Acute Renal Failure Mediated Lung Injury

急性肾衰竭介导的肺损伤

• 批准号: 8468194
• 负责人: Sarah g Faubel
• 金额: $ 35.05万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8468194
• 关键词: Acute; Acute Kidney Failure; Acute Lung Injury; Acute Renal Failure with Renal Papillary Necrosis; Affect; Alveolar; Alveolar Macrophages; Alveolus; Antibodies; Applications Grants; Bilateral; Blood; Blood capillaries; CXCL1 gene; Capillary Permeability; Cell Survival; Cessation of life; Clinical Trials; Complication; Creatinine; Data; Development; Dialysis procedure; Dichloromethylene Diphosphonate; Drug Kinetics; Encapsulated; Endothelial Cells; Environmental air flow; Epithelial; Epithelial Cells; Epithelium; Failure; Family; Flow Cytometry; Functional disorder; Grant; Health; Hemorrhage; Hour; Human; IL8 gene; Immunofluorescence Immunologic; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Interleukin-6; Intervention; Kidney; Liposomes; Liquid substance; Lung; Lung Inflammation; Mechanical ventilation; Mechanics; Mediating; Mediator of activation protein; Messenger RNA; Metabolism; Mononuclear; Mus; Nephrectomy; Neutrophil Infiltration; Operative Surgical Procedures; Organ; Organ failure; Patients; Peritoneal Dialysis; Phagocytes; Process; Production; Proteins; Protocols documentation; Publishing; Radiolabeled; Recombinants; Renal clearance function; Reperfusion Injury; Resistance; Respiratory Failure; Respiratory physiology; Risk; Role; Sepsis; Serum; Staining method; Stains; System; Testing; Therapeutic; Time; Tissues; Up-Regulation; Weaning; capillary; cell injury; chemokine; clinically relevant; cytokine; improved; inhibitor/antagonist; injured; interstitial; intraperitoneal; keratinocyte; lung injury; mortality; neutrophil; radiotracer; renal ischemia; research study; respiratory; therapy development; tool

Description (provided by applicant): Acute kidney injury (AKI) is a common complication in hospitalized patients that increases the risk of death. Death from AKI is typically due to systemic complications. Respiratory failure is an especially detrimental complication of AKI and increases patient mortality to 80%. The reason AKI causes respiratory failure is unclear, but may be due to inflammation. The systemic complications of AKI regarding the inflammatory cytokine IL-6 and lung injury are the focus of this grant proposal. We propose that AKI causes inflammation and lung injury. All studies will be completed in mice. We have three Specific Aims: 1) Determine the effect of AKI on proinflammatory cytokine production and cytokine clearance; 2) Determine the role of IL-6 in AKI mediated lung injury; 3) Determine if AKI exacerbates lung injury due to mechanical ventilation. Production of cytokines will be assessed in whole organs and serum of mice after AKI; renal cytokine clearance will be assessed by injection of recombinant forms of cytokines in mice with AKI and pharmacokinetic analysis of clearance will be performed. The effect of IL-6 on lung injury and KC (a mediator of neutrophil infiltration) will be tested IL-6 deficient and IL-6 inhibitor-treated mice with ischemic AKI or bilateral nephrectomy. Lung KC will be determined via mRNA and protein assessment of whole tissue homogenates; endothelial localization of KC will be determined via immunofluorescence. The injurious role of IL-6 and uremic factors will be assessed in vitro by adding recombinant IL-6 or uremic serum to cultured endothelial cells and assessing KC production, cell viability, and trans-endothelial resistance (a marker of capillary permeability and leak). To determine if the uremic factors that stimulate IL-6 production in AKI may be removed by dialysis, the effect of acute peritoneal dialysis on IL-6 production and serum IL-6 will be determined. Lung injury and alveolar macrophage KC production will be assessed in mice with or without mechanical ventilation in the presence or absence of AKI. Alveolar macrophage production of KC will be assessed by intracellular cytokine staining and flow cytometry of freshly isolated alveolar macrophages and by immunofluorescence. In vitro studies to assess the effect of IL-6 and uremic serum on KC production and cell viability of alveolar macrophages will be performed. The role of IL-6 in lung injury due to AKI with mechanical ventilation will be assessed using IL-6 deficient mice; the therapeutic benefit of IL-6 inhibition will be assessed by intraperitoneal or intratracheal administration of anti-IL-6 antibodies. The experiments in this grant will provide useful leads into the development of interventions to affect the systemic consequences of AKI and improve the mortality of patients with AKI.

