PPARgamma and PPARgamma agonists in septic shock

描述(申请人提供)：败血症是一种全身性感染反应，其特征是血液动力学和代谢紊乱，可能导致败血症休克、多器官系统衰竭和死亡。尽管它发生在所有年龄段的人中，但有临床证据表明，脓毒症的发病率和死亡率在老年人中不成比例地增加。抗生素疗法可能有效地治疗潜在的感染。然而，这种治疗不足以逆转全身炎症及其后果。在之前的资助期间，我们观察到具有抗炎特性的核受体PPAR3在脓毒症时在几个器官和组织中逐渐下降。PPAR3下调的程度与炎症反应的严重程度相关。相反，使用PPAR3配体治疗啮齿动物可以提高存活率，改善肺损伤和心血管紊乱。脓毒症诱导的PPAR3表达和功能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PPAR3活性的蛋白激酶。我们的研究还表明，其他核受体可能调节PPAR3的激活和调节炎症反应。例如，我们观察到PPAR3可能与肝X受体-1(LXR1)(一种类似的核配体激活的转录因子)在体外控制巨噬细胞的炎症反应中相互作用。其他体内研究表明，PPAR家族的另一种受体PPAR4的激活可以减轻内毒素休克和多菌败血症时炎症反应的严重程度。有趣的是，我们观察到肺中PPAR3、PPAR4和LXR1的表达也是衰老过程的一个函数，在成熟小鼠(11-12个月大)中它的表达下降，这些小鼠似乎更容易受到多菌败血症的影响。因此，我们的初步数据已经确定了一个复杂的信号网络的存在，这对PPAR3的抗炎作用是重要的。我们的假设是，核受体PPAR3、PPAR4和LXR1的表达下调和抗炎功能在脓毒症的全身炎症反应中起重要作用。相反，这些受体的协同上调在脓毒症中是有益的。三个具体目标将检验这一假设。(1)我们将确定PPAR3、PPAR4和LXR1在正常生理条件下和体内继发于多菌败血症的病理条件下的表达和功能的年龄依赖性。(2)通过“功能获得”和“功能丧失”研究，我们将评估PPAR4和LXR1在体内多菌败血症中协调PPAR3依赖的抗炎功能中的确切作用。(3)通过体外研究，我们将进一步确定PPAR3、LXR1或PPAR4可能诱导关键炎症基因启动子位置反式阻遏的分子机制。与公共卫生相关由革兰氏阴性或革兰氏阳性感染引起的败血症和感染性休克是继发于患者的创伤、出血或烧伤的常见并发症，是重症监护病房发病率和死亡率的主要原因。在美国，每年有超过75万例脓毒症病例导致21.5万人死亡。败血症的发病率和死亡率随着年龄的增长而增加，从儿童的10%增加到85岁的38.4%。不幸的是，传统的抗生素治疗、循环和呼吸支持并不总是足以逆转全身炎症。我们的项目旨在了解核受体PPAR3、PPAR4和LXR1在脓毒症时调节炎症反应中的作用。这一竞争性更新代表了我们先前应用的合理扩展，并将为开发新的实验方法来补充脓毒症后的抗生素治疗提供有价值的信息。

DESCRIPTION (provided by applicant): Sepsis is a systemic response to infection characterized by hemodynamic and metabolic derangements that may result in septic shock, multiple organ system failure and death. Although it occurs in people of all ages, there is clinical evidence that the incidence and mortality of sepsis is disproportionately increased in elderly adults. Antibiotic therapy may effectively treat an underlying infection. However, this treatment is not sufficient to reverse the systemic inflammation and its consequences. In the previous funding period, we have observed that the peroxisome proliferator activated receptor-3 (PPAR3), a nuclear receptor with anti-inflammatory properties, declines progressively in several organs and tissues during sepsis. The extent of PPAR3 downregulation correlates with the severity of the inflammatory response. On the contrary, treatment of rodents with PPAR3 ligands improves survival, ameliorates lung injury and cardiovascular derangement. The sepsis- induced decline in PPAR3 expression and function inversely correlates with phosporylation of the extracellular signal-regulated kinase 1 and 2 (ERK 1/2), protein kinases known to be capable of modifying PPAR3 activity. Our studies have also demonstrated that other nuclear receptors may regulate PPAR3 activation and modulate the inflammatory response. For example, we have observed that PPAR3 may interact with liver X receptor-1 (LXR1) a similar nuclear ligand-activated transcription factor, in controlling the inflammatory response in macrophages in vitro. Other in vivo studies have demonstrated that activation of PPAR4, another receptor of the PPAR family, reduces the severity of the inflammatory response in endotoxic shock and polymicrobial sepsis. Interestingly, we have observed that lung expression of PPAR3, PPAR4 and LXR1 is also a function of the aging process and it declines in mature mice (11-12 months old), which appear to be more susceptible to polymicrobial sepsis. Thus, our preliminary data have identified the existence of a complex signaling network that is important to the anti-inflammatory role of PPAR3. Our hypothesis is that downregulation of the expression and anti-inflammatory function of the nuclear receptors PPAR3, PPAR4 and LXR1 plays an important role in the systemic inflammatory response of sepsis. On the contrary, coordinate upregulation of these receptors is beneficial in sepsis. Three specific aims will test this hypothesis. (1) We will define the age-dependency of the PPAR3, PPAR4 and LXR1 expression and function under normal physiological conditions and under pathological conditions secondary to polymicrobial sepsis in vivo. (2) With "gain-of-function" and "loss-of-function" studies, we will evaluate the precise role of PPAR4 and LXR1 in coordinating the PPAR3-dependent anti-inflammatory function during polymicrobial sepsis in vivo. (3) With in vitro studies we will further identify the molecular mechanisms by which PPAR3, LXR1 or PPAR4 may induce transrepression at promoter sites of key inflammatory genes. PUBLIC HEALTH RELEVANCE Sepsis and septic shock resulting from Gram-negative or Gram-positive infection are frequent complications secondary to trauma, hemorrhage or burns in patients, and are leading causes of morbidity and mortality in critical care units. There are over 750,000 cases of sepsis resulting in 215,000 deaths each year in the USA. The incidence and mortality of sepsis increase with age from 10% in children to 38.4% in those >85 yrs old. Unfortunately, the conventional antibiotic therapies, circulatory and respiratory support are not always sufficient to reverse the systemic inflammation. Our project is aimed to understand the role of the nuclear receptors PPAR3, PPAR4 and LXR1 in regulating the inflammatory response during sepsis. This competitive renewal represents a logical extension of our previous application and will provide valuable information for the developing of novel experimental approaches to complement antibiotic therapy after sepsis.