Vaszar Laszlo T, Nishimura Toshihiko, Storey John D, Zhao Guohua, Qiu Daoming, Faul John L, Pearl Ronald G, Kao Peter N
Division of Pulmonary/Critical Care Medicine, Stanford University Medical Center, Stanford, California 94305-5236, USA.
Physiol Genomics. 2004 Apr 13;17(2):150-6. doi: 10.1152/physiolgenomics.00198.2003.
Pneumonectomized rats injected with the alkaloid toxin, monocrotaline, develop progressive neointimal pulmonary vascular obliteration and pulmonary hypertension resulting in right ventricular failure and death. The antiproliferative immunosuppressant, triptolide, attenuates neointimal formation and pulmonary hypertension in this disease model (Faul JL, Nishimura T, Berry GJ, Benson GV, Pearl RG, and Kao PN. Am J Respir Crit Care Med 162: 2252-2258, 2000). Pneumonectomized rats, injected with monocrotaline on day 7, were killed at days 14, 21, 28, and 35 for measurements of physiology and gene expression patterns. These data were compared with pneumonectomized, monocrotaline-injected animals that received triptolide from day 5 to day 35. The hypothesis was tested that a group of functionally related genes would be significantly coexpressed during the development of disease and downregulated in response to treatment. Transcriptional analysis using total lung RNA was performed on replicate animals for each experimental time point with exploratory data analysis followed by statistical significance analysis. Marked, statistically significant increases in proteases (particularly derived from mast cells) were noted that parallel the development of vascular obliteration and pulmonary hypertension. Mast-cell-derived proteases may play a role in regulating the development of neointimal pulmonary vascular occlusion and pulmonary hypertension in response to injury.
给肺切除的大鼠注射生物碱毒素野百合碱后，会出现进行性的新内膜性肺血管闭塞和肺动脉高压，导致右心室衰竭和死亡。抗增殖免疫抑制剂雷公藤内酯醇可减轻该疾病模型中的新内膜形成和肺动脉高压（Faul JL、Nishimura T、Berry GJ、Benson GV、Pearl RG和Kao PN。《美国呼吸与危重症医学杂志》162: 2252 - 2258，2000年）。在第7天注射野百合碱的肺切除大鼠，在第14、21、28和35天处死，用于测量生理学指标和基因表达模式。这些数据与从第5天到第35天接受雷公藤内酯醇治疗的肺切除、注射野百合碱的动物进行比较。检验的假设是，一组功能相关基因在疾病发展过程中会显著共表达，并在治疗后下调。对每个实验时间点的重复动物使用全肺RNA进行转录分析，先进行探索性数据分析，然后进行统计学显著性分析。结果发现蛋白酶（特别是来自肥大细胞的蛋白酶）有显著的、统计学上显著的增加，这与血管闭塞和肺动脉高压的发展平行。肥大细胞衍生的蛋白酶可能在调节新内膜性肺血管闭塞和肺动脉高压对损伤的反应发展中起作用。