描述（由申请方提供）：急性肾损伤（阿基）是住院患者的常见并发症，可增加死亡风险。阿基的死亡通常是由于全身性并发症。呼吸衰竭是阿基的一种特别有害的并发症，使患者死亡率增加至80%。阿基导致呼吸衰竭的原因尚不清楚，但可能是由于炎症。关于炎性细胞因子IL-6和肺损伤的阿基的全身性并发症是该资助提案的重点。我们认为阿基导致炎症和肺损伤。所有研究均在小鼠中完成。我们有三个具体目标：1）确定阿基对促炎性细胞因子产生和细胞因子清除的影响; 2）确定IL-6在阿基介导的肺损伤中的作用; 3）确定阿基是否加剧由于机械通气引起的肺损伤。将在阿基后的小鼠的整个器官和血清中评估细胞因子的产生;将通过在患有阿基的小鼠中注射重组形式的细胞因子来评估肾细胞因子清除率，并将进行清除率的药代动力学分析。将在具有缺血性阿基或双侧肾切除术的IL-6缺陷和IL-6调节物处理的小鼠中测试IL-6对肺损伤和KC（嗜中性粒细胞浸润的介质）的作用。将通过全组织匀浆的mRNA和蛋白质评估确定肺KC;将通过免疫荧光确定KC的内皮定位。将通过向培养的内皮细胞中加入重组IL-6或尿毒症血清并评估KC产生、细胞活力和跨内皮抗性（毛细血管通透性和渗漏的标志物），在体外评估IL-6和尿毒症因子的损伤作用。为了确定刺激阿基中IL-6产生的尿毒症因子是否可以通过透析去除，将确定急性腹膜透析对IL-6产生和血清IL-6的影响。在存在或不存在阿基的情况下，在有或无机械通气的小鼠中评估肺损伤和肺泡巨噬细胞KC产生。将通过细胞内细胞因子染色和新鲜分离的肺泡巨噬细胞的流式细胞术以及免疫荧光法评估肺泡巨噬细胞产生KC。将进行体外研究以评估IL-6和尿毒症血清对肺泡巨噬细胞的KC产生和细胞活力的影响。将使用IL-6缺陷小鼠评估IL-6在机械通气的阿基所致肺损伤中的作用;将通过腹膜内或腹膜内施用抗IL-6抗体评估IL-6抑制的治疗益处。这项资助的实验将为干预措施的发展提供有用的线索，以影响阿基的全身性后果并改善阿基患者的死亡率。

项目成果

Acute lung injury and acute kidney injury are established by four hours in experimental sepsis and are improved with pre, but not post, sepsis administration of TNF-α antibodies.

• DOI: 10.1371/journal.pone.0079037
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Bhargava R;Altmann CJ;Andres-Hernando A;Webb RG;Okamura K;Yang Y;Falk S;Schmidt EP;Faubel S
• 通讯作者: Faubel S

Intratracheal IL-6 protects against lung inflammation in direct, but not indirect, causes of acute lung injury in mice.

• DOI: 10.1371/journal.pone.0061405
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Bhargava R;Janssen W;Altmann C;Andrés-Hernando A;Okamura K;Vandivier RW;Ahuja N;Faubel S
• 通讯作者: Faubel S