PPARgamma and PPARgamma agonists in septic shock

描述（由申请人提供）：败血症是一种以血流动力学和代谢紊乱为特征的全身感染反应，可导致感染性休克、多器官系统衰竭和死亡。尽管它发生在所有年龄段的人群中，但有临床证据表明，败血症的发病率和死亡率在老年人中不成比例地增加。抗生素治疗可以有效治疗潜在感染。然而，这种治疗不足以逆转全身性炎症及其后果。在之前的资助期内，我们观察到过氧化物酶体增殖物激活受体-3 (PPAR3)，一种具有抗炎特性的核受体，在脓毒症期间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，用PPAR3配体治疗啮齿动物可提高生存率，改善肺损伤和心血管紊乱。脓毒症引起的PPAR3表达和功能的下降与细胞外信号调节激酶1和2 （erk1 /2）的磷酸化呈负相关，erk1 /2是已知能够修饰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的激活并调节炎症反应。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转录因子相互作用，在体外控制巨噬细胞的炎症反应。其他体内研究表明，PPAR家族的另一种受体PPAR4的激活可以减轻内源性休克和多微生物脓毒症中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功能，在成熟小鼠（11-12个月大）中，PPAR3、PPAR4和LXR1的表达下降，这似乎更容易发生多微生物脓毒症。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的抗炎作用很重要。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，这些受体的协调上调在败血症中是有益的。三个具体目标将检验这一假设。(1)定义体内正常生理条件和多微生物脓毒症继发病理条件下PPAR3、PPAR4和LXR1表达及功能的年龄依赖性。(2)通过“功能获得”和“功能丧失”的研究，我们将评估PPAR4和LXR1在体内多微生物脓毒症中协调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在关键炎症基因启动子位点诱导转抑制的分子机制。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创伤、出血或烧伤患者的常见并发症，也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75万例败血症导致21.5万人死亡。脓毒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岁以上的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性炎症。我们的项目旨在了解核受体PPAR3、PPAR4和LXR1在脓毒症期间调节炎症反应中的作用。这种竞争性更新代表了我们之前应用的逻辑延伸，并将为开发新的实验方法来补充败血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.