Resuscitation of smoke inhalation and burn injury with a thioredoxin mimetic

用硫氧还蛋白模拟物复苏烟雾吸入和烧伤

• 批准号: 8338756
• 负责人: ANDREW Lurie SALZMAN
• 金额: $ 29.15万
• 依托单位: RADIKAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8338756
• 关键词: 3-nitrotyrosine; ATP Synthesis Pathway; Acetylcysteine; Acute; Acute Lung Injury; Address; Aftercare; Amides; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Ascorbic Acid; Attenuated; Biological; Biological Models; Blood Vessels; Blood-Air Barrier; Breathing; Burn injury; Cardiac; Cells; Cleaved cell; Clinical; Clinical Research; Continuous Intravenous Infusion; Cultured Cells; Cysteine; Cytoplasmic Protein; DNA Repair Enzymes; DNA Single Strand Break; Development; Diffusion; Dose; Double-Blind Method; Drainage procedure; Drug Delivery Systems; Equilibrium; Exhibits; Free Radicals; Functional disorder; Gases; Generations; Genomics; Glucose; Glutathione; Glutathione Disulfide; Gold; Head; Heparin; Histologic; Hydrogen Peroxide; Hypersensitivity; Hypoxia; In Vitro; Infiltration; Inflammation; Inflammatory; Inhalation Burns; Injury; Inorganic Sulfates; Lipid Peroxidation; Lung; Lung Inflammation; Lymphatic; Measurement; Mediating; Medical; Modeling; Mus; Necrosis; Nitric Oxide; Nitrogen; Nuclear; Nuclear Translocation; Organ failure; Orphan Drugs; Oryctolagus cuniculus; Ovalbumin; Oxidants; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Pathway interactions; Patients; Peripheral; Peripheral Resistance; Peroxonitrite; Pharmaceutical Preparations; Placebo Control; Pneumonia; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerases; Production; Proline; Prospective Studies; Proteins; Pulmonary Vascular Resistance; Randomized; Reaction; Relative (related person); Resistance; Respiratory Failure; Respiratory Insufficiency; Resuscitation; Sheep; Shunt Device; Signal Transduction; Smoke; Smoke Inhalation Injury; Stress; Study models; Sulfhydryl Compounds; Superoxides; Testing; Therapeutic; Thioredoxin; Tissues; Trauma; Unspecified or Sulfate Ion Sulfates; Up-Regulation; Water; airway obstruction; base; chlorine gas; clinical efficacy; clinically relevant; cytokine; drug market; exhaustion; functional loss; hemodynamics; improved; in vivo; indexing; injured; innovation; inorganic phosphate; lung injury; mimetics; mortality; neutrophil; novel; oxidant stress; oxidation; preclinical study; pressure; prospective; respiratory; small molecule; smoke inhalation; thioredoxin reductase; wet lung

DESCRIPTION (provided by applicant): Smoke inhalation and burn injury (SIBI) induces acute lung injury (ALI) via the generation of toxic free radical and oxidant species that, in turn, trigger DNA single strand breaks (SSB) throughout the pulmonary parenchyma. When this genomic injury is then recognized by the nuclear DNA repair enzyme poly(ADP-ribose) polymerase ("PARP"), NAD is cleaved to generate the product poly(ADP-ribose). Hyperactivation of PARP depletes NAD stores, resulting in the loss of oxidative phosphorylation and interference with ATP synthesis. In severe instances, the ultimate exhaustion of high energy phosphates (ATP) triggers cellular necrosis and the functional loss of the alveolocapillary membrane. To address this unmet clinical need and potential orphan drug market, we are developing a cell-permeable thioredoxin mimetic (R-901), a thiol-rich tripeptide that is closely analogous to the native thioredoxin (TRX) motif. R-901 exhibits in vitro potency 450- and 50-fold > than N-acetylcysteine (NAC) and ascorbic acid, respectively, and in vivo potency substantialy greater than NAC. Therapeutic administration of R-901 has been shown in a murine model of pulmonary inflammation (induced by ovalbumin sensitization and re-challenge) to reduce histologic injury, diminish neutrophil (PMN) infiltration, attenuate tissue oxidation, block pro-inflammatory cytokine expression and nuclear translocation of NF-?B, diminish the degradation of the anti-inflammatory cytoplasmic protein I?B¿, and restore the balance of reduced and oxidized forms of glutathione. In a murine LD100 model of severe redox stress induced by acute chlorine gas inhalation, post-insult administration of R-901 reduced pulmonary PMN infiltration by 50%. The Specific Aim of this proposal is to compare the potency of R-901 and NAC in an ovine model of combined SIBI-ALI. We will carry out a prospective, placebo-controlled, randomized, double-blinded, study in which respiratory insufficiency is induced in mechanically-ventilated Merino sheep by acute SIBI. Resuscitation with R-901, NAC, or vehicle control will be initiated 1 h after thermal insult and continued for 48 h, a timepoint characterized by massive respiratory failure. We expect that R-901 will demonstrate statistically significant superiority relative to NAC as noted for the following indices: 1) Reduced lung inflammation and injury, as manifested in lung wet/dry ratio, lymphatic drainage, lipid peroxidation, airway obstruction, histologic scoring, PMN infiltration, ONOO- (3-nitrotyrosine, "3-NT") formation, and poly(ADP-ribose) ("PAR") formation; 2) Improved hemodynamics and airway pressures, as revealed by reductions in pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (MPAP), and peak inspiratory pressure (PIP), without impacting systemic vascular resistance (SVR), mean peripheral arterial pressure (MAP), and cardiac index (CI); and 3) Reduced pulmonary shunt, as indicated by diminished arterioalveolar (Aa) gradient and an increased ratio of arterial O2 tension to inspired O2 concentration (PaO2/FiO2). These benefits, taken together, will justify continued development of R-901 for treatment of acute SIBI. PUBLIC HEALTH RELEVANCE: Smoke inhalation with associated burn injury is a leading cause of respiratory failure. At present, there is no approved therapy for this condition and mortality remains high. We are developing a novel drug that targets the basic mechanisms of lung injury in this condition and will test this agent in a clinically-relevant large animal model f trauma.

