Resistance of Beta 2 Microglobulin Null Mice to Sepsis

Beta 2 微球蛋白无效小鼠对脓毒症的抵抗力

• 批准号: 8292209
• 负责人: EDWARD R SHERWOOD
• 金额: --
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2012-07-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292209
• 关键词: Address; Animals; CXCL10 gene; CXCL9 gene; CXCR3 gene; Cell physiology; Cells; Critical Illness; Disease model; Evaluation; Experimental Models; Functional disorder; Funding; Greater sac of peritoneum; Infection; Inflammation; Inflammatory; Injury; Knockout Mice; Knowledge; Left; Ligands; Ligation; Liquid substance; Mediating; Modeling; Morbidity - disease rate; Mus; NK Cell Activation; Natural Killer Cells; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Peritoneal lavage; Physiological; Plasma; Population; Production; Puncture procedure; Research; Resistance; Sepsis; Sepsis Syndrome; Septic Shock; Signal Transduction; Site; Source; Spleen; Testing; Tissues; autocrine; base; beta-2 Microglobulin; cell motility; chemokine receptor; improved; innovation; macrophage; mortality; neutralizing antibody; paracrine; septic

We have convincingly shown that natural killer (NK) cells facilitate the pathogenesis of sepsis caused by cecal ligation and puncture (CLP). However, the mechanisms that contribute to NK cell-mediated pro-inflammatory activity during sepsis are poorly understood. Our recent studies indicate large numbers of CXCR3+ NK cells leave the spleen and enter the peritoneal cavity during CLP-induced sepsis. The CXCR3 ligands CXCL9 and CXCL10 are present at high concentrations during sepsis and CXCR3-deficient mice are resistant to CLP-induced physiologic dysfunction. Based on these observations, we hypothesize that CXCR3 signaling is critical for the recruitment and activation of NK cells and that the actions of CXCR3 are important in the pathogenesis of sepsis. The following specific aims will test these hypotheses. Specific Aim 1: To determine the importance of CXCR3 for NK cell migration and activation as well as its impact on the pathogenesis of CLP- induced sepsis. The expression of CXCR3 and markers of activation will be evaluated on NK cells at the primary site of infection and in remote tissues. Further studies will assess NK cell recruitment and activation in CXCR3-deficient mice and after blockade of CXCR3 with neutralizing antibodies. We will also determine the importance of CXCR3 in the pathogenesis of sublethal sepsis, sepsis-induced multi- organ dysfunction and septic shock. Specific Aim 2. To determine the importance of CXCR3 ligands (CXCL9 and CXCL10) for NK cell recruitment and activation as well as their impact on the pathogenesis of CLP-induced sepsis. The cellular sources of CXCR3 ligands at the primary site of infection and remote tissues will be examined. NK cell migration and activation will be studied in CXCR3 ligand-deficient mice or after blockade of CXCR3 ligands using neutralizing antibodies. Physiological function, organ injury and systemic inflammation will be examined in CXCR3 ligand- deficient mice using models of sublethal sepsis, sepsis-induced multi-organ dysfunction and septic shock. We will also determine the ability of CXCR3 ligands to directly induce the sepsis syndrome in control mice or mice with sublethal sepsis. Specific aim 3. Evaluation of factors that regulate the CXCR3 axis during CLP-induced sepsis. These studies will examine the contributions of NK cells to CXCR3 ligand production and the factors that regulate NK cell CXCR3 expression during sepsis. Although LPS-induced CXCL10 production by isolated macrophages is considered to be regulated by Trif-dependent signaling and require production of IFN¿, we propose that NK cells will facilitate MyD88- dependent CXCL10 production through the production of IFN¿. Studies are proposed in this application to address that assertion. Further studies will evaluate the importance of paracrine and autocrine mechanisms for NK cell CXCR3 activation and the factors that regulate CXCR3 expression by NK cells.

我们已经令人信服地表明，自然杀伤（NK）细胞促进了败血症引起的发病机制 盲肠结扎穿孔术（CLP）然而，有助于NK细胞介导的机制 脓毒症期间的促炎活性知之甚少。我们最近的研究表明， 在CLP诱导期间，大量CXCR 3 + NK细胞离开脾脏并进入腹腔。 败血症CXCR 3配体CXCL 9和CXCL 10在脓毒症期间以高浓度存在， CXCR 3缺陷型小鼠对CLP诱导的生理功能障碍具有抗性。基于这些 通过观察，我们假设CXCR 3信号传导对于细胞的募集和激活是至关重要的。 CXCR 3的作用在脓毒症的发病机制中是重要的。的 以下具体目标将检验这些假设。具体目标1：确定 CXCR 3对NK细胞迁移和活化的作用及其对CLP发病机制的影响 诱发败血症。CXCR 3和活化标志物的表达将在NK细胞上评估， 感染的主要部位和远处组织。进一步的研究将评估NK细胞的募集， 在CXCR 3缺陷型小鼠中以及在用中和抗体阻断CXCR 3后，我们将 还确定了CXCR 3在亚致死性脓毒症发病机制中的重要性，脓毒症诱导的多 器官功能障碍和感染性休克具体目标2。确定CXCR 3的重要性 NK细胞募集和活化的配体（CXCL 9和CXCL 10）及其对 CLP诱导脓毒症的发病机制。CXCR 3配体在主要位点的细胞来源 将检查感染和远端组织。NK细胞迁移和活化将在 CXCR 3配体缺陷小鼠或使用中和抗体阻断CXCR 3配体后。 生理功能、器官损伤和全身炎症将在CXCR 3配体中检查。 使用亚致死性脓毒症、脓毒症诱导的多器官功能障碍和脓毒症 冲击.我们还将确定CXCR 3配体直接诱导脓毒症综合征的能力。 对照小鼠或患有亚致死性脓毒症的小鼠。具体目标3。评价影响妇女地位的因素 CLP诱导脓毒症期间的CXCR 3轴。这些研究将检查NK细胞对 脓毒症期间CXCR 3配体产生和调节NK细胞CXCR 3表达的因子 尽管LPS诱导的分离的巨噬细胞产生CXCL 10被认为是受 Trif依赖的信号传导和需要IFN的产生，我们提出NK细胞将促进MyD 88- CXCL 10通过IFN产生。在本申请中提出了研究 来回应这一说法进一步的研究将评估旁分泌和自分泌的重要性 NK细胞CXCR 3活化的机制和调节NK细胞CXCR 3表达的因子。