The anti-inflammatory response after acute kidney injury

急性肾损伤后的抗炎反应

• 批准号: 8971956
• 负责人: Sarah g Faubel
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8971956
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Blood capillaries; Brain; CXCL1 gene; Cardiac Catheterization Procedures; Cardiopulmonary Bypass; Cardiovascular Diseases; Cells; Cessation of life; Chronic Kidney Failure; Complication; Containment; Data; Diabetes Mellitus; Distant; Event; Excision; Flow Cytometry; Goals; Grant; Health; Hospitalization; Hour; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-10; Interleukin-6; Lead; Liver; Lung; Malignant Neoplasms; Mechanical ventilation; Mediating; Mediator of activation protein; Modeling; Mus; Operative Surgical Procedures; Organ; Patients; Population; Production; Protocols documentation; Publishing; Recruitment Activity; Reporter; Resolution; Respiratory Failure; Rest; Risk; Risk Factors; Role; Serum; Source; Spleen; Splenectomy; Supportive care; Testing; Therapeutic; Time; Veterans; Wild Type Mouse; capillary; chemokine; chemotherapy; cytokine; expectation; improved; in vivo; lung injury; macrophage; mortality; neutrophil; novel; prevent; recombinase-mediated cassette exchange; research study; respiratory; response; targeted treatment

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) occurs in 20% of hospitalized patients and increases the risk of death. Death from AKI is typically due to systemic complications. Respiratory failure is an especially detrimental complication of AKI and can increase patient mortality to 60 to 80%. The reason AKI causes respiratory failure is unclear, but may be due to inflammation. Our data in mice demonstrate that AKI is a pro-inflammatory state that is characterized by increased serum proinflammatory mediators (cytokines) at 2 hours and lung injury that occurs by 4 hours. Lung injury after AKI in mice is characterized by lung neutrophil accumulation and lung capillary leak. In this grant, we propose that AKI is a proinflammatory event that normally initiates a counter inflammatory response via production of IL-10. IL-10 is a potent anti-inflammatory cytokine that inhibits production of proinflammatory mediators. We suggest that cells known as macrophages are the key source of IL-10 production after AKI. Our overall hypothesis is that IL-10 production in macrophages is necessary to contain proinflammatory cytokine production and lung injury after AKI. Studies to understand the normal counter inflammatory response after AKI in mice are proposed with the goal of identifying therapies that facilitate resolution of inflammation and lung injury after AKI. In Specific Aim 1, we will determine whether macrophages in the spleen increase IL-10 production after AKI. We hypothesize that macrophages are the major source and that IL-6 is a key mediator of this response. GFP reporter mice (IL-10 producing cells are GFP positive) and flow cytometry will also be used to determine if splenic macrophages produce IL-10. The role of IL-6 in mediating splenic IL-10 production will be tested in vivo and in vitro. n Specific Aim 2, we will determine if IL-10 is necessary to reduce proinflammatory cytokine production and limit lung injury in AKI. We hypothesize that IL-10 limits proinflammatory cytokine production and lung injury after AKI. To determine the beneficial role of IL-10 after AKI serum cytokines, organ cytokine production, and lung injury will be determined in AKI with IL-10 deficiency. The therapeutic potential of IL-10 in AKI will be tested in wild type and IL-10 deficiet mice; IL-10 will be administered prior to injury or at times after injury to determine if IL-10 may be a potential treatment. In Specific Aim 3, we will determine if IL-10 producing macrophages facilitate resolution of AKI- mediated lung injury. We hypothesize that IL-10 producing macrophages limit lung injury after AKI. The role of IL-10 producing macrophages in AKI will be assessed in mice with deletion of IL-10 in macrophages; administration of IL-10 producing or deficient macrophages will also be performed.

描述(由申请人提供)： 急性肾损伤(AKI)发生在20%的住院患者中，并增加了死亡风险。AKI的死亡通常是由于全身并发症。呼吸衰竭是AKI的一种特别有害的并发症，可将患者死亡率增加到60%至80%。AKI导致呼吸衰竭的原因尚不清楚，但可能是由于炎症。我们在小鼠身上的数据表明，AKI是一种促炎状态，其特征是2小时血清促炎介质(细胞因子)增加，4小时发生肺损伤。AKI后小鼠肺损伤主要表现为肺中性粒细胞聚集和肺毛细血管渗漏。在这项资助中，我们提出AKI是一种促炎事件，通常通过产生IL-10来启动抗炎反应。IL-10是一种有效的抗炎细胞因子，可抑制促炎介质的产生。我们认为巨噬细胞是AKI后产生IL-10的关键来源。我们的总体假设是，巨噬细胞产生IL-10是AKI后抑制促炎细胞因子产生和肺损伤所必需的。为了解小鼠AKI后的正常抗炎反应，提出了一项研究，目的是确定促进炎症和肺部消退的治疗方法。 AKI后受伤。在特定的目标1中，我们将确定AKI后脾内巨噬细胞是否增加IL-10的产生。我们假设巨噬细胞是这种反应的主要来源，而IL-6是这种反应的关键介质。GFP报告鼠(产生IL-10的细胞呈GFP阳性)和流式细胞术也将用于确定脾巨噬细胞是否产生IL-10。IL-6在调节脾IL-10产生中的作用将在体内和体外进行测试。在特定的目标2中，我们将确定IL-10是否是AKI中减少促炎细胞因子产生和限制肺损伤所必需的。我们假设，IL-10限制了AKI后促炎细胞因子的产生和肺损伤。为确定IL-10在急性心肌梗死后的有益作用，我们将对IL-10缺乏的急性KI患者的血清细胞因子、器官细胞因子的产生和肺损伤进行检测。IL-10在AKI中的治疗潜力将在野生型和IL-10缺陷的小鼠身上进行测试；IL-10将在损伤前或损伤后给予，以确定IL-10是否可以 是一种潜在的治疗方法。在具体目标3中，我们将确定产生IL-10的巨噬细胞是否促进AKI介导的肺损伤的解决。我们推测，产生IL-10的巨噬细胞可以限制AKI后的肺损伤。产生IL-10的巨噬细胞在AKI中的作用将在删除巨噬细胞中的IL-10的小鼠中进行评估；也将进行产生IL-10的巨噬细胞或缺乏IL-10的巨噬细胞的给药。