，hTRX-1转基因小鼠的肺泡损伤明显减轻。暴露于高氧后，hTRX-1转基因小鼠的凋亡指数显著低于野生型（WT）小鼠。暴露于高氧后，hTRX-1转基因小鼠肺中细胞色素c的蛋白表达显著低于WT小鼠。暴露于高氧后，hTRX-1转基因小鼠肺中Bcl-2的蛋白表达和mRNA水平显著高于WT小鼠。TRX-1对Bax和p21的蛋白及mRNA水平无影响。hTRX-1转基因小鼠中p53的蛋白和mRNA水平不受高氧影响。暴露于高氧后，hTRX-1转基因小鼠中白细胞介素-6的细胞因子水平显著高于WT小鼠。TRX-1对白细胞介素-1β的细胞因子水平无影响。
这些发现表明，hTRX-1的过表达可保护肺泡壁细胞免受高氧诱导的凋亡。上调Bcl-2蛋白被认为是TRX-1在高氧诱导肺损伤中的抗凋亡作用之一。
