Microtubule control of septic inflammation

 描述(由申请人提供)：严重败血症是一种常见的、昂贵的、经常是致命的疾病，是美国ICU的主要死亡原因。S在老年人中尤其常见，随着美国人口老龄化，这种情况可能会大幅增加。脓毒症是机体对感染反应的结果，通常表现为全身炎症反应综合征(SIRS)，但也可发展为多器官衰竭(MOF)，血管内皮细胞炎症和肺功能障碍是危重患者的主要致命并发症。通常，50%的脓毒症病例始于肺部感染。在过去的十年中，革兰氏阳性细菌，最常见的葡萄球菌，被认为是导致50%以上的脓毒症的原因。激活的血管内皮细胞通过增加炎症细胞、细胞因子和趋化因子的外渗，在炎症的传播中发挥关键作用。脓毒症状态下的内皮炎症和屏障受损可能导致多器官功能障碍和弥散性血管内凝血。尽管内皮细胞在这些事件中的重要作用已被充分认识，但在脓毒症条件下调节血管内皮细胞炎症激活的确切机制却知之甚少。我们以前的研究明确了微管动力学在血管活性生长因子和激动剂引起的肺内皮屏障破坏和血管渗漏中的作用。然而，微管依赖机制在内皮细胞炎症过程中的作用有待进一步研究。我们的新的初步数据支持的中心假设是，在金黄色葡萄球菌攻击的内皮细胞中，微管特异性的组蛋白脱乙酰酶HDAC6的激活导致微管失稳和细胞因子信号转导的微管相关抑制物SOCS3的抗炎活性降低。由于SOCS3失活，增强的JAK2/STAT3信号将释放细胞因子，加剧对细菌病原体正在进行的炎症反应，导致宿主机体的附带损害。我们推测，通过抑制HDAC6来稳定微管，从而保持SOCS3的活性，可能对过度的脓毒症炎症具有保护作用。AIM-1将描述肺脓毒症炎症模型中内皮细胞微管动力学的变化以及HDAC6对其的调节；AIM-2将研究微管动力学改变如何调节细菌病原体诱导的SOCS3依赖的炎症信号；AIM-3将研究微管相关信号在体内炎症反应调节中的作用。我们相信，这项研究将为设计钝化脓毒症激活的病理信号通路的治疗确定新的靶点，并可能导致目前脓毒症治疗实践的突破。

 DESCRIPTION (provided by applicant): Severe sepsis is a common, expensive, and frequently fatal condition which is the leading cause of death in the ICU in the United States. It s especially common in the elderly and is likely to increase substantially as the U.S. population ages. Sepsis develops as a result of the host response to infection, and often presents as systemic inflammatory response syndrome (SIRS), but may also develop into multiple organ failure (MOF) with vascular endothelial inflammation and lung dysfunction among major fatal complications in critically ill patients. Typically, 50% of all sepsis cases start as an infection n the lungs. In the last decade, gram-positive bacteria, most commonly staphylococci, are thought to cause more than 50% of cases of sepsis. Activated vascular endothelium plays a key role in propagation of inflammation by increasing the extravasation of inflammatory cells, cytokines and chemokines. Endothelial inflammation and barrier compromise in septic conditions may lead to multiple organ dysfunction and disseminated intravascular coagulation. Although the essential role of endothelium in these events is well recognized, precise mechanisms modulating inflammatory activation of vascular endothelium in septic conditions are poorly understood. Our previous studies defined the role of microtubule dynamics in the disruption of lung endothelial barrier and vascular leak caused by vasoactive growth factors and agonists. However, the involvement of microtubule-dependent mechanisms in endothelial inflammatory processes awaits further investigation. The central hypothesis supported by our novel preliminary data which will be tested in this application is that activation of microtubule-specific histone deacetylase HDAC6 in endothelial cells challenged with Staphylococcus aureus causes microtubule destabilization and reduction in anti-inflammatory activity of microtubule-associated Suppressor Of Cytokine Signaling, SOCS3. As a result of SOCS3 inactivation, augmented Jak2/STAT3 signaling will unleash cytokine release and exacerbate ongoing inflammatory reaction to bacterial pathogen causing collateral damage of the host organism. We speculate that stabilization of the microtubules via inhibition of HDAC6 leading to preservation of SOCS3 activity may protect against excessive septic inflammation. Aim-1 will characterize the changes in endothelial microtubule dynamics and their regulation by HDAC6 in the models of lung septic inflammation; AIm-2 will examine how altered microtubule dynamics modulate SOCS3-dependent inflammatory signaling induced by bacterial pathogens; and Aim-3 will study the role of microtubule-associated signaling in the modulation of inflammatory response in vivo. We believe that this study will identify new targets for therapies designed to blunt sepsis-activated pathologic signaling circuits and may result in a breakthrough in current practices of sepsis treatment.