PPARgamma and PPARgamma agonists in septic shock

描述（由申请方提供）：脓毒症是对感染的全身反应，其特征为血流动力学和代谢紊乱，可能导致脓毒性休克、多器官系统衰竭和死亡。虽然它发生在所有年龄的人，有临床证据表明，败血症的发病率和死亡率是不成比例地增加在老年人。抗生素治疗可以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。在上一个资助期，我们观察到过氧化物酶体增殖物激活受体3（PPAR 3），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。PPAR 3下调的程度与炎症反应的严重程度相关。相反，用PPAR 3配体治疗啮齿动物提高了存活率，改善了肺损伤和心血管紊乱。脓毒症诱导的PPAR 3表达和功能的下降与细胞外信号调节激酶1和2（ERK 1/2）的磷酸化负相关，细胞外信号调节激酶1和2是已知能够修饰PPAR 3活性的蛋白激酶。我们的研究还表明，其他核受体可以调节PPAR 3激活和调节炎症反应。例如，我们已经观察到，PPAR 3可能与肝脏X受体-1（LXR 1）（一种类似的核配体激活的转录因子）相互作用，在体外控制巨噬细胞的炎症反应。其他体内研究已经证明，PPAR 4（PPAR 4家族的另一种受体）的活化降低了内毒素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PPAR 3、PPAR 4和LXR 1的肺表达也是衰老过程的函数，并且在成熟小鼠（11-12个月大）中下降，这似乎更容易受到多微生物败血症的影响。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，这是重要的抗炎作用的PPAR 3。我们的假设是，核受体PPAR 3，PPAR 4和LXR 1的表达和抗炎功能的下调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)我们将定义年龄依赖性的PPAR 3，PPAR 4和LXR 1的表达和功能，在正常生理条件下，并在病理条件下继发于体内多微生物败血症。(2)通过“功能获得”和“功能丧失”研究，我们将评估PPAR 4和LXR 1在体内多微生物脓毒症期间协调PPAR 3依赖性抗炎功能的确切作用。(3)通过体外研究，我们将进一步确定PPAR 3，LXR 1或PPAR 4可能在关键炎症基因的启动子位点诱导反式阻遏的分子机制。公共卫生相关性革兰氏阴性或革兰氏阳性感染导致的脓毒症和脓毒性休克是继发于患者创伤、出血或烧伤的常见并发症，是重症监护室发病和死亡的主要原因。在美国，每年有超过750，000例败血症，导致215，000人死亡。脓毒症的发病率和死亡率随年龄增长而增加，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炎症。我们的项目旨在了解核受体PPAR 3，PPAR 4和LXR 1在脓毒症炎症反应中的作用。这种竞争性的更新代表了我们先前应用的逻辑延伸，并将为开发新的实验方法以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.