Effect of Diet on Inflammation in Sicke Cell Mice

饮食对病细胞小鼠炎症的影响

• 批准号: 7660916
• 负责人: JACQUELINE M HIBBERT
• 金额: $ 19.66万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-08 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660916
• 关键词: Acids; Acute-Phase Proteins; Acute-Phase Reaction; Adherence; Affect; Amino Acids; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Arginine; Attenuated; Blood Chemical Analysis; C-reactive protein; Cells; Characteristics; Child; Chronic; Clinical; Data; Development; Diet; Erythrocytes; Erythropoiesis; Genetic Transcription; Glycoproteins; Hemoglobin; Hemolysis; Histopathology; Human; IL6 gene; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Interferon Type II; Interleukin-10; Interleukin-13; Interleukin-4; Intervention; Investigation; Ischemia; Kidney; Left; Leukocytes; Leukocytosis; Liver; Mediating; Metabolism; Modality; Mus; Muscle Proteins; Nature; Nitric Oxide; Nutritional; Organ; Patients; Pattern; Plasma; Production; Proteins; RNA; Randomized; Reducing diet; Reperfusion Therapy; Reporting; Research; Risk Factors; Role; Serum amyloid A protein; Severity of illness; Sickle Cell; Sickle Cell Anemia; Spleen; Supplementation; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Transgenic Organisms; Vascular Endothelium; Vasodilator Agents; Weaning; arginase; cytokine; depressed; enzyme activity; feeding; high standard; inflammatory marker; mouse model; protein expression; public health relevance; repaired; research study; response; sickling; wasting

DESCRIPTION (provided by applicant): Characteristic chronic hemolysis in sickle cell anemia is presumed to induce an inflammatory response through sub-clinical vasooclusion. Acute phase reactants such as C-reactive protein are elevated in both stable patients and during vasoocusive crisis. However, the role and pattern of inflammatory cytokines, which are generally depressed in stable HbSS patients, remains inconclusive and there is very limited information about the inflammatory response in organs, e.g. liver, where acute phase proteins and cytokine production are initiated. In sickle cell anemia patients, abnormal adherence of 'sickled' red cells to vascular endothelium induces local inflammation via sub-clinical ischemia, vasoocclusion, reperfusion and hemolysis. In our preliminary studies, we have found that in asymptomatic sickle cell children and a transgenic sickle cell mouse model, plasma L-arginine concentration is significantly low compared with healthy controls. Also sickle cell transgenic mice grew faster on a 35% (high) protein diet and this diet was associated with reduced concentrations of inflammatory indicators CRP and IL6, compared with sickle cell transgenics on a 20% (normal) diet. It is our hypothesis that the sickle cell mice on the high protein diet have less inflammation due to increased L-arginine availability from their diet for nitric oxide production and subsequent repair functions. We will test this hypothesis by studying a transgenic mouse model with human sickle cell hemoglobin over three months, to determine the effect of short term and chronic sub-clinical ischemia on the production of acute phase proteins and cytokines. Experiments will include blood chemistry, enzyme activity, and RNA and protein expression analysis of plasma, liver, spleen and kidney, plus histopathology of these organs. Specific aims are: 1) to determine the temporal changes of proinflammatory and anti-inflammatory markers affecting nitric oxide production in weanling transgenic sickle cell mice versus control mice, fed standard and high protein diets and 2) to determine the effect of supplementing the standard diet for sickle cell mice with L-arginine, thus investigating the mechanism for the reduced inflammation observed on the high protein diet. This research will assist in seeking nutritional remedies for reducing sub-clinical tissue injury in sickle cell disease. PUBLIC HEALTH RELEVANCE: Chronic inflammation is a component of sickle cell anemia, demonstrated by high levels of white blood cells and inflammatory proteins. However, the role and pattern of inflammatory proteins in sickle cell anemia remain inconclusive, and the development of the chronic inflammation over time is unknown. In our preliminary data, a high protein diet reduces circulating and liver inflammation in the Berkeley sickle cell mouse model. The use of this mouse model is important for investigating the time course of sickle cell induced tissue inflammation, and for seeking practical and effective dietary treatment to reduce the tissue injury.

描述（由申请人提供）：假定镰状细胞贫血中的特征性慢性溶血是通过亚临床下血管肿块引起炎症反应的。在稳定的患者和血管疾病期间，急性相反应物（例如C反应蛋白）均升高。但是，在稳定的HBSS患者中通常会抑制炎性细胞因子的作用和模式，但仍尚无定论，并且有关器官炎症反应的信息非常有限，例如肝脏，启动急性相蛋白和细胞因子的产生。在镰状细胞贫血患者中，“镰状”红细胞对血管内皮的依从性异常，可通过亚临床缺血，血管酸性，再灌注和溶血引起局部炎症。在我们的初步研究中，我们发现在无症状的镰状细胞儿童和转基因镰状细胞小鼠模型中，血浆L-精氨酸浓度与健康对照组相比明显低得多。镰状细胞转基因小鼠的生长速度也加快了35％（高）蛋白质饮食，与镰状细胞转基因相比，这种饮食与炎症指标浓度降低相关，而在20％（正常）饮食中相比。我们的假设是，高蛋白饮食上的镰状细胞小鼠由于饮食的L-精氨酸可用性增加而导致一氧化氮产生和随后的修复功能较小。我们将通过研究三个月内用人类镰状细胞血红蛋白的转基因小鼠模型来检验这一假设，以确定短期和慢性亚临床缺血对急性相蛋白和细胞因子的产生的影响。实验将包括血浆，肝脏，脾脏和肾脏的血液化学，酶活性以及RNA和蛋白质表达分析，以及这些器官的组织病理学。具体目的是：1）确定促炎和抗炎标记的时间变化，影响断奶的转基因镰状细胞小鼠与对照小鼠，喂养标准和高蛋白质饮食和高蛋白质饮食的时间变化，以确定对L-Arginine的标准饮食的效果，从而确定较高的饮食，从而使机械化较高，从而使机械化量很高。这项研究将有助于寻求营养补救措施，以减少镰状细胞疾病中的临床组织损伤。公共卫生相关性：慢性炎症是镰状细胞性贫血的组成部分，由高水平的白细胞和炎症蛋白证明。然而，炎症蛋白在镰状细胞贫血中的作用和模式仍然尚无定论，随着时间的流逝，慢性炎症的发展尚不清楚。在我们的初步数据中，高蛋白质饮食可减少伯克利镰状细胞小鼠模型中的循环和肝脏炎症。该小鼠模型的使用对于研究镰状细胞引起的组织炎症的时间过程至关重要，并寻求实用有效的饮食治疗以减少组织损伤。