Amelioration of Sepsis by Macrophage Activation

描述(申请人提供)：危重患者经常出现复杂的疾病谱，可能包括成人呼吸窘迫综合征(ARDS)、全身炎症反应综合征(SIRS)、脓毒症综合征和/或感染性休克。目前，我们还不清楚败血症损伤发生和传播的细胞和分子机制，也不清楚败血症患者试图限制炎症反应、维持体内平衡和促进生存的内在生理机制。磷脂酰肌醇3-激酶/Akt(PI3K/Akt)是一个保守的信号转导酶家族，参与调节细胞的增殖和存活。在最后一次资助期间，我们发现PI3K信号转导酶家族通过限制对多菌败血症的炎症反应而发挥重要的生理作用。具体地说，内源性PI3K抑制脓毒症宿主中促炎症细胞因子的释放和细胞凋亡。它还可以促进暴发性脓毒症的存活率。更有意义的是，我们发现与膜相关的模式识别受体结合的碳水化合物配体刺激了PI3K/Akt途径，从而降低了暴发型脓毒症的发病率，增加了生存结局。这些数据表明，刺激PI3K通路可能是预防和/或治疗脓毒症/感染性休克的有效途径。在目前的提案中，我们将扩展这些研究，以检查葡聚糖配体刺激PI3K/Akt信号的细胞和分子机制。我们将重点了解激活PI3K的配体-受体相互作用，刺激PI3K/Akt/GSK3的受体后信号转导事件，以及最终导致PI3K调节和诱导脓毒症损伤保护性表型的细胞变化。这项研究的结果不仅将增加我们对炎症/败血症疾病先天反应的基础科学知识，而且还可能导致针对几种重要疾病状态的新治疗策略的开发。

DESCRIPTION (provided by applicant): The critically ill patient frequently develops a complex disease spectrum that may include adult respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), sepsis syndrome and/or septic shock. At present, we do not understand the cellular and molecular mechanisms that are involved in the initiation and propagation of septic injury; nor do we understand the innate physiologic mechanisms that attempt to limit inflammation maintain homeostasis and promote survival in the septic patient. The phosphoinsitide 3-kinases/Akt (PI3K/Akt) is a conserved family of signal transduction enzymes which are involved in regulating cellular proliferation and survival. During the last grant period, we discovered that the PI3K family of signal transduction enzymes plays an important physiologic role by limiting the inflammatory response to plymicrobial sepsis. Specifically, endogenous PI3K suppresses pro-inflammatory cytokine release and apoptosis in the septic host. It also promotes survival in fulminating sepsis. Of greater significance, we discovered that a carbohydrate ligand that is bound by membrane associated pattern recognition receptors stimulates the PI3K/Akt pathway resulting in decreased morbidity and increased survival outcome in fulminating sepsis. These data suggest that stimulation of the PI3K pathway may be an effective approach for preventing and/or treating sepsis/septic shock. In the current proposal, we will extend these studies to examine the cellular and molecular mechanisms by which glucan ligands stimulate PI3K/Akt signaling. We will focus on understanding the ligand-receptor interactions that activate PI3K, the postreceptor signal transduction events that stimulate PI3K/Akt/GSK3 and the cellular changes that culminate in modulation of PI3K and induction of the protective phenotype in sepsis injury. Not only will the results of this research increase our basic science knowledge of the innate response to inflammatory/septic disease, but it may also result in the development of new treatment strategies for several important disease states.