Hsu Yi-Chiang, Wang Leng-Fang, Chien Yie W
InnovaTherapeutics Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
Free Radic Biol Med. 2007 Mar 1;42(5):599-607. doi: 10.1016/j.freeradbiomed.2006.11.031. Epub 2006 Dec 15.
By studying the responses of nitric oxide in pulmonary fibrosis, the role of inducible nitric oxide synthase in diffuse pulmonary fibrosis as caused by lipopolysaccharide (LPS) treatment was investigated. When compared to rats treated with LPS only, the rats pretreated with 1400W (an iNOS-specific inhibitor) were found to exhibit a reduced level in: (i) NOx (nitrate/nitrite) production, (ii) collagen type I protein expression, (iv) soluble collagen production, and (iv) the loss of body weight and carotid artery PO2. In the pulmonary fibroblast culture, exogenous NO from LPS-stimulated secretion by macrophages or from a NO donor, such as DETA NONOate, was observed to induce the expression of TIMP-1, HSP47, TGF-beta1, and collagen type I as well as the phosphorylation of SMAD-2. After inhalation of NO for 24 h, an up-regulation of collagen type I protein was also noted to occur in rat pulmonary tissue. The results suggest that the NO signal pathway enhanced the expression of TGF-beta1, TIMP-1, and HSP47 in pulmonary fibroblasts, which collectively demonstrate that the NO signal pathway could activate the SMAD-signal cascade, by initiating a rapid increase in TGF-beta1, thereby increasing the expression of TIMP-1 and HSP47 in pulmonary fibroblasts, and play an important role in pulmonary fibrosis.
通过研究一氧化氮在肺纤维化中的反应，探讨了诱导型一氧化氮合酶在脂多糖（LPS）诱导的弥漫性肺纤维化中的作用。与仅用LPS处理的大鼠相比，用1400W（一种iNOS特异性抑制剂）预处理的大鼠表现出以下水平降低：（i）NOx（硝酸盐/亚硝酸盐）产生，（ii）I型胶原蛋白表达，（iv）可溶性胶原蛋白产生，以及（iv）体重减轻和颈动脉PO2降低。在肺成纤维细胞培养中，观察到巨噬细胞LPS刺激分泌产生的外源性NO或NO供体（如DETA NONOate）诱导TIMP-1、HSP47、TGF-β1和I型胶原蛋白的表达以及SMAD-2的磷酸化。吸入NO 24小时后，大鼠肺组织中I型胶原蛋白蛋白也出现上调。结果表明，NO信号通路增强了肺成纤维细胞中TGF-β1、TIMP-1和HSP47的表达，共同表明NO信号通路可通过引发TGF-β1的快速增加来激活SMAD信号级联，从而增加肺成纤维细胞中TIMP-1和HSP47的表达，并在肺纤维化中起重要作用。
