Weiss Scott L, Cvijanovich Natalie Z, Allen Geoffrey L, Thomas Neal J, Freishtat Robert J, Anas Nick, Meyer Keith, Checchia Paul A, Shanley Thomas P, Bigham Michael T, Fitzgerald Julie, Banschbach Sharon, Beckman Eileen, Howard Kelli, Frank Erin, Harmon Kelli, Wong Hector R
Division of Critical Care Medicine, Department of Anesthesia and Critical Care, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, 3620 Hamilton Walk, Philadelphia, PA, 19104, USA.
Center for Resuscitation Science, University of Pennsylvania Perelman School of Medicine, 3620 Hamilton Walk, Philadelphia, PA, 19104, USA.
Crit Care. 2014 Nov 19;18(6):623. doi: 10.1186/s13054-014-0623-9.
Increasing evidence supports a role for mitochondrial dysfunction in organ injury and immune dysregulation in sepsis. Although differential expression of mitochondrial genes in blood cells has been reported for several diseases in which bioenergetic failure is a postulated mechanism, there are no data about the blood cell mitochondrial transcriptome in pediatric sepsis.
We conducted a focused analysis using a multicenter genome-wide expression database of 180 children ≤ 10 years of age with septic shock and 53 healthy controls. Using total RNA isolated from whole blood within 24 hours of PICU admission for septic shock, we evaluated 296 nuclear-encoded mitochondrial genes using a false discovery rate of 1%. A series of bioinformatic approaches were applied to compare differentially expressed genes across previously validated gene expression-based subclasses (groups A, B, and C) of pediatric septic shock.
In total, 118 genes were differentially regulated in subjects with septic shock compared to healthy controls, including 48 genes that were upregulated and 70 that were downregulated. The top scoring canonical pathway was oxidative phosphorylation, with general downregulation of the 51 genes corresponding to the electron transport system (ETS). The top two gene networks were composed primarily of mitochondrial ribosomal proteins highly connected to ETS complex I, and genes encoding for ETS complexes I, II, and IV that were highly connected to the peroxisome proliferator activated receptor (PPAR) family. There were 162 mitochondrial genes differentially regulated between groups A, B, and C. Group A, which had the highest maximum number of organ failures and mortality, exhibited a greater downregulation of mitochondrial genes compared to groups B and C.
Based on a focused analysis of a pediatric septic shock transcriptomic database, nuclear-encoded mitochondrial genes were differentially regulated early in pediatric septic shock compared to healthy controls, as well as across genotypic and phenotypic distinct pediatric septic shock subclasses. The nuclear genome may be an important mechanism contributing to alterations in mitochondrial bioenergetic function and outcomes in pediatric sepsis.
越来越多的证据支持线粒体功能障碍在脓毒症器官损伤和免疫失调中起作用。尽管已有报道称血细胞中线粒体基因的差异表达与几种以生物能量衰竭为假定机制的疾病有关，但尚无关于儿童脓毒症血细胞线粒体转录组的数据。
我们使用了一个多中心全基因组表达数据库进行重点分析，该数据库包含180名10岁及以下的感染性休克儿童和53名健康对照。利用在儿科重症监护病房（PICU）因感染性休克入院24小时内从全血中分离的总RNA，我们以1%的错误发现率评估了296个核编码线粒体基因。应用一系列生物信息学方法比较了儿童感染性休克先前经验证的基于基因表达的亚类（A、B和C组）中差异表达的基因。
与健康对照相比，感染性休克患者中共有118个基因受到差异调节，其中48个基因上调，70个基因下调。得分最高的典型通路是氧化磷酸化，与电子传递系统（ETS）相对应的51个基因普遍下调。排名前两位的基因网络主要由与ETS复合体I高度相关的线粒体核糖体蛋白，以及与过氧化物酶体增殖物激活受体（PPAR）家族高度相关的编码ETS复合体I、II和IV的基因组成。A、B和C组之间有162个线粒体基因受到差异调节。A组器官衰竭和死亡率最高数量最多，与B组和C组相比，其线粒体基因下调程度更大。
基于对儿童感染性休克转录组数据库的重点分析，与健康对照相比，以及在基因型和表型不同的儿童感染性休克亚类中，核编码线粒体基因在儿童感染性休克早期受到差异调节。核基因组可能是导致儿童脓毒症线粒体生物能量功能改变和预后的重要机制。
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