Wesselkamper Scott C, Case Lisa M, Henning Lisa N, Borchers Michael T, Tichelaar Jay W, Mason John M, Dragin Nadine, Medvedovic Mario, Sartor Maureen A, Tomlinson Craig R, Leikauf George D
Department of Environmental Health, P.O. Box 670056, University of Cincinnati, Cincinnati, OH 45267-0056, USA.
Am J Respir Crit Care Med. 2005 Dec 1;172(11):1399-411. doi: 10.1164/rccm.200502-286OC. Epub 2005 Aug 11.
Acute lung injury can occur from multiple causes, resulting in high mortality. The pathophysiology of nickel-induced acute lung injury in mice is remarkably complex, and the molecular mechanisms are uncertain.
To integrate molecular pathways and investigate the role of transforming growth factor beta (TGF-beta) in acute lung injury in mice.
cDNA microarray analyses were used to identify lung gene expression changes after nickel exposure. MAPPFinder analysis of the microarray data was used to determine significantly altered molecular pathways. TGF-beta1 protein in bronchoalveolar lavage fluid, as well as the effect of inhibition of TGF-beta, was assessed in nickel-exposed mice. The effect of TGF-beta on surfactant-associated protein B (Sftpb) promoter activity was measured in mouse lung epithelial cells.
Genes that decreased the most after nickel exposure play important roles in lung fluid absorption or surfactant and phospholipid synthesis, and genes that increased the most were involved in TGF-beta signaling. MAPPFinder analysis further established TGF-beta signaling to be significantly altered. TGF-beta-inducible genes involved in the regulation of extracellular matrix function and fibrinolysis were significantly increased after nickel exposure, and TGF-beta1 protein was also increased in the lavage fluid. Pharmacologic inhibition of TGF-beta attenuated nickel-induced protein in bronchoalveolar lavage. In addition, treatment with TGF-beta1 dose-dependently repressed Sftpb promoter activity in vitro, and a novel TGF-beta-responsive region in the Sftpb promoter was identified.
These data suggest that TGF-beta acts as a central mediator of acute lung injury through the alteration of several different molecular pathways.
急性肺损伤可由多种原因引起，导致高死亡率。镍诱导的小鼠急性肺损伤的病理生理学非常复杂，其分子机制尚不确定。
整合分子途径并研究转化生长因子β（TGF-β）在小鼠急性肺损伤中的作用。
采用cDNA微阵列分析来鉴定镍暴露后肺基因表达的变化。利用微阵列数据的MAPPFinder分析来确定显著改变的分子途径。在镍暴露的小鼠中评估支气管肺泡灌洗液中的TGF-β1蛋白以及TGF-β抑制的效果。在小鼠肺上皮细胞中测量TGF-β对表面活性剂相关蛋白B（Sftpb）启动子活性的影响。
镍暴露后下降最多的基因在肺液吸收或表面活性剂及磷脂合成中起重要作用，而增加最多的基因参与TGF-β信号传导。MAPPFinder分析进一步证实TGF-β信号传导显著改变。镍暴露后，参与细胞外基质功能调节和纤维蛋白溶解的TGF-β诱导基因显著增加，灌洗液中的TGF-β1蛋白也增加。TGF-β的药物抑制减弱了镍诱导的支气管肺泡灌洗蛋白。此外，TGF-β1处理在体外剂量依赖性地抑制Sftpb启动子活性，并鉴定出Sftpb启动子中的一个新的TGF-β反应区域。
这些数据表明，TGF-β通过改变几种不同的分子途径，作为急性肺损伤的中心介质发挥作用。
