Muscle-mediated protection against MODS

 描述（由申请人提供）：患有脓毒症、创伤和其他严重医疗状况的危重患者通常会发展为多器官功能障碍综合征（MODS），死亡率高（30-80%）。除了治疗基础疾病外，没有特异性治疗来预防或治愈MODS。新出现的证据表明，重要器官中氧化应激诱导的内皮活化是病理学中的关键步骤，因为它导致加重的炎性细胞浸润和组织损伤。不幸的是，没有目标特异性的一般抗氧化剂在临床试验中失败了。相反，运动训练诱导骨骼肌和其他器官的深刻适应，并赋予显着的保护。我们在小鼠中获得了新的证据，支持骨骼肌细胞外超氧化物歧化酶（EcSOD）的保护作用，它具有靶向内皮细胞的肝素结合结构域。运动训练的小鼠和肌肉特异性EcSOD转基因小鼠免受内毒素血症的影响，内毒素血症是导致MODS的条件。我们推测骨骼肌中增强的EcSOD表达通过减少外周血管内皮的氧化应激和活化来保护MODS。我们提出了两个具体的目的来验证这一假设：1）确定肌肉来源的EcSOD是否介导对MODS的保护; 2）确定肌肉来源的EcSOD抑制内皮细胞活化和炎症细胞-内皮细胞相互作用的机制。这些目标是假设驱动的，并基于文献和我们的初步研究结果的证据。我们将在临床相关的动物模型中使用最先进的方法来阐明骨骼肌源性抗氧化剂对严重疾病的新型非收缩功能。

 DESCRIPTION (provided by applicant): Critically ill patients with sepsis, trauma and other serious medical conditions often develop multiple organ dysfunction syndrome (MODS) with high mortality rate (30-80%). There is no specific therapy to prevent or cure MODS beyond treatment of the underlying illness. Emerging evidence suggests that oxidative stress- induced endothelial activation in vital organs is a key step in the pathology as it leads to exacerbated inflammatory cell infiltration and tissue damage. Unfortunately, general antioxidants with no target specificity have failed in clinical trials. On the contrary, exercise training induces profond adaptations in skeletal muscle and other organs and confers significant protection. We have obtained new evidence in mice supporting a protective role of extracellular superoxide dismutase (EcSOD) from skeletal muscle, which has a heparin- binding domain for targeting endothelial cells. Exercise trained mice and muscle-specific EcSOD transgenic mice are protected from endotoxemia, a condition leads to MODS. We hypothesize that enhanced EcSOD expression in skeletal muscle protects against MODS by reducing endothelium oxidative stress and activation in peripheral vasculature. We propose two specific aims to test this hypothesis: 1) To determine if muscle-derived EcSOD mediates protection against MODS; and 2) To define the mechanism by which muscle- derived EcSOD inhibits endothelial cell activation and inflammatory cell-endothelial cell interaction. These aims are hypothesis-driven and based on evidence from the literature and our preliminary findings. We will use state-of-the-art approaches in clinically relevant animal models to elucidate a novel non-contractile function of skeletal muscle-derived antioxidant against a serious disease condition.