Acute Renal Failure Mediated Lung Injury

急性肾衰竭介导的肺损伤

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：急性肾脏损伤（AKI）是住院患者的常见并发症，可增加死亡风险。 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，将患者死亡率提高到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。 AKI关于炎症性细胞因子IL-6和肺损伤的系统并发症是该赠款提案的重点。我们建议AKI引起炎症和肺损伤。所有研究将在小鼠中完成。我们有三个特定的目的：1）确定AKI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AKI介导的肺损伤中的作用； 3）确定AKI是否由于机械通气而加剧了肺损伤。在AKI之后，将在整个器官和血清中评估细胞因子的产生；将通过AKI的小鼠注射重组形式的细胞因子来评估肾细胞因子清除率，并将对清除的药代动力学分析进行评估。 IL-6对肺损伤和KC（中性粒细胞浸润的介体）的影响将测试IL-6缺陷和IL-6抑制剂治疗的小鼠，具有缺血性AKI或双侧肾切除术。肺KC将通过mRNA和整个组织匀浆的蛋白质评估确定。 KC的内皮定位将通过免疫荧光确定。通过在培养的内皮细胞中添加重组IL-6或尿毒症血清并评估KC的产生，细胞活力和跨内层耐药性（毛细管渗透的标志和毛细血管渗透和泄漏），将在体外评估IL-6和尿毒症因素的有害作用。。为了确定可以通过透析去除刺激AKI中IL-6产生的尿毒症因子，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AKI的情况下，将评估在有或没有机械通气的小鼠中评估肺损伤和肺泡巨噬细胞KC的产生。通过细胞内细胞因子染色和新鲜分离的肺泡巨噬细胞和免疫荧光的细胞内细胞因子染色和流式细胞仪，将评估KC的肺泡巨噬细胞产生。将进行体外研究，以评估IL-6和尿毒血清对肺泡巨噬细胞KC产生和细胞活力的影响。 IL-6在具有机械通气的AKI引起的肺损伤中的作用将使用IL-6缺陷小鼠进行评估； IL-6抑制作用的治疗益处将通过腹膜内或气管内抗IL-6抗体进行评估。该赠款中的实验将为干预措施的发展提供有用的潜在客户，以影响AKI的系统性后果并改善AKI患者的死亡率。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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