Age Effects on Liver Inflammation and Injury

年龄对肝脏炎症和损伤的影响

• 批准号: 7233572
• 负责人: Alex B. Lentsch
• 金额: $ 29.11万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7233572
• 关键词: 15 year old; Ablation; Acute; Adult; Age; Age-Months; Apoptosis; Apoptotic; CD4 Positive T Lymphocytes; Cell Count; Cell Death; Cells; Childhood; Clinical; Clinical Research; Data; Depressed mood; Endopeptidases; Endothelial Cells; Event; Experimental Animal Model; Genetic Transcription; Goals; Heat-Shock Proteins 70; Hemorrhagic Shock; Hepatic; Hepatocyte; Human; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Ischemia; Knockout Mice; Kupffer Cells; Life; Literature; Liver; Liver Dysfunction; Liver Extract; Liver Failure; Liver parenchyma; Lymphocyte; Lymphocyte Function; Modeling; Molecular; Morbidity - disease rate; Multiple Organ Failure; Mus; NF-kappa B; Necrosis; Numbers; Organ; Organ Transplantation; Organ failure; Oxidants; Patients; Pattern; Peptide Hydrolases; Phenotype; Physiological reperfusion; Population; Production; Proteins; Proteome; Proteomics; Range; Rate; Rattus; Reperfusion Injury; Reperfusion Therapy; Research Personnel; Role; Stress; Testing; Thinking; Tissues; Trauma; Up-Regulation; Vascular Cell Adhesion Molecule-1; Vascular Diseases; Week; age effect; age related; base; cell type; chemokine; cytokine; juvenile animal; mortality; neutrophil; prevent; programs; protein expression; protein function; response; transcription factor

DESCRIPTION (provided by the applicant): Hepatic injury is a primary cause of liver dysfunction in both pediatric and adult patients. Our preliminary studies using an established model of murine hepatic I/R indicate that mature mice (12-13 months of age) have significantly greater liver injury after I/R than do young mice (6-8 weeks of age). These findings are consistent with clinical studies of trauma patients which suggest that pediatric patients have a far lower incidence of multiple organ dysfunction syndrome than do adult patients. The long-term goal of this proposal is to determine the molecular and cellular mechanisms that differentiate young and mature mice in their response to hepatic I/R. Aim 1 will test the hypothesis that the transcription factor, NF-KB, is selectively depressed in hepatocytes of mature mice, leading to increased cell death and organ injury. We show that NF-KappaB activation is decreased in whole livers from mature mice, but that proinflammatory cytokine production is unaltered, suggesting that Kupffer cell activation of NF-KappaB is unaltered with age. Aim 2 will test the hypothesis that reduced hepatic expression of HSP70 in mature mice leads to increased oxidative tissue injury and hepatocyte cell death contributing to augmented I/R injury. We provide evidence that HSP70 protein expression is reduced in livers from mature mice and that this is associated with increased hepatocellular injury of both necrotic and apoptotic mechanisms. Aim 3 will test the hypothesis that CD4 lymphocytes serve to regulate hepatic I/R injury and that in mature mice altered function of CD4 lymphocytes contributes to augmented liver injury. Our preliminary data demonstrates that CD4-knockout mice have increased liver injury after I/R in a pattern that is identical to that observed in mature mice. We also show significant differences in the phenotypes of liver-resident lymphocytes between young and mature mice. Aim 4 will test the hypothesis that there are a number of cell-specific alterations in the proteomes of liver cells between young and mature mice and that these changes contribute to the divergent responses to I/R injury in these age populations. We will employ proteomics to determine the subcellular proteomes of Kupffer cells, hepatocytes, sinusoidal endothelial cells, and liver-resident lymphocytes before and after I/R to identify age-related alterations. These studies will advance our understanding of the age-dependent mechanisms that differentiate the hepatic inflammatory response of adult and pediatric patient populations to acute liver injury.

描述（由申请方提供）：肝损伤是儿科和成人患者肝功能障碍的主要原因。我们使用已建立的小鼠肝I/R模型进行的初步研究表明，成熟小鼠（12-13月龄）在I/R后的肝损伤明显大于年轻小鼠（6-8周龄）。这些发现与创伤患者的临床研究一致，这些研究表明，儿科患者的多器官功能障碍综合征的发病率远低于成人患者。这项计划的长期目标是确定区分年轻和成熟小鼠对肝脏I/R反应的分子和细胞机制。目的1将检验转录因子NF-κ B在成熟小鼠肝细胞中被选择性抑制，导致细胞死亡和器官损伤增加的假设。我们发现，在成熟小鼠的整个肝脏中，NF-κ B的活化减少，但促炎细胞因子的产生没有改变，这表明NF-κ B的库普弗细胞活化没有随年龄的变化而改变。目的2将验证以下假设：在成熟小鼠中，HSP 70的肝表达减少导致氧化组织损伤增加和肝细胞死亡，从而导致I/R损伤增强。我们提供的证据表明，HSP 70蛋白表达减少，从成熟小鼠的肝脏，这是与增加肝细胞损伤的坏死和凋亡机制。目的3将验证CD 4淋巴细胞调节肝I/R损伤的假设，以及在成熟小鼠中，CD 4淋巴细胞功能的改变有助于加重肝损伤。我们的初步数据表明，CD 4基因敲除小鼠在I/R后肝损伤增加，其模式与在成熟小鼠中观察到的相同。我们还显示年轻小鼠和成熟小鼠之间肝脏驻留淋巴细胞的表型存在显着差异。目的4将检验以下假设：年轻和成熟小鼠之间肝细胞蛋白质组中存在许多细胞特异性改变，并且这些改变有助于这些年龄群体对I/R损伤的不同反应。我们将采用蛋白质组学来确定枯否细胞，肝细胞，窦内皮细胞和肝驻留淋巴细胞的亚细胞蛋白质组之前和之后I/R，以确定年龄相关的变化。这些研究将促进我们对年龄依赖性机制的理解，这些机制将成人和儿童患者人群的肝脏炎症反应与急性肝损伤区分开来。