Differential gene profiling in acute lung injury identifies injury-specific gene expression
Differential gene profiling in acute lung injury identifies injury-specific gene expression
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DOI：
10.1097/ccm.0b013e3181659333
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发表时间：
2008-03-01
影响因子：
8.8
通讯作者：
Liu, Mingyao
中科院分区：
文献类型：
--
作者：
dos Santos, Claudia C.;Okutani, Daisuke;Liu, Mingyao
目标。急性肺损伤可由不同的损伤引起，如脓毒症、缺血再灌注和呼吸机诱导的肺损伤。不同形式的损伤的生理和形态表现往往难以区分。我们试图证明，不同的侮辱导致的急性肺损伤可能导致不同的基因表达谱。应用微阵列分析技术检测了三种急性肺损伤大鼠模型肺组织中的早期分子事件：内毒素、失血性休克/复苏和大容量机械通气。单位：大学实验室。受试者。雄性SD大鼠，体重300~350g。干预：给予失血性休克或脂多糖复苏或假手术。第一次打击后，分别以低潮气量(6mL/kg)和高潮气量(112mL/kg)进行4h的机械通气。测量和主要结果：评估生理和形态变量。总RNA与Affymetrix芯片杂交。生物导体被用来鉴定显著改变的基因。在基因本体论树机中进行功能丰富预测。确证研究包括实时聚合酶链式反应、免疫印迹和免疫组织化学。生理和形态变量在确定急性肺损伤的原因方面没有贡献。相反，分子分析揭示了独特的基因表达模式，其特征是暴露于内毒素和高通气量。我们使用超几何概率来证明特定的功能富集基受到生化和生物物理因素的调节。内毒素刺激的基因参与新陈代谢、防御反应、免疫细胞增殖、分化和迁移以及细胞死亡。相反，大容量通气量导致主要涉及器官发生、形态发生、细胞周期、增殖和分化的基因的调节。这些结果证明了功能基因组学在急性肺损伤的分子“指纹”中的应用，以及将生物物理和生化损伤分离的可能性。
Objectives. Acute lung injury can result from distinct insults, such as sepsis, ischemia-reperfusion, and ventilator-induced lung injury. Physiologic and morphologic manifestations of disparate forms of injury are often indistinguishable. We sought to demonstrate that acute lung injury resulting from distinct insults may lead to different gene expression profiles.Design. Microarray analysis was used to examine early molecular events in lungs from three rat models of acute lung injury: lipopolysaccharide, hemorrhage shock/resuscitation, and high-volume ventilation. Setting: University laboratory. Subjects. Male Sprague-Dawley rats (body weight, 300-350 g).Interventions: Rats were subjected to hemorrhagic shock or lipopolysaccharide followed by resuscitation or were subjected to sham operation. First hit was followed by ventilation with either low (6 mL/kg) or high (112 mL/kg) tidal volume for 4 hrs.Measurements and Main Results: Physiologic and morphologic variables were assessed. Total RNA was hybridized to Affymetrix chips. Bioconductor was used to identify significantly altered genes. Functional enrichment predictions were performed in Gene Ontology Tree Machine. Confirmation studies included real-time polymerase chain reaction, Western blots, and immunohistochemistry. Physiologic and morphologic variables were noncontributory in determining the Cause of acute lung injury. In contrast, molecular analysis revealled unique gene expression patterns that characterized exposure to lipopolysaccharide and high-volume ventilation. We used hypergeometric probability to demonstrate that specific functional enrichment groups were regulated by biochemical vs. biophysical factors. Genes stimulated by lipopolysaccharide were involved in metabolism, defense response, immune cell proliferation, differentiation and migration, and cell death. In contrast, high-volume ventilation led to the regulation of genes involved primarily in organogenesis, morphogenesis, cell cycle, proliferation, and differentiation.Conclusions. These results demonstrate the application of functional genomics to the molecular "fingerprinting" of acute lung injury and the potential for decoupling biophysical from biochemical injury.