Microtubule control of septic inflammation

 描述（由申请人提供）：严重脓毒症是一种常见、昂贵且经常致命的疾病，是美国ICU的主要死亡原因。这种情况在老年人中尤其常见，而且随着美国人口老龄化，这种情况可能会大幅增加。脓毒症是由于宿主对感染的反应而发生的，通常表现为全身炎症反应综合征（SIRS），但也可能发展为多器官衰竭（MOF），伴血管内皮炎症和肺功能障碍，是危重患者的主要致命并发症。通常，50%的败血症病例开始于肺部感染。在过去的十年中，革兰氏阳性菌，最常见的葡萄球菌，被认为是导致超过50%的败血症病例。活化的血管内皮通过增加炎性细胞、细胞因子和趋化因子的外渗在炎症传播中起关键作用。脓毒症条件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。虽然内皮在这些事件中的重要作用是公认的，但在脓毒症条件下调节血管内皮炎症活化的精确机制知之甚少。我们以前的研究确定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，微管依赖性机制在内皮炎症过程中的参与有待进一步研究。由我们的新的初步数据支持的中心假设将在本申请中进行测试，该中心假设是在用金黄色葡萄球菌攻击的内皮细胞中微管特异性组蛋白脱乙酰酶HDAC 6的活化导致微管不稳定和微管相关的细胞因子信号传导抑制因子SOCS 3的抗炎活性的降低。作为SOCS 3失活的结果，增强的Jak 2/STAT 3信号传导将释放细胞因子释放并加剧对细菌病原体的持续炎症反应，从而引起宿主生物体的附带损伤。我们推测，通过抑制HDAC 6导致SOCS 3活性的保留来稳定微管可能会防止过度的脓毒性炎症。Aim-1将表征肺脓毒性炎症模型中内皮微管动力学的变化及其由HDAC 6调节; AIm-2将研究改变的微管动力学如何调节由细菌病原体诱导的SOCS 3依赖性炎症信号传导; Aim-3将研究微管相关信号传导在体内炎症反应调节中的作用。我们相信，这项研究将确定新的治疗目标，旨在钝化脓毒症激活的病理信号通路，并可能导致目前的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.