Mechanisms of age-related inflammatory response in hemorrhagic shock

描述（由申请人提供）：创伤和严重出血的临床场景以几种炎症介质的压倒性激活和白细胞与内皮细胞之间相互作用的改变为特征，导致中性粒细胞被隔离到组织和器官中。临床观察表明，儿童外伤患者的多器官功能障碍综合征（MODS）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，肺中具有抗炎作用的核受体过氧化物酶体增殖物激活受体（party）的表达是衰老过程的一个功能，在年轻时表达最多，而在成熟大鼠中表达减少。这种年龄依赖性的PPARy表达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是已知能够调节PPARy活性的蛋白激酶。我们还发现，成年大鼠在遭受失血性休克时，与年轻大鼠相比，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依赖性的，并在核水平上通过pparty途径的多种调节进行调节。三个相互关联的具体目标将检验这一假设。(1)我们将在体内定义正常生理条件下衰老过程和失血性休克后pparty通路的年龄依赖性。(2)通过功能获得（gain-of-function）和功能丧失（loss-of-function）研究，我们将评估pparty通路在年轻和成熟大鼠体内失血性休克时全身性炎症反应中的确切作用。(3)我们将通过评估上游调控激酶ERK1/2的作用来确定年龄依赖性pparty失调的分子机制。在重症监护病房的一个常见的临床观察是，儿科患者不容易发展为多器官功能障碍综合征和恢复相对平稳比成人创伤受害者。我们的项目旨在确定成人和儿童患者不同炎症反应的分子机制，并将为创伤和出血治疗新方法的开发提供有价值的信息。

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.