The anti-inflammatory response after acute kidney injury

急性肾损伤后的抗炎反应

• 批准号: 8624513
• 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/8624513
• 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; 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; Technology; Testing; Therapeutic; Time; Veterans; Wild Type Mouse; capillary; chemokine; chemotherapy; cytokine; expectation; improved; in vivo; lung injury; macrophage; mortality; neutrophil; novel; prevent; public health relevance; research study; respiratory; response

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）： 急性肾脏损伤（AKI）发生在20％的住院患者中，并增加了死亡风险。 AKI死亡通常是由于全身并发症。呼吸衰竭是AKI特别有害的并发症，可以将患者死亡率提高到60％至80％。 AKI导致呼吸衰竭的原因尚不清楚，但可能是由于炎症引起的。我们在小鼠中的数据表明，AKI是一种促炎性状态，其特征是在2小时时血清促炎性介质（细胞因子）增加，肺损伤发生了4小时。小鼠AKI后的肺损伤的特征是肺嗜中性粒细胞积累和肺毛细血管渗漏。在这笔赠款中，我们建议AKI是一种促进性事件，通常通过IL-10产生发起反炎症反应。 IL-10是一种有效的抗炎细胞因子，可抑制促炎性介质的产生。我们建议称为巨噬细胞的细胞是AKI后IL-10产生的关键来源。我们的总体假设是，巨噬细胞中的IL-10产生对于含有促炎性细胞因子的产生和AKI后的肺损伤是必要的。提出了对小鼠AKI后正常反炎症反应的研究，其目的是确定促进炎症和肺部解决的疗法 AKI后受伤。在特定的目标1中，我们将确定脾脏中的巨噬细胞在AKI后是否会增加IL-10产量。我们假设巨噬细胞是主要来源，而IL-6是这种反应的关键中介。 GFP报告基因小鼠（IL-10产生的细胞为GFP阳性），流式细胞仪也将用于确定脾巨噬细胞是否产生IL-10。 IL-6在介导脾脏IL-10产生中的作用将在体内和体外进行测试。 n具体目标2，我们将确定IL-10是否需要减少促炎性细胞因子的产生并限制AKI的肺损伤。我们假设IL-10限制了AKI后促炎性细胞因子的产生和肺损伤。为了确定AKI血清细胞因子后IL-10的有益作用，将在IL-10缺乏的AKI中确定器官细胞因子和肺损伤。 IL-10在AKI中的治疗潜力将在野生型和IL-10缺陷小鼠中进行测试； IL-10将在受伤之前或受伤后有时在确定IL-10是否5月 成为潜在的治疗方法。在特定的目标3中，我们将确定产生巨噬细胞的IL-10是否有助于分辨出Aki介导的肺损伤。我们假设产生巨噬细胞的IL-10限制了AKI后的肺损伤。 IL-10在AKI中产生巨噬细胞的作用将在巨噬细胞中删除IL-10的小鼠中评估；还将执行IL-10产生或不足的巨噬细胞的给药。