Mechanisms of age-related inflammatory response in hemorrhagic shock

失血性休克年龄相关炎症反应机制

• 批准号: 7483099
• 负责人: BASILIA ZINGARELLI
• 金额: $ 30.14万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483099
• 关键词: 2,4-thiazolidinedione; 9-deoxy-delta-9-prostaglandin D2; Adult; Age; Age-Months; Aging-Related Process; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Cardiovascular system; Cell Adhesion Molecules; Cells; Cessation of life; Childhood; Clinical; Condition; Dependency; Development; Down-Regulation; Endothelial Cells; Event; Exhibits; Functional disorder; Hemorrhage; Hemorrhagic Shock; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injury; Intensive Care Units; Intercellular adhesion molecule 1; Intervention; Leukocytes; Ligands; Liquid substance; Liver; Lung; Mediating; Mediator of activation protein; Metabolic; Mitogen-Activated Protein Kinase 3; Modification; Molecular; Multiple Organ Failure; Neutrophil Infiltration; Nuclear; Nuclear Receptors; Nutritional Support; Organ; Oxidative Stress; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Physiological; Physiological reperfusion; Population; Process; Production; Prostaglandins; Protein Kinase; Proteins; RNA Interference; Rattus; Regulation; Reperfusion Therapy; Research Personnel; Resuscitation; Role; Secondary to; Severities; Shock; Signal Transduction; Small Interfering RNA; Small RNA; Syndrome; Testing; Thiazolidinediones; Tissues; Trauma; age related; chemokine; ciglitazone; clinically relevant; cyclopentenone; gain of function; hemodynamics; in vivo; in vivo Model; juvenile animal; kinase inhibitor; loss of function; lung injury; macrophage; migration; monocyte; neutrophil; novel therapeutics; pediatric trauma; programs; research study; trafficking; transcription factor; upstream kinase

DESCRIPTION (provided by applicant): The clinical scenario of trauma and severe hemorrhage is characterized by an overwhelming activation of several inflammatory mediators and by modification of the interactions between leukocytes and endothelial cells, leading to sequestration of neutrophils into the tissues and organs. Clinical observations suggest that pediatric trauma victims have lower incidence of multiple organ dysfunction syndrome (MODS) than adult patients. However, the precise molecular mechanisms are not clear. In preliminary in vivo studies we have found that under physiological conditions, lung expression of the peroxisome proliferator activated receptor-y PARY), a nuclear receptor with putative anti-inflammatory role, is a function of the aging process and is maximally expressed at young age, while it declines in mature rats. This age-dependent decline of PPARy expression inversely correlates with phosporylation of the extracellular signal-regulated kinase 1 and 2 (ERK 1/2), protein kinases known to be capable of modifying PPARy activity. We also have found that mature rats, when subjected to hemorrhagic shock, exhibit a more pronounced lung and liver injury when compared with young rats. Our hypothesis is that the severity of the systemic inflammatory response during hemorrhagic shock is age-dependent and is modulated at the nuclear level by a diverse regulation of the PPARy pathway. Three interrelated specific aims will test this hypothesis. (1) We will define the age-dependency of the PPARy pathway during the aging process under normal physiological conditions and after hemorrhagic shock in vivo. (2) With "gain-of-function" and "loss-of-function" studies, we will evaluate the precise role of the PPARy pathway on the systemic inflammatory response during hemorrhagic shock in vivo in young and mature rats. (3) We will identify the molecular mechanisms of the age-dependent dysregulation of PPARy by evaluating the role of the upstream regulatory kinases ERK1/2. A common clinical observation in intensive care units is that pediatric patients are less susceptible to develop multiple organ dysfunction syndrome and recover relatively uneventfully than adult trauma victims. Our project is aimed to identify the molecular mechanisms responsible of the diverse inflammatory response in the adult and the pediatric patients, and will provide valuable information for the developing of novel therapeutic approaches for the treatment of trauma and hemorrhage.

描述（由申请方提供）：创伤和严重出血的临床情况的特征在于几种炎症介质的压倒性激活以及白细胞和内皮细胞之间相互作用的改变，导致中性粒细胞隔离到组织和器官中。临床观察表明，儿童创伤患者的多器官功能障碍综合征（MODS）的发生率低于成人患者。然而，确切的分子机制尚不清楚。在初步的体内研究中，我们发现在生理条件下，过氧化物酶体增殖物激活受体-γ PARY（一种具有假定的抗炎作用的核受体）的肺表达是衰老过程的函数，并且在年轻时表达最大，而在成熟大鼠中表达下降。PPARy表达的这种年龄依赖性下降与细胞外信号调节激酶1和2（ERK 1/2）的磷酸化负相关，ERK 1/2是已知能够修饰PPARy活性的蛋白激酶。我们还发现，当遭受失血性休克时，与年轻大鼠相比，成熟大鼠表现出更明显的肺和肝损伤。我们的假设是，在出血性休克过程中，全身炎症反应的严重程度是年龄依赖性的，并在核水平上通过对PPARy通路的不同调节进行调节。三个相互关联的具体目标将检验这一假设。(1)我们将定义在正常生理条件下和体内出血性休克后衰老过程中PPARy途径的年龄依赖性。(2)通过“功能获得”和“功能丧失”研究，我们将评估PPARy途径在年轻和成熟大鼠体内出血性休克期间对全身炎症反应的确切作用。(3)我们将通过评估上游调节激酶ERK 1/2的作用来确定年龄依赖性PPARy失调的分子机制。在重症监护病房中的一个常见临床观察结果是，儿科患者较不容易发展为多器官功能障碍综合征，并且比成人创伤受害者相对顺利地恢复。我们的项目旨在确定负责成人和儿童患者的不同炎症反应的分子机制，并将为开发治疗创伤和出血的新治疗方法提供有价值的信息。