Mechanisms of age-related inflammatory response in hemorrhagic shock

失血性休克年龄相关炎症反应机制

基本信息

批准号：
7917223
负责人：
BASILIA ZINGARELLI
金额：
$ 29.83万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
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/7917223
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 Dependency Development Down-Regulation Endothelial Cells Event Exhibits Hemorrhage Hemorrhagic Shock Incidence Inflammation Inflammation Mediators Inflammatory Response Injury Intensive Care Units Intercellular adhesion molecule 1 Intervention Leukocytes Ligands Liquid substance Liver Lung Mediating 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 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 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 therapeutic intervention pediatric trauma programs research study trafficking transcription factor upstream kinase

项目摘要

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（由申请人提供）：创伤和严重出血的临床情况的特征是多种炎症介质的压倒性激活以及修改白细胞与内皮细胞之间的相互作用，从而导致中性粒细胞进入组织和器官。临床观察结果表明，小儿创伤受害者的多器官功能障碍综合征（MOD）的发生率低于成年患者。但是，精确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的受体-y pary的肺表达是一种具有假定的抗炎作用的核受体，是衰老过程的功能，并且在年龄较小，而在成年大鼠中则下降。 PPARY表达的年龄依赖性下降与细胞外信号调节的激酶1和2（ERK 1/2）的挥霍型（ERK 1/2），蛋白激酶能够修饰PPARY活性。我们还发现，与年轻大鼠相比，成熟的大鼠在出血性休克时表现出更为明显的肺和肝损伤。我们的假设是，出血性休克期间系统性炎症反应的严重程度是年龄依赖性的，并且通过对PPARY途径的多种调节在核水平上进行了调节。三个相互关联的特定目标将检验这一假设。（1）我们将在正常的生理条件下和体内出血性休克之后定义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途径在年轻大鼠体内出血性休克期间的系统性炎症反应上的确切作用。（3）我们将通过评估上游调节激酶ERK1/2的作用来确定PPARY年龄依赖性失调的分子机制。重症监护病房中常见的临床观察是，小儿患者与成人创伤受害者相比，小儿患者不易患上多个器官功能障碍综合征，并且相对不明显。我们的项目旨在确定成人和小儿患者各种炎症反应的分子机制，并将为开发新型治疗方法提供有价值的信息来治疗创伤和出血。