描述（由申请人提供）：烟雾吸入和烧伤（西比）通过产生毒性自由基和氧化剂物质诱导急性肺损伤（ALI），反过来， 在整个肺实质中引发DNA单链断裂（SSB）。当这种基因组损伤然后被核DNA修复酶聚（ADP-核糖）聚合酶（“PARP”）识别时，NAD被切割以产生产物聚（ADP-核糖）。PARP的过度活化消耗NAD储存，导致氧化磷酸化的损失和ATP合成的干扰。在严重的情况下，高能磷酸盐（ATP）的最终耗尽引发细胞坏死和肺泡毛细血管膜的功能丧失。为了解决这一未满足的临床需求和潜在的孤儿药市场，我们正在开发一种细胞可渗透的硫氧还蛋白模拟物（R-901），这是一种富含巯基的三肽，与天然硫氧还蛋白（TRX）基序非常相似。R-901的体外效力分别是N-乙酰半胱氨酸（NAC）和抗坏血酸的450倍和50倍，体内效力基本上大于NAC。在小鼠肺部炎症模型（由卵清蛋白致敏和再激发诱导）中，R-901的治疗性给药已显示出减少组织学损伤、减少中性粒细胞（PMN）浸润、减弱组织氧化、阻断促炎细胞因子表达和NF-？B、减少抗炎细胞质蛋白I的降解？B，并恢复还原型和氧化型谷胱甘肽的平衡。在急性氯气吸入诱导的严重氧化还原应激的小鼠LD 100模型中，损伤后给予R-901使肺PMN浸润减少50%。本提案的具体目的是比较R-901和NAC在合并SIBI-ALI的绵羊模型中的效力。我们将进行一项前瞻性、安慰剂对照、随机、双盲研究，在该研究中，急性西比诱导机械通气美利奴羊呼吸功能不全。在热损伤后1 h开始使用R-901、NAC或溶剂对照进行复苏，并持续48 h，该时间点的特征为严重呼吸衰竭。我们预期R-901将显示出相对于NAC的统计学显著优效性，如以下指标所示：1）减少肺部炎症和损伤，如肺湿/干比、淋巴引流、脂质过氧化、气道阻塞、组织学评分、PMN浸润、ONOO-（3-硝基酪氨酸，“3-NT”）形成和多聚（ADP-核糖）（“PAR”）形成; 2）改善血液动力学和气道压力，如肺血管阻力（PVR）、平均肺动脉压（MPAP）的降低所揭示的，和峰值吸气压（PIP），而不影响全身血管阻力（SVR）、平均外周动脉压（MAP）和心脏指数（CI）;和3）肺分流减少，如动脉肺泡（Aa）梯度减小和动脉O2张力与吸入O2浓度（PaO 2/FiO 2）比值增加所示。这些益处综合起来，将证明继续开发R-901治疗急性西比是合理的。 公共卫生相关性：烟雾吸入伴烧伤是呼吸衰竭的主要原因。目前，没有批准的治疗这种疾病和死亡率仍然很高。我们正在开发一种针对这种情况下肺损伤基本机制的新药，并将在临床相关的大型创伤动物模型中测试这种药物。