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Evaluation of a peptide that inhibits the activation of NOX2 and the generation of reactive oxygen species in protection against acute lung injury

抑制 NOX2 激活和活性氧生成的肽在预防急性肺损伤中的评估

基本信息

批准号：
9908865
负责人：
SHELDON I FEINSTEIN
金额：
$ 29.99万
依托单位：
PEROXITECH, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908865
关键词：
Acids Acute Acute Lung Injury Adult Respiratory Distress Syndrome Affect Amino Acids Animal Model Antibiotics Bacterial Infections Bacterial Pneumonia Berlin Binding Blood gas Cause of Death Cecum Cells Complex Complication DNA Development Disease Dose Effectiveness Encapsulated Enzyme Activation Enzymes Etiology Evaluation Family Future Generations Genetic Goals Greater sac of peritoneum Harvest Hemorrhage Human Hybrids Infection Inflammation Inflammatory Investigation Klebsiella Klebsiella Infections Klebsiella pneumoniae Knock-in Lipids Liposomes Lung Lung Inflammation Lung infections Mediating Modeling Mus NADPH Oxidase Names Organ Oxidants Oxidative Stress Pathogenesis Pathway interactions Patients Peptides Peritoneal Sepsis Permeability Pharmaceutical Preparations Phase Phospholipase A2 Play Pneumonia Prevention Production Proteins Publishing Pulmonary Surfactant-Associated Protein A Puncture procedure Rattus Reactive Inhibition Reactive Oxygen Species Role Route Sepsis Signal Transduction Small Business Technology Transfer Research Source Structure of parenchyma of lung Substrate Specificity Syndrome Testing Therapeutic Time Tissues Toxic effect Toxicology Trauma Viral Pneumonia bactericide cecal ligation puncture clinical application clinically relevant cytokine efficacy testing inhibitor/antagonist intraperitoneal lung injury macromolecule mortality mouse model neutrophil optimal treatments oxidant stress oxidation oxidative damage peroxiredoxin phospholipase A2 inhibitor prevent septic

项目摘要

SUMMARY: Acute lung injury (ALI) is a devastating complication of sepsis,viral and bacterial pneumonias, severe trauma with or without major blood loss, acid aspiration and other conditions that affect the lung either primarily or secondarily.This relatively common syndrome (~200,000 cases per yr in the US) currently has an overall mortality rate of ~40%. Lung inflammation associated with the production of reactive oxygen species (ROS) is an important contributor to the ALI syndrome. We have shown that activation of NADPH oxidase, type 2 (NOX2), the major source of ROS in lungs, requires the PLA2 activity of peroxiredoxin 6 (Prdx6) and have recently identified a 9 amino acid peptide that binds to Prdx6 and inhibits its PLA2 activity; we have named this Prdx6 inhibitory peptide (PIP-2). PIP-2 encapsulated in liposomes and administered intratracheally (IT) to mice inhibited the lung generation of ROS by >80% for 24 h. PIP-2 administered 12-16 h after low dose LPS (given IT) markedly decreased lung inflammation and tissue oxidative injury when examined at 24 h and greatly decreased mortality (from 100% to 28%) after high dose LPS. PIP-2 also markedly decreased mouse mortality after intraperitoneal LPS as a model of sepsis. We now propose to evaluate the effect of PIP-2 on lung injury in 2 mouse models of ALI associated with infection. The first will be the Klebsiella pneumoniae infection model (Sp.Aim 1); the 2nd model will be the cecal ligation and puncture (Sp. Aim 2). PIP-2 will be administered at either 12 or 24 hrs after the bacterial insult. We will evauate the effect of PIP on lung inflammation, disruption of the blood-gas barrier,and oxidative injury. We also will determine the effect of PIP on lung bacterial load as the NOX2 inhibitor may interfere with PMN bactericidal mechanisms. We propose that PIP-2 will have clinical application for the prevention of lung inflammation and tissue oxidative injury that are major contributors to the pathogenesis of ALI. We plan a phase 2 STTR application to evaluate the effect of PIP treatment on more complex models of acute lung injury in large animal models and to determine possible toxicological effects of peptide administration.

总结：急性肺损伤（ALI）是一种毁灭性的并发症脓毒症，病毒和细菌肺炎、严重创伤伴或不伴大量失血、酸吸入和其他主要或次要影响肺部的疾病。这相对常见综合症（美国每年约200，000例）目前的总体死亡率为 ~ 40%。与活性氧产生相关的肺部炎症 (ROS)是导致急性肺损伤综合征的重要因素我们已经证明， NADPH氧化酶，2型（NOX 2），肺中ROS的主要来源，需要PLA 2 过氧化物氧还蛋白6（Prdx 6）的活性，并且最近鉴定了一种9个氨基酸的肽结合Prdx 6并抑制其PLA 2活性;我们将其命名为Prdx 6抑制剂肽（PIP-2）。PIP-2包封在脂质体中并经鞘内（IT）给药对小鼠肺内ROS生成的抑制作用>80%，持续24 h。PIP-2给药12-16 低剂量LPS（给予IT）后3 h，在24小时检查时，氧化损伤大大降低了死亡率（从100%到100%）。 28%。PIP-2也显著降低了小鼠死亡率，腹腔内LPS作为脓毒症模型。我们现在建议评估 PIP-2对2种感染相关性ALI小鼠模型肺损伤的影响第一个将是肺炎克雷伯菌感染模型（Sp.Aim 1）;第二个模型为盲肠结扎和穿刺（Sp. Aim 2）。PIP-2将在施用后12或24小时施用。细菌的侮辱。我们将评估PIP对肺部炎症的影响，血气屏障和氧化损伤。我们还将确定PIP对肺细菌负荷作为NOX 2抑制剂可能干扰PMN杀菌机制等我们认为PIP-2将在临床上应用于预防肺部炎症和组织氧化损伤是导致 ALI的发病机制。我们计划进行第二阶段的STTR应用，以评估PIP的效果在大型动物模型中更复杂的急性肺损伤模型的治疗，确定肽施用的可能的毒理学作用。