Ye Shui Q, Simon Brett A, Maloney James P, Zambelli-Weiner April, Gao Li, Grant Audrey, Easley R Blaine, McVerry Bryan J, Tuder Rubin M, Standiford Theodore, Brower Roy G, Barnes Kathleen C, Garcia Joe G N
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, MFL Building/Center Tower #664, Baltimore, MD 21224, USA.
Am J Respir Crit Care Med. 2005 Feb 15;171(4):361-70. doi: 10.1164/rccm.200404-563OC. Epub 2004 Dec 3.
Although the pathogenic and genetic basis of acute lung injury (ALI) remains incompletely understood, the identification of novel ALI biomarkers holds promise for unique insights. Expression profiling in animal models of ALI (canine and murine) and human ALI detected significant expression of pre-B-cell colony-enhancing factor (PBEF), a gene not previously associated with lung pathophysiology. These results were validated by real-time polymerase chain reaction and immunohistochemistry studies, with PBEF protein levels significantly increased in both bronchoalveolar lavage fluid and serum of ALI models and in cytokine- or cyclic stretch-activated lung microvascular endothelium. We genotyped two PBEF single-nucleotide polymorphisms (SNPs) in a well characterized sample of white patients with sepsis-associated ALI, patients with severe sepsis, and healthy subjects and observed that carriers of the haplotype GC from SNPs T-1001G and C-1543T had a 7.7-fold higher risk of ALI (95% confidence interval 3.01-19.75, p < 0.001). The T variant from the SNP C-1543T resulted in a significant decrease in the transcription rate (1.8-fold; p < 0.01) by the reporter gene assay. Together, these results strongly indicate that PBEF is a potential novel biomarker in ALI and demonstrate the successful application of robust genomic technologies in the identification of candidate genes in complex lung disease.
尽管急性肺损伤（ALI）的发病机制和遗传基础仍未完全明确，但新型ALI生物标志物的鉴定有望带来独特的见解。在ALI动物模型（犬和小鼠）及人类ALI中的表达谱分析检测到前B细胞集落增强因子（PBEF）有显著表达，该基因此前未与肺部病理生理学相关联。这些结果通过实时聚合酶链反应和免疫组织化学研究得到验证，在ALI模型的支气管肺泡灌洗液和血清以及细胞因子或循环拉伸激活的肺微血管内皮中，PBEF蛋白水平均显著升高。我们对一组特征明确的白人脓毒症相关ALI患者、严重脓毒症患者及健康受试者样本中的两个PBEF单核苷酸多态性（SNP）进行了基因分型，观察到单核苷酸多态性T - 1001G和C - 1543T的单倍型GC携带者发生ALI的风险高7.7倍（95%置信区间3.01 - 19.75，p < 0.001）。通过报告基因检测，单核苷酸多态性C - 1543T的T变体导致转录率显著降低（1.8倍；p < 0.01）。总之，这些结果有力地表明PBEF是ALI中一种潜在的新型生物标志物，并证明了强大的基因组技术在复杂肺部疾病候选基因鉴定中的成功应用。
