Muscle-mediated protection against MODS

 描述(申请人提供)：有脓毒症、创伤和其他严重疾病的危重患者经常发生多器官功能障碍综合征(MODS)，死亡率高(30%-80%)。除了基础疾病的治疗之外，没有特殊的治疗方法来预防或治愈MODS。新的证据表明，氧化应激诱导的重要器官内皮细胞激活是病理过程中的关键步骤，因为它会导致炎性细胞浸润和组织损伤的加剧。不幸的是，没有靶标特异性的通用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充分适应，并提供显著的保护。我们在小鼠身上获得了新的证据，支持来自骨骼肌的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的EcSOD转基因小鼠可以免受内毒素血症的保护，内毒素血症是一种导致MODS的疾病。我们推测，增加骨骼肌中EcSOD的表达可以通过减少内皮细胞氧化应激和外周血管系统的激活来保护机体免受MODS的侵袭。我们提出了两个特定的目的来验证这一假说：1)确定肌肉来源的EcSOD是否介导了对MODS的保护；2)确定肌肉来源的EcSOD抑制内皮细胞激活和炎性细胞-内皮细胞相互作用的机制。这些目标是假设驱动的，基于文献中的证据和我们的初步发现。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衍生的抗氧化剂针对严重疾病的一种新的非收缩功能。

 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.