Respiratory Endothelial Injury by Xanthine Oxidase

描述(申请人提供)：由于未知的原因，强化胰岛素治疗不仅可以使升高的血糖水平恢复正常，而且显著地提高了非糖尿病患者和患有危重(ICU类型)疾病的糖尿病患者的存活率。我们的基本前提是(1)高血糖增加炎症和急性肺损伤(ALI)；(2)胰岛素治疗减少炎症和ALI。我们的特定假设是，高血糖增加了细胞因子，这些细胞因子增加了单核巨噬细胞(MNP)黄嘌呤氧化还原酶(XOR)的活性，增加了NF-B的激活和IL-8的产生，进而增加了中性粒细胞(PMN)的募集和ALI的严重程度；这一假设的推论是，胰岛素对这一机制具有相反的作用。我们的初步数据支持这一方法：1.吸入IL-1和干扰素-1的大鼠肺中新招募的MNP的XOR增加，而MNP XOR能促进PMN在对照组大鼠肺内的募集。2.高血糖可增加IL-1和干扰素-1诱导的大鼠肺组织ALI、CINC(大鼠IL-8当量)水平和PMN募集，并在体外诱导细胞因子上调XOR的表达。3.胰岛素治疗可降低IL-1和IFN-1体内染毒大鼠肺组织中MNP-C/EBPp活性、MNP-XOR活性、MNP-NF-B活性、PMN募集和肺组织损伤。4.细胞因子、MAP激酶和C/EBP-3可促进体外培养上皮细胞的XOR表达。我们的三个特定目标如下：特定目标1：确定葡萄糖输注和/或胰岛素治疗对体内MNP向肺内募集PMN能力的影响。具体目的2：确定在葡萄糖和/或胰岛素治疗的大鼠中，MNP中XOR活性的改变是否有助于MNP不同的PMN招募活动。具体目的3：确定葡萄糖输注和/或胰岛素治疗调节MNP XOR表达和ROS信号转导的机制。意义：这项转化性研究将使用一种创新的新技术，连续、非侵入性地测量血糖水平，以确定高血糖和/或胰岛素治疗对ALI的影响。通过明确这一救命临床发现的潜在机制，我们将提高对ALI发病机制的理解，并找到更好的控制高血糖、给予胰岛素和/或使用其他干预措施来治疗和预防ALI的策略。

DESCRIPTION (provided by applicant): For unknown reasons, intensive insulin therapy not only normalizes the elevated blood glucose levels but also, and remarkably, increases the survival of non-diabetics and diabetics with critical (ICU-type) illnesses. Our basic premise is that (1) hyperglycemia increases inflammation and acute lung injury (ALI) and (2) insulin therapy decreases inflammation and ALI. Our specific hypothesis is that hyperglycemia increases cytokines which increase mononuclear phagocyte (MNP) xanthine oxidoreductase (XOR) activity, NF-(B activation and IL-8 production which, in turn, increase neutrophil (PMN) recruitment and ALI severity; the corollary to this hypothesis is that insulin has an opposing effect on this mechanism. Our preliminary data supports this approach: 1. XOR increases in newly recruited MNP which are recovered from lungs of rats insufflated with IL-1 and IFN-( and MNP XOR can promote recruitment of PMN into lungs of control rats. 2. Hyperglycemia increases ALI, CINC (rat IL-8 equivalent) levels and PMN recruitment in lungs of rats insufflated with IL-1 and IFN-( in vivo and induces cytokines that up-regulate XOR expression in vitro. 3. Insulin therapy decreases MNP C/EBPp activity, MNP XOR activity, MNP NF-(B activity, PMN recruitment and injury in lungs of rats insufflated with IL-1 and IFN-( in vivo. 4. Cytokines, MAP kinases and C/EBP-3 increase the XOR expression of epithelial cells in vitro. Our three specific aims are the following: Specific Aim 1: To determine the effect of glucose infusion and/or insulin therapy on the ability of MNP to recruit PMN into the lung in vivo. Specific Aim 2: To determine if alterations in XOR activity in MNP contribute to the different PMN recruiting activities of MNP from rats given glucose infusions and/or insulin therapy. Specific Aim 3: To determine the mechanism by which glucose infusion and/or insulin therapy regulate MNP XOR expression and ROS signaling. Significance: This translational research will determine the effect of hyperglycemia and/or insulin therapy on ALI using an innovative, new technology that measures blood glucose levels continuously and non-invasively. By defining the underlying mechanisms for this life-saving clinical finding, we will improve understanding of the pathogenesis of ALI and find better strategies for controlling hyperglycemia, giving insulin and/or using other interventions to treat and prevent ALI.