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: 7666191
• 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/7666191
• 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

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(申请人提供)：创伤和严重出血的临床情况的特点是几种炎症介质被压倒性地激活，白细胞和内皮细胞之间的相互作用被改变，导致中性粒细胞隔离到组织和器官中。临床观察表明，儿童创伤患者多器官功能障碍综合征(MODS)的发生率低于成人患者。然而，其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，具有抗炎作用的核受体--过氧化体增殖物激活受体(Peroxisome Proplator Actiated Receptor，Pary)在肺中的表达是衰老过程的一种功能，在年轻时表达最高，而在成年大鼠中表达下降。这种PPARy表达的年龄依赖性下降与细胞外信号调节激酶1和2(ERK 1/2)的磷酸化呈负相关，ERK 1/2是已知能够改变PPARy活性的蛋白激酶。我们还发现，与年轻大鼠相比，成年大鼠在失血性休克时，表现出更明显的肺和肝损伤。我们的假设是，失血性休克期间全身炎症反应的严重程度是年龄相关的，并在核水平上受到PPARy途径的不同调节。三个相互关联的具体目标将检验这一假设。(1)我们将确定PPARy通路在正常生理条件下和失血性休克后的衰老过程中的年龄依赖性。(2)通过“功能获得”和“功能丧失”研究，我们将评估PPARy通路在幼年和成年大鼠失血性休克时全身炎症反应中的确切作用。(3)我们将通过评估上游调节激酶ERK1/2的作用来确定PPARy的年龄依赖性失调的分子机制。重症监护病房中的一个常见临床观察是，儿童患者比成人创伤患者更不容易发生多器官功能障碍综合征，恢复相对平稳。我们的项目旨在确定导致成人和儿童患者不同炎症反应的分子机制，并将为发展创伤和出血的新治疗方法提供有价值的信息。