Mechanisms of microvascular endothelial cell injury caused by extracellular histones

细胞外组蛋白致微血管内皮细胞损伤的机制 摘要 尽管最近在理解血管通透性增加和 由循环血管活性多肽、脂类和外源性物质(细菌、毒素、 颗粒物)，损伤组织释放的细胞内化合物的影响，称为危险- 脓毒症所致持续急性呼吸综合征严重程度的相关分子模式(DAMP) 或创伤性损伤仍然知之甚少，而潜在的有害影响的分子机制 潮湿的情况需要进一步调查。这项翻译研究将调查核相关的影响 组蛋白对血管内皮细胞功能的抑制作用并测试一种新的假想的循环机制 组蛋白以肺微血管内皮细胞为靶点，加重肺损伤。在这里检验的中心假说 应用是在急性肺损伤、脓毒症、创伤、严重炎症、 或大手术以血管内皮细胞为靶点，并导致整体血管功能障碍、器官损害和 死亡率。这可能是通过：1)组蛋白诱导清道夫受体簇参与 分化36(CD36)导致内皮细胞炎症和屏障功能障碍的扩散；以及2) CD36通过循环组蛋白激活死亡信号，有助于增强正在进行的 内皮功能障碍和肺损伤。拟议的研究可能会对其他方面产生更广泛的影响 血管对炎性或促血管生成刺激的反应。拟议的研究将提供机械性的 洞察力提供更好地理解定义脓毒症和创伤严重程度的因素。这些研究可能 导致识别分子靶点并开发新的治疗方法来缓解这种情况 循环潮湿的有害影响。

Mechanisms of microvascular endothelial cell injury caused by extracellular histones Abstract Despite the recent progress towards understanding of the basis of increased vascular permeability and inflammation caused by circulating vasoactive peptides, lipids, and exogenous agents (bacteria, toxins, particulate matter), the impact of intracellular compounds released by injured tissues and known as danger- associated molecular patterns (DAMPs) on severity of ongoing acute respiratory syndrome caused by sepsis or traumatic injury remain poorly understood, and molecular mechanisms underlying deleterious effects of DAMPs warrant further investigations. This translational study will investigate effects of nucleus-associated DAMPs, histones, on vascular endothelial function and test a new hypothetical mechanism by which circulating histones target lung microvascular endothelium and worsen lung injury. The central hypothesis tested in this application is that circulating histones elevated during acute lung injury, sepsis, trauma, severe inflammation, or major surgery target vascular endothelium and contribute to overall vascular dysfunction, organ damage and mortality. This may be achieved through: 1) histone-induced engagement of scavenger receptor cluster of differentiation 36 (CD36) leading to propagation of endothelial inflammation and barrier dysfunction; and 2) CD36-induced activation of death signaling by circulating histones contributing to augmentation of ongoing endothelial dysfunction and lung injury. The proposed study may have a broader impact on the other aspects of vascular responses to inflammatory or pro-angiogenic stimuli. Proposed studies will provide mechanistic insights offering better understanding of factors that define severity of sepsis and trauma. These studies may lead to identification of molecular targets and developing new therapeutic approaches to mitigate such deleterious effects of circulating DAMPs.