Molecular signatures of sepsis - Multiorgan gene expression profiles of systemic inflammation
Molecular signatures of sepsis - Multiorgan gene expression profiles of systemic inflammation
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DOI：
10.1016/s0002-9440(10)62505-9
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发表时间：
2001-10-01
影响因子：
6
通讯作者：
Ward, PA
中科院分区：
文献类型：
--
作者：
Chinnaiyan, AM;Huber-Lang, M;Ward, PA
在败血症期间，宿主对微生物入侵的全系统反应似乎失调。在本研究中，我们探讨了大鼠盲肠结扎/穿刺脓毒症模型中全身性炎症期间激活的多种多器官转录程序。利用代表7398个基因的DNA微阵列，我们检测了脓毒症诱导的主要器官系统（包括肺、肝、肾、胸腺、脾和脑）的基因表达模式的时间序列。虽然我们通过全球转录分析确定了已知与全身性炎症相关的基因，但许多先前未与脓毒性反应相关的基因和表达序列标签也被阐明。综上所述，我们的结果表明在脓毒症动物的单个器官中激活了高度复杂的转录反应。从我们的基因组规模分析中出现了几个重叠的主题，包括1)败血症反应引发的基因表达谱要么是器官特异性的，在多个器官中常见，要么在某些器官中明显相反；2)相对于其他器官，大脑免受败血症诱导的基因激活的保护；3)胸腺和脾脏有一个有趣的基因序列，它们的基因表达模式相反；4)具有促炎作用的基因通常被具有抗炎作用的基因(如：干扰素-1 β /诱饵受体、黄嘌呤氧化酶/超氧化物歧化酶、Ca2+依赖性PLA（2)/Ca2+非依赖性PLA(2)）平衡；5)在预防组织损伤和促进体内平衡的蛋白中，包括抗蛋白酶（TIMP-1、Cpi-26）、氧化中和酶（金属硫蛋白）、细胞因子诱变受体（白细胞介素- 1rii）和组织/血管通透性因子（水通道蛋白5、血管内皮生长因子），观察到差异基因表达。这种脓毒症反应的全局视角应该为未来研究全身性炎症的病理生理学提供一个分子框架。在基因组尺度上了解生物体对感染的反应，可能有助于开发增强的败血症检测和治疗方式。
During sepsis the host's system-wide response to microbial invasion seems dysregulated. Here we explore the diverse multiorgan transcriptional programs activated during systemic inflammation in a cecal ligation/puncture model of sepsis in rats. Using DNA microarrays representing 7398 genes, we examined the temporal sequence of sepsis-induced gene expression patterns in major organ systems including lung, liver, kidney, thymus, spleen, and brain. Although genes known to be associated with systemic inflammation were identified by our global transcript analysis, many genes and expressed sequence tags not previously linked to the septic response were also elucidated. Taken together, our results suggest activation of a highly complex transcriptional response in individual organs of the septic animal. Several overlying themes emerged from our genome-scale analysis that includes 1) the sepsis response elicited gene expression profiles that were either organ-specific, common to more than one organ, or distinctly opposite in some organs; 2) the brain is protected from sepsis-induced gene activation relative to other organs; 3) the thymus and spleen have an interesting cohort of genes with opposing gene expression patterns; 4) genes with proinflammatory effects were often balanced by genes with anti-inflammatory effects (eg, interfeukin-1 beta /decoy receptor, xanthine oxidase/superoxide dismutase, Ca2+-dependent PLA(2)/Ca2+-independent PLA(2)); and 5) differential gene expression was observed in proteins responsible for preventing tissue injury and promoting homeostasis including anti-proteases (TIMP-1, Cpi-26), oxidant neutralizing enzymes (metallothionein), cytokine decoy receptors (interleukin-1RII), and tissue/vascular permeability factors (aquaporin 5, vascular endothelial growth factor). This global perspective of the sepsis response should provide a molecular framework for future research into the pathophysiology of systemic inflammation. Understanding, on a genome scale, how an organism responds to infection, may facilitate the development of enhanced detection and treatment modalities for sepsis.