Respiratory Endothelial Injury by Xanthine Oxidase

黄嘌呤氧化酶引起的呼吸内皮损伤

• 批准号: 7386676
• 负责人: JOHN E REPINE
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-02-10 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7386676
• 关键词: 3-nitrotyrosine; Acute; Acute Lung Injury; Aging; Allopurinol; Alveolar; Animals; Apoptosis; Atherosclerosis; Blood Glucose; Blood Vessels; Bronchoalveolar Lavage; Caring; Cell model; Clinical; Complex; Critical Illness; Cytokeratin 18; Data; Development; Diabetic Angiopathies; Diagnosis; Disease; Epithelial Cells; Exhibits; Genetic; Glucose; Goals; Hyperglycemia; Hypertension; IL8 gene; In Vitro; Individual; Infiltration; Inflammation; Infusion procedures; Injury; Insufflation; Insulin; Insulin Resistance; Interferons; Interleukin-1; Intervention; Investigation; Irrigation; Knowledge; Lactate Dehydrogenase; Lactate Dehydrogenases; Learning; Life; Light; Lung; Measurement; Measures; Metabolic syndrome; Mitogen-Activated Protein Kinases; Modeling; Mononuclear; Oxidative Stress; Pathogenesis; Patients; Peptidyl-Dipeptidase A; Phagocytes; Prevention; Principal Investigator; Production; RNA Interference; Rattus; Reactive Oxygen Species; Recruitment Activity; Research; Research Personnel; Scientist; Severities; Signal Transduction; Staining method; Stains; Subfamily lentivirinae; Techniques; Testing; Translational Research; Tungsten; Xanthine Dehydrogenase; Xanthine Oxidase; bench to bedside; concept; cytokine; design; diabetic; diabetic rat; feeding; improved; in vivo; inhibitor/antagonist; innovation; insight; lung injury; neutrophil; new technology; non-diabetic; oxidoreductase inhibitor; prevent; programs; research study; respiratory; response

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.

描述（由申请人提供）：由于未知原因，强化胰岛素治疗不仅使升高的血糖水平正常化，而且还显著增加了非糖尿病患者和患有重症（ICU型）疾病的糖尿病患者的生存率。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。我们的具体假设是，高血糖增加细胞因子，从而增加单核吞噬细胞（MNP）黄嘌呤氧化还原酶（XOR）活性、NF-β B活化和IL-8产生，进而增加中性粒细胞（PMN）募集和ALI严重程度;该假设的推论是胰岛素对该机制具有相反的作用。我们的初步数据支持这种方法：1。吸入IL-1和IFN-γ的大鼠肺内新募集的MNP的XOR增加，而MNP XOR可促进对照组大鼠肺内PMN的募集。2.在体内，高血压增加了用IL-1和IFN-β吹入的大鼠肺中的ALI、CINC（大鼠IL-8当量）水平和PMN募集，并在体外诱导上调XOR表达的细胞因子。3.胰岛素治疗可降低体内注入IL-1和IFN-α的大鼠肺部的MNP C/EBPp活性、MNP XOR活性、MNP NF-α B活性、中性粒细胞募集和损伤。4.细胞因子、MAP激酶和C/EBP-3在体外增加上皮细胞的XOR表达。我们的三个具体目标如下：具体目标1：确定葡萄糖输注和/或胰岛素治疗对MNP在体内将PMN募集到肺中的能力的影响。具体目标二：确定MNP中XOR活性的改变是否有助于给予葡萄糖输注和/或胰岛素治疗的大鼠的MNP的不同PMN募集活性。具体目标3：确定葡萄糖输注和/或胰岛素治疗调节MNP XOR表达和ROS信号传导的机制。重要性：这项转化研究将使用一种创新的新技术来确定高血糖和/或胰岛素治疗对ALI的影响，该技术可以连续和非侵入性地测量血糖水平。通过定义这一挽救生命的临床发现的潜在机制，我们将提高对ALI发病机制的理解，并找到更好的策略来控制高血糖，给予胰岛素和/或使用其他干预措施来治疗和预防ALI。